Brain Research Reviews, 11 ( 1986) 157- 198 157

Elsevier

BRR 90048

Enduring Changes in Brain and Behavior Produced by Chronic

Amphetamine Administration: A Review and Evaluation of
Anima1 Models of Amphetamine Psychosis

TERRY E. ROBINSON and JILL B. BECKER

Deparrmenr of Psychology and Neuroscience Laboratory Building. The University of Michigan. Ann Arbor, MI 48104.1687 (U.S.A.)

(Accepted December 3lst, 1985)

Key words: amphetamine - sensitization - reverse tolerante - dopamine - catecholamine - schizophrenia -

amphetamine psychosis - anima1 mode1 - striatum - stress - sex differente - conditioning -
neurotoxicity - stereotypy - autoreceptor

CONTENTS

1. Introduction ............................................................................................................................................. 158

2. The effects of continuous amphetamine administration on brain and behavior (amphetamine neurotoxicity) ..................... 159

3 The behavioral
_ consequences of repeated intermittent amphetamine administration (behavioral sensitization) ................. 160
3.1. The major characteristics of behavioral sensitization .................................................................................... 161
3.1.1. Behavior .................................................................................................................................. 161
3.1.2. Injection paradigm ..................................................................................................................... 163
3.1.3. Sex differences ........................................................................................................................... 163
3.1.4. Summary .................................................................................................................................. 164

4. Behavioral sensitization and amphetamine neurotoxicity as anima1 models of amphetamine psychosis ............................. 164

5. The biologica1 basis of behavioral sensitization .................................................................................................. 167

5.1. Drugdispositionaliperipheral hypotheses .................................................................................................. 167
5.2. Drug-environment conditioning hypotheses ............................................................................................... 167
5.3. Neural hypotheses ............................................................................................................................... 169
5.3.1. The nigrostriatal dopamine system .................................................................................................. 169
5.3.1.1. Evidente for postsynaptic changes ....................................................................................... 169
5.3.1.2. Evidente for presynaptic changes ........................................................................................ 172
5.3.1.3. Dopamine autoreceptor subsensitivity ................................................................................. 176
5.3. I .4. Other hypotheses ............................................................................................................ 179
5.3.2. The mesolimbic and mesocortical dopamine systems ........................................................................... 179
5.3.3. Other neurotransmitter systems ..................................................................................................... 182
5.3.3.1. Opiate peptide-dopamine interactions ................................................................................ 182
5.3.3.2. Norepinephrine .............................................................................................................. 1x2
5.3.3.3. Serotonin ...................................................................................................................... 183
5.3.3.4. Aminoacids .................................................................................................................. 1X3
5.4. The neural basis of behavioral sensitization: conclusions and a hypothesis .......................................................... 184

6. Generalizability of sensitization ._.._....<........<.<<.........<<<<_._......<<..__....<........<<._...

185
6.1. Stimulants and stress . . . . . . . ..__..............._.................. .<<..___.................<<<.........<<<<...._....<<<<_.........._.......,..... 18.5
6.2. Sex differences. stimulants and stress ___. .. .......<.<........<.<<..__....<<<<_..._..<<<_..............
186

7. Conclusions __.._....<<.<..................<<<<..<......<<......<<.........<<<<.._................................
187

Correspondence: T.E. Robinson, The University of Michigan, Neuroscience Laboratory Building, 1103 E. Huron St.. Ann Arbor,
MI 48104-1687, U.S.A.

0165-0173/861$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedica1 Division)

X. Summary ., .<.......... .<... IXH
Acknowlcdgements Ihh
References _. ._. 1K’i

1. INTRODUCTION nence*“.““’ (cf. ref. 99). There are also anecdotal re-
ports that ‘physical or psychological stress’ can pre-
The use of stimulant drugs to decrease fatigue and cipitate a psychotic episode in X-29% of former
to heighten physical and menta1 abilities began when AMPH addicts’“‘.“‘3. This suggests that chronic
people first identified plants with these properties. AMPH use produces a vcry long-lasting change in
For example, in ancient China herbal teas were some neural system(s) involved in the psychotomi-
brewed with plants containing ephedrine. and coca metic effects of AMPH.
leaves, the source of cocaine, were chewed in South These clinica1 observations generated considera-
America by the ancestors of the Incas (see ref. 12 for ble interest in the effects of chronic AMPH adminis-
an excellent historical review of centra1 nervous sys- tration on brain and behavior in non-human animals.
tem stimulants). Today, stimulant drugs such as the and in the development of anima1 models of AMPH-
amphetamines remain among the most widely used induced psychosis. There art now many studies
and abused of the many psychoactive compounds showing that chronic AMPH administration has en-
available. Although at one time amphetamine during consequences for behavior and brain function
(AMPH) was prescribed in great numbers, for exam- in non-human animals, and one purpose of this paper
ple as an anorexic in the treatment of obesity. its is to review this literature. However. even a cursory
medica1 use has been greatly curtailed in recent examination of the literature reveals that at least two
years. AMPH is now usually prescribed only for the different paradigms have been used to study the ef-
treatment of narcolepsy and childhood hyperkinesis. fects of chronic AMPH administration. With onc
Nevertheless, illicit AMPH is stili widely available paradigm, elevated brain concentrations of AMPH
and extensively used for its ability to decrease fa- are maintained fora few days. either by the continu-
tigue, elevate mood and produce euphoria” (AMPH ous administration of AMPH or by multiple repeated
will be used to refer collectively to D-. L-. DL- and injections of high doses. The other paradigm involve\
meth-amphetamine). the repeated inrermittent administration of AMPH,
However, it is not fully appreciated that AMPH is usually by discrete daily injections of relatively low
also a potent psychotomimetic. In some schizophren- doses. Since it will become obvious that these two
ics it can rapidly intensify psychotic symptoms. and if paradigms produce different effects on brain and bc-
a patient is in remission AMPH may precipitate a havior, studies relevant to each will be reviewed sep-
psychotic episode XSJ’~ In fact , an AMPH-induced arately.
exacerbation of symptoms in medicated schizophren- Continuous AMPH administration produces a syn-
ics is predictive of relapse following neuroleptic with- drome that will be called ‘AMPH neuroroxiciy’. The
drawa13”‘. Perhaps the most dramatic effect of literature on AMPH neurotoxicity has been rc-
AMPH has been described in people who chronically viewed recently (e.g. ref. 81). and therefore will be
use the drug. It has been well documented that non- only briefly summarized to provide a comparison
psychotic individuals who repeatedly use AMPH with the effects of repeated intermittent AMPH ad-
sometimes develop a psychosis that is very similar to ministration. The major portion of this paper will fo-
paranoid schizophrenia4”.‘“’ (for reviews of AMPH cus on a phenomenon that will be called ‘hehavioral
psychosis see refs. 124. 213. 264. 268. 275). This sensitization' , which is produced by repeated inter-
AMPH-induced psychosis usually dissipates upon mittent AMPH administration. In particular. an in-
withdrawal from the drug, but former AMPH addicts depth and critica1 analysis of hypotheses concerning
are reported to remain hypersensitive to the psycho- the biologica1 basis of behavioral sensitization is pre-
tomimetic effects of AMPH even after years of absti- sented. In addition. AMPH neurotoxicity and behav-
 159

ioral sensitization are evaluated as anima1 models of es about as though stimulated on various parts of the
AMPH psychosis. skin’*’ (p. 756). This behavior is similar to that re-
The review is confined almost exclusively to stud- ported to sometimes accompany tattile hallucina-
ies with AMPH, because much more is known about tions in AMPH addicts (e.g. ref. 253).
AMPH than about other psychomotor stimulants. There are now many studies showing that continu-
The enduring effects of cocaine have been reviewed ous AMPH treatment is neurotoxic, and that the ap-
recently by R.M. Post21”.‘16. pearance of hallucinatory-like behavior in non-hu-
man animals is accompanied by brain damage. It was
2. THE EFFECTS OF CONTINUOUS AMPHETAMINE originally thought that hallucinatory-like behavior
ADMINISTRATION ON BRAIN AND BEHAVIOR (AM- was related to the inactivation of serotonin systems.
PHETAMINE NEUROTOXICITY) but more recent evidente suggests it may be due to
alterations in dopaminergic function85.‘97. The con-
AMPH addicts often ingest increasing quantities tinuous infusion of relatively low doses of D-AMPH
of AMPH in ‘runs’ that can last 3-6 days, during via pellet implants has a fairly selettive effect on the
which time their behavior becomes increasingly dis- nigrostriatal DA system, resulting in a depletion of
organized 16’. Since blood levels of AMPH may re- striata1 DA and its metabolites, a decrease in striata1
main elevated during these ‘runs’, some investigators tyrosine hydroxylase (TH) activity and a decline in
have continuously administered AMPH to non-hu- the number of striata1 DA receptors82~83~8s~20(‘~~29(for
man animals in an attempt to mimic this pattern of review see ref. 81). These effects are presumably due
drug use. In this context the phrase ‘continuous to degeneration of striata1 DA terminals77~82~203~230.
AMPH administration’ refers to the maintenance of Similar damage to nigrostriatal DA neurons has been
elevated blood levels of AMPH for a prolonged peri- reported following a single injection of D-AMPH or
od of time (usually 3-6 days). This can be achieved in meth-AMPH in rats pretreated with iprindole, a drug
one of 3 ways. The first is to implant a silastic pellet”’ which inhibits the metabolism of AMPH94~“07~2X4.2R.
or osmotic pump that slowly and continuously re- or following repeated injections of extremely high
leases AMPH’9R.22y~‘X5.The second is by frequent re- doses of D_AMPH*~“~**‘~~~~,
peated systemic injections of high doses (e.g. refs. There are a number of factors that determine how
270, 308. 309), and the third by concomitant treat- regionally and neurochemically specific the neuro-
ment with drugs, such as iprindole, that inhibit the toxic effects of continuous AMPH treatment are, in-
metabolism of AMPH”4,2X4. As will be described, al1 3 cluding: (1) the dose of AMPH, (2) the duration of
methods can produce comparable effects on brain AMPH treatment, (3) the species. (4) the age of the
monoamine systems and behavior. organism, (5) the type of AMPH used (D-, L-, DL-, or
The behavioral changes associated with continu- meth-AMPH) and (6) prior drug history. For exam-
ous AMPH administration have been reviewed re- ple, Steranka’*” studied the effects of infusing D-
cently by Ellison and Eison” (see also refs. 80, 83, AMPH for various periods of time on striata1 DA. He
199, 200, 231). Briefly, in rats there is an initial short gave rats a priming injection of 15 mgikg of AMPH
period of hyperactivity and then almost continuous (i.p.), and then continuously infused 1.36 mgih via an
intense stereotypy, followed by a period of inactivity. osmotic minipump. Six hours of infusion did not de-
After 4-5 days, what has been described ‘hallucina- plete striata1 DA, 8 h produced a moderate depletion
tory-like’ behavior appears. The details of this hallu- and 16 h produced a marked depletion (approx.
cinatory-like behavior depend on the species, but it is SO%). This depletion of striata1 DA may be perma-
similar to that seen after the administration of hallu- nent because it had not recovered 6 months later. In a
cinogenic drugs, such as LSD’**,‘*“. In the rat it is similar study, Ricaurte et al.22y found that the contin-
characterized by ‘wet dog’ shakes, limb flicks and ex- uous infusion of meth-AMPH via an osmotic pump
cessive grooming and biting of the skin. This groom- (with no ‘priming’ injection) at a rate of 4 mgiday for
ing and biting behavior is also pronounced in mon- 3 days produced toxic effects in the striatum. Howev-
keys and may ‘develop into episodes of parasitotic- er, lower doses, for example, 1 mgiday for 12 days, 2
like picking at the fur, during which the anima1 danc- mgiday for 6 days or 4 mglday for 1.5 day. were not
160

sufficient to deplete striata1 DA. Since the average tection against the neurotoxic effects of high doses
rat in these studies weighed approximately 250 g it given later. an effect that may be partly due to
can be concluded that in the rat AMPH is neurotoxic changes in the disposition of meth-AMPH2’“.
only if approximately 48 mg/kg is continuously ad- The mechanism by which continuous AMPH pro-
ministered over 3 days (16 mg/kg/day2’“), or if 102 duces its toxic effects is not weli understood. One
mg/kg is given over 16 h’s”. Schuster and Johanson”’ possibility is that 6-hydroxydopamine is formed from
report that if D-AMPH is given to rats by discrete the massive quantities of DA released following high
multiple injections a minimum of 12.5 mg/kg (s.c.) doses of meth-AMPH25h,27’. This idea is consistent
twice a day for 4 days is required to deplete striatal with the observation that the integrity of the DA up-
DA. take carrier is required for meth-AMPH to have its
Whether D-AMPH is toxic to other monoaminer- toxic effects on striatal DA neurot#.
gic systems depends partly on how extreme the drug Although it has been argued bere that the different
treatment regimen is. Ridley et al.“’ reported that treatment paradigms which continuously elevatr
vervet monkcys given D-AMPH in increasing doses brain levels of AMPH produce comparable effects on
(from 4 to 12 mg/kg/day for 35 days) were depleted of brain and behavior, it should bc remembered that
norepinephrine (NE), serotonin and DA in the cau- they are not identical. For examplt. the neural
date and cortex. In addition. striata1 tyrosine hydrox- changes produced by the continuous infusion of low
ylase activity was reduced and the turnover of ah the doses from a pellet implant are not exactly the same
monoamines decreased. Interestingly, striatal cho- as those produced by multiple repeated injections of
line acetyltransferase and glutamine decarboxylase extremely high doses, and even the continuous infu-
activity were normal”‘. Cats seem to be especialiy sion with pellets vs pumps may produce slightly dif-
sensitive to the neurotoxic effects of AMPHz9’. For ferent effects”. Therefore, there actually may be
example. Levine et al. “’ found that caudate DA was more than one ‘AMPH neurotoxicity syndromr’.
depleted in cats for up to a year after only 3 injections Nevertheless, there is no doubt that the prolonged
of 1, 2 and 4 mg/kg of D-AMPH. with each injection and sustained exposure to AMPH produces progres-
separated by 10 days. This is probably due at least in sive changes in behavior that are associated with
part to the much longer half-life of AMPH in cats brain damagc.
(6.5-8.5 h) than in rats (45-60 min; see ref. 268. The repeated intermittent administration ot
p. 147 for references). AMPH also produces progressive changes in brain
Most studies on the neurotoxic effects of AMPH and behavior. but these are quite distinct from those
have utilized its methylated form. Methampheta- produced by continuous AMPH treatment, and are
mine (meth-AMPH) appears to be more toxic than discussed ncxt.
D-AMPH, and more non-selettive. There are man-
reports of damage not only to striatal DA neurons 3. ‘THE BEHAVIORAL CONSEOUENCES OF REPEAT-
following sustained treatment with meth- ED INTERMI’ITENT AMPHETAMINE ADMINISTRA-
AMPH :7~IIl.IXI.~?K.2?0.30~‘.
but also tu, serotonin and I‘ION (BEHAVIORAL SENSITIZATION)
NE systems. especially in cats ..zi 1 1 3 . 1 v 4 .‘0 7 .?? x . z . ~ ~ . 1 9 7 . ~ ~ ~

Nevertheless, there is stili some selectivity. In adult Many of the initial studies on the effects of repeat-
animals the striatum. olfactory tubercle and cortex ed AMPH administration were primarily concerned
appear to be more sensitive to the toxic effects of with its potent effects on the autonomie nervous sys-
meth-AMPH than the nucleus accumbens, hypothal- tem. It was found that with repeated administration,
amus or median eminente; and cholinergic and gluta- rapid tolerante developed to AMPH’s autonomie ef-
minergic systems are not affected (e.g. refs. 23. 194. fects. including those on body temperature. blood
2 I 8,228). In immature gerbils frontocortical neurons pressure. heart rate and respiration. Tolerante to
may be especially sensitive”“. Prior drug history a l s o AMPH’s anorexic effects were also observed (e.g.
influences the toxicity of meth-AMPH. For example. for reviews see refs. SO, 164. 180). However, the first
Schmidt et al.2s7 found that pre-exposure to increas- studies on the motor stimulant effects of AMPH werc
ing doses of meth-AMPH provides considerable pro- equivoca1 conceming the development of tolerante
 161

(e.g. refs. 68,262,321; for review see ref. 164). of forward locomotion, head movements, sniffing
In the iste 1960s a re-examination of the effects of and rearing (i.e., the anima1 becomes generally hy-
repeated AMPH treatment was prompted by de- peractive) and a concomitant decrease in the inci-
scriptions of an evolving syndrome of progressively dente of other behaviors, such as grooming”‘“.‘sl (for
bizarre stereotyped behavior produced by repeated, reviews see refs. 51, 120). If a low dose of AMPH is
increasing doses of AMPH7”.75.76s7Y.It soon became administered, this general hyperactivity persists for
apparent that there was not merely a lack of toler- the duration of the drug’s action. With higher doses
ance to the motor stimuiant effects of AMPH, but the initial hyperactivity is soon followed by stereo-
that the repeated intermittent administration of the typed behavior. During the stereotypy phase, loco-
same dose of AMPH produced a progressive en- motion and rearing cease. the anima1 assumes a
hancement in many behaviors. In addition, it was crouched posture and engages in continuous or near-
found that this enhanced sensitivity to AMPH per- Iy continuous repetitive head movements. forehmb
sisted for very long periods of time following withdra- movements, sniffing, licking or biting. The intensity
wal from the drug. For example, Magos”’ reported and duration of focused stereotyped behavior in-
that in rats two injections of 6 mgikg of D-AMPH creases with increasing doses of AMPH.
giva 2-S weeks apart enhanced the behavioral ster- When a constant dose of AMPH is repeatedly and
eotypy produced by a third injection given 4 weeks intermittently administered many (but not ah) of the
later. This treatment did not change the LD,* for behaviors described above are progressively en-
AMPH. Similarly, Wallach and Crershon”’ reported hanced or otherwise altered. For example, in animals
that the daily administration of AMPH to rats, cats or that have been previously exposed to AMPH, subse-
dogs enhanced the stereotypy produced by a subse- quent AMPH treatment produces: (1) more intense
quent injection of a lower dose. stereotyped behavior; (2) a reduced time to the onset
It is now well established that repeated intermit- of stereotypy following injection of AMPH; and!or
tent injections of AMPH sensitize animals to its ster- (3) the development of stereotyped behavior follow-
eotypy-producing effects’52.153.267, Since the early ing administration of a lower dose of AMPH than
1970s there have been many studies on the behavior- would usually produce stereotypy (e.g. refs. 49. 112,
al consequences of repeated intermittent AMPH ad- 146, 152, 176, 177, 185,263,267.316). However, the
ministration (for reviews see refs. 17, 157. 158, 210, stereotyped behavior produced by AMPH actually
216, 264. 268), and these will be summarized here consists of a complex array of discrete behavioral ele-
only for the purpose of outlining the most salient fea- ments, and not al1 of these show the same pattern of
tures of the behavioral phenomenon. The term be- sensitization. For example, in rats, sniffing and re-
havioral sensitization will be used to refer to the pro- petitive head and limb movements show rapid sensiti-
gressive and enduring enhancement in many AMPH- zation, but oral behaviors (licking and biting) do
induced behaviors produced by the repeated inter- nothy,“‘. We recentlv confirmed these findings and
mittent administration of AMPH. Other terms that the results are shown in Fig. 1 to illustrate the typical
have been used to refer to the same phenomenon in- pattern of sensitization to the stereotypy-producing
clude reverse tolerante, behavioral augmentation effects of AMPH (see also ref. 191). The effects of
and behavioral facilitation. repeated AMPH treatment on ora1 behaviors may be
especially complex. Eichler et al.h’) reported that
3.1. The ma@ characteristics of behaviorai sensitì- daily AMPH injections resulted in the development
zation of tolerante to AMPH-induced stereotyped licking
behavior over the first 21 days of treatment. followed
3.1.1, Behavior by the sensitization of licking behavior over the next
The behavior produced by AI\IIPH depends on a 44 days of treatment.
number of factors, including the species and sex of The ~oco~otio~ and rearing produced by low doses
the subject, the dose administered and environ- of AMPI-I are similarly enhanced with repeated in-
menta1 surroundings. In rats, an acute injection of termittent AMPH administration, but this may also
AMPH initially produces an increase in the incidente result in the emergente of focused stereotypy, After
 NOT ALL BEHAVIORAL ELEMENTS OF intense stereotypy; but not by any change in the du-
STEREOTYPY SHOW SENSITIZATION
ration of stereotypy (see Sega1 et al.‘W for review).
On the other hand. Eichler et al.“’ reported that daily
321 A. AMPH treatment produced a progressive increase tn
28 the duration (and intensity) of strreotyped sniffing.
I.eith and Kuczenski “’ have shown that it is possible
lr’
to dissociate different componente of behavioral sen-
J
l-
SNIFFING STEREOTYPY
sitization
the decreased
within the same animal.
latency to the onset of stereotypy
They found that
and
the enhancement of Post-stereotypy locomotor activ-
ity secn with repeated AMPH developed at different
0 24 rates and persisted for different peri& of time. Fur-
aw
thcrmore. of 10 different strains of rats. all showctl
= 20
m the decreased latency to the onset of strreotypy with
16 repeated AMPH treatment. but only 5 showed an en-
ORAL MVTS. hancement in Post-stereotypy loccjmotion’7q. Some
12
of these differences between studics are probably re-
I 3 5 9
latcd to procedura1 differences. and especially to dif-
NUMBER OF AMPHETAMINE INJECTIONS
(3.0 mg/ kg) fcrences in how behavior is quantified. However. IIX
pointed out previously”“~“‘.‘“. many may bc rcal
Fig. 1. ‘The effects of rcpeated intermittcnt injections 01 an-
phetamine on stercotyped behavior. Adult remale rats (Holtz- and reflect a multiplicity of neural changes. Obvious-
man) received an i.p. injection of 3.0 mgikg of n-amphetaminc Iy. it will be nnportant to consider thcse aspects of he-
sulfate in their home cage once evcry 3-4 days for a total of 9
havioral sensitization in trying to relate behavioral
injections. Stereotyped behavior was rated at IOand 30 min fol-
lowing the injection. and then every 30 min for a total of 150 sensitization to enduring changes m specific ncural
min, following the first, 3rd. 5th and 9th injection. Overall ster- systems.
eotypy was rated using the scale drscribed by Dougherty and
Although in most studics ot bchavioral sensitiza-
Ellinwood”. and the individua1 components of stereotyped hc-
havior as described by Rebcc and Sega?“. Note the progre\- tion. stereotypy or locomotor acttvity were quanti-
sive increase in stereotyped sniffing. repetitive head and limb fied. it should be noted that the repeated administra-
movemcnts and overall stereotypy. In this experiment therc
tion of AMPH sensitizes many other behaviors as
was no significant change in orai movements (mvts.) over time
well. These include: (1) rofafional behuvior. in either
animals with unilateral damage to the nigrostriatal
the emergente of stereotypy the enhanced locomo- system or animals without lesions’“.~“.2J”?JJ: (2)
tion and rearing produced by repeated AMPH treat- drinking behuvior’7.‘J’,“‘J: (3) intracranial self-slimu-
lalion21’.23h:
ment are confined to the initial ‘pre-phase’ of hyper- (3) acoustic .startle behavior”“.““: (5 )
activity. before the appearance of stereotypy, and cap dimhing bchavior in mice”“: (6) rai1 pinch-
the later ‘after-phase’ of hyperactivity. when the ef- induceci behavior”; and (7) performance in a Y-
fects of AMPH are in decline??.II(‘.I;h,I?7.‘h7.~‘~, It rnU$‘. In addition. repeated AMPH administra-
should be noted that the pattern of locomotion pro- tion has been reported to progressively disrupt meas-
duced by AMPH is not norma1 in ali respects. but is urcs of ~.selectivr attention and ‘lu~r~r inhibition“h.“-
itself abnormally stereotyped’2’.‘5’~‘“. ‘The sensitizing effects of AMPH do not seem to bc
Although there is general agreement that stereo- species-specific. An enduring bchavioral sensitiza-
typed behavior and locomotion are augmented by re- tion to the repeated intermittcnt administration c)t
peated intermittent AMPH treatment, not al1 re- AMPH has been reported in evt!ry mammahan spe-
searchers have reported exactly the same profile of cies studied to date, including: rats. cats. guinea pigs.
changes. For example, Sega1 and his colleagues havc mice, non-human primates and humans (ratsJV.“‘.‘Ji
1 7 h .li’.I X S . 2 ? 4 . 2 4 1 ~ . 2 6 3 . 2 6 7 . c a t s K X.3 1 1: guin e a p i g s l“.l C .‘;
typically found that the sensitization of stereotyped
m i c e ? 2 , 6 :. 1 x 6 .‘i_.? ~ 4 ~ d o g s ”‘I: n o n-h u m a n p ri m a t e s ”’
behavior is characterized by a decrease in the latency
l/s ? 3 1 .:. 7 2 .j(lj: and h u r n a n s ”‘, ~ “ ~ ,‘ 4 ~ ,“‘~ ~
to the onset of stereotypy. and at some doses, more
 163

3.1.2. Injection paradigm havioral sensitization 15 or 30 days after withdrawal

The paradigm used to administer AMPH is an ex- from repeated AMPH treatment than after only 3
tremely important variable to consider in evaluating days of withdrawal.
studies on sensitization (cf. ref. 147). It will be docu- The importance of allowing time between treat-
mented below that many of the conflicting reports in ments, presumably for some change in the nervous
the literature, particularly regarding the neural con- system to develop, has been discussed previously by
sequences of repeated AMPH administration, can be Antelman and Chiodo’h and Post”“,“’ (although, for
traced to the enormous variety of treatment para- an incongruent report see ref. 87). These authors
digms that have been used. have suggested that the closer together in time injec-
One variable to be considered is the number of in- tions are given, the more likely tolerante will devel-
jections. In most studies of sensitization AMPH is ad- op, and the less likely sensitization will occur. Of
ministered (i.p. or s.c.) once or twice daily for 1-2 course, giving injections too close together in time,
weeks. However. there is tremendous variation especially when large doses are used, is functionally
around this ‘average’. For example, AMPH has been equivalent to continuous administration and will pro-
administered for up to 9 months, by injection, or in duce AMPH neurotoxicity. In order to evaluate re-
lOY.125~205.231; see Table 3 in ref,
the food or water (e.g. ports of sensitization, it is critica1 to exclude studies in
210). But it is not necessary to repeatedly administer which toxic AMPH injection regimens were used
AMPH for long periods of time to produce behav- (see below).
ioral sensitization. In fact, one injection is sufficient. Behavioral sensitization has been reported follow-
A single injection of AMPH has been reported to en- ing the repeated administration of both very low
hance the stereotypy’“.83.‘68, drinking behavior”, (<l .O mg/kg2”“) and very high (10 mg/kg”j) doses of
and rotational behaviorh7.‘““.244 produced by a subse- AMPH, and therefore this does not seem to be a cru-
quent injection of AMPH given weeks later. Never- cial variable”“. More robust changes may be pro-
theless, the repeated intermittent administration of duced by higher doses. but extreme doses are not
AMPH does produce a progressive enhancement in necessary and only increase the risk of producing
behavior. over-and-above that produced by a single neurotoxic effects.
injection (e.g. ref. 240).
A second, and probably even more important vari- 3.1.3. Se,r differences
able, is the interval between AMPH treatments’6.211. Although most researchers use male animals, fe-
TO produce robust behavioral sensitization AMPH males show much greater rates of sensitization than
must be given intermittently”4,‘97.2’1. There is even do males. Robinson et al.?“” first reported that gona-
evidente to suggest that injections given relatively dally intact female rats show a greater enhancement
far apart in time are more efficacious than those in rotational behavior following a single injection of
given more frequently MQ” For example, locomo- AMPH than do gonadally intact males. This obser-
tion in mice is progressively enhanced to a greater ex- vation was verified and expanded in a later study
tent if 10 injections of meth-AMPH are given 3-4 using rats with unilateral6-OHDA lesions of the sub-
days or 7 days apart than if they are administered stantianigra 24” Again, a greater enhancement in
daily’“‘. Similarly, male rats given 1.0 mgikg of D- AMPH-induced rotational behavior was found in fe-
AMPH once a week for 5 weeks show a greater el- male than in male rats after either a single injection
evation in rotational behavior than those given 5 in- or repeated intermittent injections of AMPH. The
jections once a day for 5 days2”“. In addition, Hitze- sex differente in sensitization to AMPH is not unique
mann et al.“’ reported that after 3 weeks of twice to rotational behavior. Unpublished studies in this
daily AMPH injections it was necessary to withdraw laboratory by D.M. Camp”” have revealed similar
the animals from the drug for more than one day to sex differences in the sensitization of stereotyped be-
observe behavioral sensitization (i.e., animals with- havior and locomotion (see also ref. 213).
drawn for one day did not show evidente of sensitiza- Sex differences in behavioral sensitization may be
tion, whereas those withdrawn for 7, 14 or 28 days due to the influente of endogenous gonadal hor-
did). Similarly, Kolta et al.161 reported greater be- mones on this form of neuroplasticity. Ovariecto-
164

mized (OVX) and gonadally intact female rats sensi- above for references). The repeated intermittent ad-
tize at a comparable rate. However, castrated male ministration of AMPH produces behavioral sensiti-
rats show increased rates of sensitization relative to zation, does not deplete DA, hut cnhances DA re-
gonadally intact males, and are comparable to fe- lease (see below). It is obvious that behavioral sensi-
males in this respect 43*240.244.
The lower rate of sensi- tization and AMPH neurotoxicity cannot both be
tization in gonadally intact males may therefore be ‘anima1 models’ of the same thing, i.e.. AMPH psy-
due to the suppression of sensitization by a testicular chosis. Unfortunately. there is no single piece of evi-
hormone. Of course, testicular hormones could influ- dente that clearly establishes one or the other syn-
ente sensitization indirectly, perhaps by their action drome as the more valid animai mode1 of AMPH psy-
on the pituitary. There is evidente that at least one chosis. However. it is argued below that the weight ot
pituitary hormone (vasopressin) can modulate the the evidente supports the idea that the phenomenon
sensitization to cocaine214. of behavioral sensitization provides a reasonably
good mode1 of AMPH psychosis. but that the AMPH
3.1.4. Summary neurotoxicity syndrome does not. Arguments against
In summary, the most salient features of behavior- the AMPH neurotoxicity syndromc as a mode1 ot
al sensitization include the following: (1) Behavioral AMPH psychosis are given first.
sensitization can be produced by a single injection of (1) The main reason neurotoxic AMPH treatment
a relatively low dose of AMPH. (2) Behavioral sensi- regimens have been used to mode1 AMPH psychosis
tization is greater after multiple intermittent injec- is because it has been suggested this more closely
tions (as opposed to continuous treatment) than after mimics the conditions that resuh in AMPH psycho-
a single injection. (3) Behavioral sensitization per- si?‘. This idea comes mainly from the observation
sists for months following withdrawal from AMPH. that many AMPH addicts. who present at hospital
(4) Behavioral sensitization is greater in females than emergency wards with psychotic symptoms. have
in males, and greater in castrated males than intact taken large quantities of AMPH. usually in ‘runs‘
males. lasting a few days 74.‘6s Although this is truc. it does
not follow that extremely large doscs of AMPH art
4. BEHAVIORAL SENSITIZATION AND AMPHETA- necrssary to produce AMPH psychosis. lt may be
MINE NEUROTOXICITY AS ANIMAL MODELS OF AM- misleading to rely on doses used by hard-core ‘speed
PHETAMINE PSYCHOSIS freaks’ to estimate the dose required to produce
AMPH psychosis. People using smaller quantities of
Much of the interest in the effects of chronic AMPH may also develop psychotic symptoms, but
AMPH treatment in non-human animals is because because they would be less likely to turn up in hospi-
AMPH is commonly abused by humans, and because tal emergency wards, their symptoms would proba-
chronic AMPH use can produce a psychosis similar to bly go undiagnosed. Angrist and Gcrshon” describe
paranoid schizophrenia4s. It is therefore important to such a case (see also ref. 1). In fact . there is consider-
discuss the fact that two completely different syn- able evidente in the clinica1 literature which suggests
dromes, behavioral sensitization and AMPH neuro- that large doses of AMPH are not necessary to pro-
toxicity, have been proposed as anima1 models of duce AMPH psychosis’“,‘“X.
AMPH psychosis (e.g. refs. 81, 264, 268). As de- A brief and selettive review ot studies In whrch
scribed above, behavioral sensitization and AMPH psychotic symptoms werc produced in non-schizo-
neurotoxicity are produced by different treatment phrenic subjects following the administration of rela-
regimens and have different effects on behavior. tively low known doses of AMPH follows (see also
They also have different long-term effects on the ner- ref. 264). Griffith et al.““’ administered 10 mg of I)-
vous system. (This latter point will be dealt with in AMPH i.v.. and then S- 10 mg orally each hour unti1
detail in the next section of this review.) For exam- psychotic symptoms appeared. Six subjects devel-
ple. continuous AMPH administration. which pro- oped an AMPH psychosis within l-4 days following
duces the AMPH neurotoxicity syndrome, destroys a total of 120-375 mg of AMPH. Two subjects devel-
striatal DA terminals and depletes striatal DA (see oped symptoms within one day. two within 2.5-2.75
 165

days and two within 4 days. For the sake of estimat- over 3-4 days to produce AMPH neurotoxicity in
ing the dose relative to body weight, let us assume the rats. In striking contrast, AMPH psychosis can be
subjects weighed around 65 kg, on average. Using produced by as little as 0.5-2.0 mg/kg/day, that is,
the 65 kg figure, it is estimated that the subjects in the with doses at least 12.5-50 times less than those that
Griffith et al.lw study showed psychotic symptoms are toxic in rats.
after a tota1 cumulative dose of 1.8-5.8 mg/kg. If cal- (2) A prediction that follows from the idea that the
culated on a mglkgiday basis, on the order of 3.1-6.2 AMPH neurotoxicity syndrome models the changes
mglkglday was required to produce psychotic symp- in brain and behavior associated with AMPH psycho-
toms. Be1132obtained similar results. Be1132infused sis, is that people who have experienced AMPH psy-
meth-AMPH in divided doses over 60-75 min. His chosis should show signs of degenerative changes in
subjects showed psychotic symptoms following a to- brain DA systems. Unfortunately, we know of no ev-
tal of 50-640 mg. The 640 mg dose was unusually idence available on dopaminergic function in such
high, as the subject requiring the next highest dose to people. It has been reported that AMPH psychosis is
produce psychosis showed symptoms after only 260 accompanied by increased cerebral blood flow, es-

mg. Again, assuming an average weight of 65 kg, pecially in the anterior frontal lobes33. However, it is
psychotic symptoms were produced after only not clear if this is consistent with damage in this re-
0.8-4.0 mg/kg over 1 h. Similarly, Sato et a1.248re- gion or not. TO resolve the issue, PET studies or stud-
cently reported that 30-90 mg over 1-6 days ies on DA metabolite levels in the CSF of former
(0.5-1.4 mgikg, assuming a 65 kg b. wt.) was suffi- AMPH addicts would be extremely valuable (cf. ref.
cient to produce AMPH psychosis. Sega12@s268has 218).
compiled a Table listing 13 different reports of (3) The idea that a paranoid psychosis is due to de-
AMPH psychosis following doses of less than 100 mg creased dopaminergic activity runs counter to nearly
of AMPH (see also ref. 99). It is clear from this Table al1 the available evidente on the neurobiology of
that there are many cases in which the daily adminis- schizophrenia. There is considerable evidente that
tration of only 0.3-1.2 mgikg of AMPH produced paranoid schizophrenia is not accompanied by DA
AMPH psychosis (assuming an average weight of 65 depletion, and most current theories stress the idea
kg). In addition, it is supposedly common for narco- that DA systems are hyperactive in schizophre-
niaS8,30h
leptics being treated with low doses of AMPH to de-
velop paranoid tendencies (S. Watson, personal (4) One salient characteristic of AMPH psychosis
communication and ref. 320). is that it typically appears only during the time an in-
Although there are clearly problems in making do- dividual is on the drug and dissipates following with-
se-response comparisons across species, and caution drawal from the drug. But the depletion of brain
is required in doing SO, the available evidente sug- monoamines produced by toxic doses of AMPH ap-
gests the dose required to produce AMPH neurotox- pears to be permanent, and certainly is present fol-
icity is many times higher than that required to pro- lowing withdrawal from AMPH (see above for refer-
duce AMPH psychosis. Studies by Ricaurte et a1.229 ences). If the depletion of brain monoamines were
and Steranka’*’ in rats suggest that it is necessary to causally related to AMPH psychosis it might be ex-
administer approximately 48 mgikg of AMPH con- pected that the psychosis would also persist following
tinuously over 3 days, or 102 mg/kg over 16 h to pro- withdrawal from the drug; but it does not. Of course,
duce neurotoxic effects. Schuster and Johanson258 re- it might be argued that presynaptic compensatory
port that, if given twice daily, 25 mgikgiday for 4 days processes mask the ‘depletion-induced psychosis’.
is required to produce neurotoxicity. Furthermore, if (5) Lastly, it is well documented that former
animals are initially exposed to low doses of AMPH AMPH addicts show an enduring hypersensitivity to
(as is usually the case with addicts), even much high- AMPH2”8.‘64.2h8. and the AMPH neurotoxicity syn-
er doses than this would be required to produce neu- drome does not account for this important feature of
rotoxicity, because of the protettive effect of pre-ex- AMPH psychosis. Animals given toxic doses of
posure to low doses *” Therefore, on the order of ut AMPH, then withdrawn from AMPH and later chal-
least 25-50 mgikg of AMPH must be administered lenged with an acute injection are not hypersensitive
to AMPH (e-g. ref. 197). That is. the AMPH neuro- ious objects, including own body: repetition of single
toxicity syndrome is not accompanied by an enduring words or phrases; stereotyped writing and/or draw-
hypersensitivity to AMPH. This is not surprising, be- ing. (2) Socia1 stereotypies: prolonged sexual inter-
cause the DA depletion produced by toxic doses of course without ejaculation. Collettive monologues
AMPH (around 3%70%) is not sufficient to produce (talking without listening). (3) Social withdrawal
postsynaptic DA receptor supersensitivity. This (‘autism’. socia1 isolation). (4) Paranoia. (5) Halluci-
usually requires a greater DA depletion, on the order nations and illusions; auditory, visual, tattile. olfac-
of 85-90s (e.g. refs. 54,190,288). tory. (6) Micro-hallucinations (Worms. insects. etc..
It is concluded. therefore. that the changes in brain comingout of the skin)““’ (p. 114). Segal264 has com-
and behavior produced by neurotoxic AMPH treat- mented extensively on the similarities in the increas-
ment regimens in non-human animals do not provide ingly perseverative and restricted behavior patterns
a good mode1 of AMPH psychosis (see also refs. 204. seen in both human and non-human animals repeat-
231,264). It is more likely that the neurotoxic effects edly exposed to AMPH. Although more speculative.
of AMPH are related to the toxicity produced by Solomon and his colleagues”“.“’ have also attempted
structurally similar compounds, such as p-chloroam- 10 relate progressive alterations in attentional proc-
phetamine or MPTP (1-methyl-4-phenyl-1,2,3.6-t+ esses produced by repeated AMPH treatment in rats.
trahydropyridine). and as such may represent a mod- to theoretically similar deficits in schizophrenics.
el of presymptomatic Parkinson’s disease (e-g. ref. (2) ‘A sustained course of changes’. The progres-
Y.3). sive development of increasingly stereotyped behav-
Next, how well behavioral sensitization modcls ior with repeated intermittent injections of AMPH
AMPH psychosis will be addressed. Schiorring’” has been thoroughly documented. and was described
(p. 115) has suggested that the basic requirements for in detail above. In a similar fashion, the probability
;I ‘model’ of schizophrenia or AMPH psychosis are: of producing the cognitive abnormalities associated
(1) ‘similarities in behavioral disorders‘; (2) ‘a sus- with AMPH psychosis in people is thought to in-
tained course of changes’. i.e.. progressive changes crease with repeated exposure to the drug”. Howev-
in brain and behavior: (3) ‘liability to exacerbation’. er. it should be noted that AMPH psychosis has been
i.e.. an enduring hypersensitivity to AMPH: and (4) reported following the firil exposure to
the ‘absence of gross morphological lesions in the AMPHw.?‘%?“i, just as an appropriate acute dose of
brain’. The phenomenon of behavioral sensitization AMPH can produce stereotypy in rats. Nevertheless.
produced by the repeated intermittent administra- with the repeated intermittent administration of
tion of AMPH meets all of these requirements. AMPH, and the development of sensitization.
f 1) ‘Similarities in behavioral disorders’. Obvious- AMPH becomes progressively more potent in pro-
Iy, it is impossible to determine if non-human animals ducing stereotyped behavior and psychosis.
experience cognitive abnormalities comparable to (3) ‘Liability to exacerbation’. .I‘he enduring na-
those described in people repeatedly exposed tu ture of the changes in brain and behavior produced
AMPH. However, it is possible to compare the ef- by repeated intermittent AMPH treatment is one of
fects of AMPH on motor behavior. and striking simi- the most intriguing aspects of sensitization. Both hu-
larities have been found’Yh.“9.~~“.2i’. Indeed. the de- man and non-human animals thnt have bcen pre-
scriptions of AMPH-induced stereotyped activities viously exposed to AMPH remain hypersensitive tcl
shown by human and non-human animals are somc- the drug for very long periods of time. Former
times eerie in their remarkable similarityZST. In hu- AMPH addicts have been reported to be hypersensi-
mans AMPH-induced changes in behavior include: tivt: to the psychotomimetic effects of AMPH even
*‘(I ) stereotyped. bizarre movements of arms. bands, after years of abstinence”“-‘“‘. ;rnd animals sensi-
legs; continuous chewing on the tongue or lips: lick- tized to AMPH remain hypersensitive to the motor
mg on the lips; nail-biting; plus other kinds of aimless stimulant effects of AMPH for at least months, and
activities such as walking up and down the streets perhaps much Ionger’8s.ZJ”.
without any goal; walking in circles: standing immo- (4) .Absence of gross morphological lesions’.
bile for severa1 hours; ‘pottering’, ‘punding’ with var- There is no doubt that robust behavioral sensitization
 167

can be produced by the repeated intermittent admin- mention in their paper that the changes in AMPH up-
istration of AMPH in doses that do not produce brain take they found could be due to the loss of body fat or
damage, as will be documented in the following sec- decreased metabolism of AMPH resulting from liver
tion. In fact, it will be argued below that if an AMPH damage associated with these extremely high doses
treatment paradigm damages DA neurons this con- of AMPH.
stitutes prima facie evidente for AMPH neurotoxici- Further examination of the literature reveals little
ty, not behavioral sensitization. support for any simple dispositionaliperipheral hy-
pothesis, as noted in a number of recent pa-
5. THE BIOLOGICAL BASIS OF BEHAVIORAL SENSI- pers 62.16y.2”‘.‘6’.For example, it has been reported
TIZATION that chronic AMPH treatment with lower doses does
not alter whole brain or regional brain (e.g. striatum,
It is clear that the repeated intermittent adminis- cortex, olfactory tubercle) levels of AMPH”‘,‘“,
tration of AMPH produces very long-lasting changes ‘27.3’2.There is certainly no evidente that the behav-
in behavior, and there has been a great deal of inter- ioral sensitization produced by a single injection, or
est in how this occurs. An understanding of how stim- intermittent injections of relatively small doses of
ulant drugs produce enduring behavioral changes AMPH is accompanied by changes in the uptake of
may provide insight into how they produce their psy- AMPH into the brain.
chotomimetic effects. and thus into the neurobiology It has also been suggested that the formation and
of psychosis. But regardless of whether behavioral retention of the major metabolites of AMPH, p-hy-
sensitization is analogous to AMPH psychosis, it is droxyamphetamine @OHA) and p-hydroxynore-
important to determine how such a short-term altera- phedrine @OHE), could contribute to either the tol-
tion in neural function can produce such long-lasting erance or sensitization produced by repeated AMPH
consequences. A number of hypotheses have been administration”“. However. there is very little experi-
entertained, and these can be divided into 3 catego- menta1 support for this idea (see ref. 62 for review).
ries: (1) drug dispositional or peripheral hypotheses; For example, some authors have reported that
(2) drug-environment conditioning hypotheses; and AMPH pretreatment does not alter the formation of
(3) neural hypotheses. Each of these hypotheses will pOHA or pOHE”“. More importantly. these metab-
be evaluated in turn, taking into consideration the olites are not formed after the administration of L-
characteristics of behavioral sensitization summa- AMPH or methylphenidate, but repeated injections
rized above. of these drugs do produce behavioral sensitiza-
tion4”.“‘6. In addition, guinea pigs do not form pOHE
5.1. Drug dispositionallperipheral hypotheses from D-AMPH, but still show behavioral sensitiza-
tion’72. Lastly. as noted by Lewander”“, it is difficult
It is possible that the increasing behavioral re- to imagine how dispositionaliperipheral factors could
sponse produced by repeated AMPH administration account for the development of tolerante to some of
is due to some change in the disposition of AMPH. the effects of AMPH (e.g. autonomie effects) simul-
For example, AMPH pretreatment may increase the taneously with the sensitization of others (e.g. ster-
amount of AMPH that reaches the brain due to eotyped head movements, rotational behavior).
changes in AMPH metabolism, or because AMPH In conclusion. there is a general consensus that dis-
accumulates in adipose tissue and is released lat- positionaliperipheral factors cannot account for the
er255.28”. In support of a dispositional hypothesis, behavioral sensitization produced by repeated inter-
Kuhn and Schanberg”” reported that AMPH pre- mittent injections of low doses of AMPH62~‘hy~2’0~26~.
treatment increased the rate of AMPH uptake into
the brain (at 10 min), although it did not influente its 5.2. Drug-environment conditioning hypotheses
rate of removal from the brain (at 1, 4 and 12 h). It
should be noted, however, that Kuhn and Schan- When the administration of a psychoactive drug is
berg”” administered AMPH daily, increasing the repeatedly paired with a unique test environment,
dose by 1 mglkg each day from 10 to 32 mg/kg. They the test environment can sometimes acquire the
properties of a conditioned stimulus (CS). In this sit- AMPH-induced rotational behavlor in 3 different
uation, behavior previously elicited only by the drug groups of rats, al1 of which had a unilateral 6-OHDA
(the unconditioned stimulus) is eventuaily elicited by lesion of the substantia nigra. Onc group (sensitized)
the environment (the CS) in the absence of the was given AMPH in the rotometcrs (the uniquc en-
,
drug ‘n’.29Z Psvchomotor stimulant drugs. including vironment). and a second group saline in the rotome-
AMPH. are subject to this kind of drug-environment ters weekly for 3 weeks. During the first 3 weckly test
conditioning. It has been suggested. therefore. that sessions. a third group (pseudoconditioned) rrceived
drug-environment conditioning may be at least par- saline in the rotometcrs. and A.MPH in thcir homc
tially responsible for the development of behavioral cages following removal from the rotometer. On the
~en~iti~ation7?.llO.~~~.~l~,~~~.~~l~.~~~
The important 4th week. all rats received 3.0 mg/kg of AMPH in the
question here is not whether the behavioral effects of rotomcters and rotational behavior was rccordcd.
AMPH can be conditioned, because there is no doubt Both of the AMPH pretreated groups showcd grcat-
they can. but whether drug-environment condition- cr AMPH-induced rotational behavior during the 4th
ing is necessary for behavioral sensitization. That is. test session than did saline pretreated rats. The sa-
can drug-environment conditioning alone account line pretreated rats made the same number of rota-
for the characteristics of behavioral sensitization? A tions as the sensitized animals the first time sensitized
rcview of the literaturc revcals that it CUWW~,as illus- animals receivcd AMPH in the rotomcters. Thcsc
trated by the following points. studies establish that it is not nccessary to pair
(1) Segal2”3 has previously argued that drug-cnvir- AMPH administration with a uniquc test envircjn-
onment conditioning cannot account for behavioral ment to produce sensitization.“‘,“”
sensitization. For drug-environment conditioning to (3) The evidente discussed thus far does not sup-
occur it is necessary to pair drug administration with port a drug-environment conditioning hypothesis.
a unique test environment’5’1.‘9”. However, in al1 but it is stili possible that some form of interoceptive
their studies on sensitization, Sega1 and his col- conditioning is involved. Howevcr, this idea is not
leagues minimized conditioning variables by housing supported by studies showing that under appropriate
animals continuously in the ‘test’ chambers. The? experimental conditions. a saline injection fails to
found that under these conditions the repeated ad- mimic the locomotor and stereotypy producinp ef-
ministration of AMPH still ptoduces sensitiza- fects of AMPH in sensitized animals’3~2h7.‘“‘, and
tionJ”.263.2M.167.Similar results have been obtained in weekly injections of AMPH do not produce condi-
this lab. For example. the data illustrated in Fig. 1 tioned rotational behavio?’
were obtained from rats that were always adminis- (4) A further argument agaimt conditioning hy-
tcred AMPH in their home (wire-hanging) cages. not potheses has been raised by SegaI”“. He pointed out
in a unique test environment. that when rats are repeatedly administered a ION
(2) Sega1 and his colleagues have also shown that it dose of AMPH, which initially produces only loco-
is not necessary to treat animals with AMPH in the motion. that dose eventually comes to elicit stereo-
test environment to produce sensitizationJ”. Brownc typy. That is. the pattern and charactcr of the behav-
and Sega14” pretreated rats with 2.5 mg/kg of AMPH ior elicited hy the drug evolves from that associated
or saline daily for 4 days in one of 3 different environ- with a low dose to that associated with a higher dose
ments: (a) the test chamber. (b) a plastic cage. singiy of the drug. This is not consistent uith a conditioning
housed. or (c) a plastic cage, group housed. On the hypothesis. because if locomotion were being condi-
5th day. all rats received 2.5 mg/kg of AMPH in the tioned to the test environment une would expect to

test chambers. Al1 3 groups pretreated with AMPH observe conditioned locomotion: not the appearance
(regardless of environment) showed sensitization. as of a new behavio?‘.‘.
indicated by a more rapid onset of stereotypy relative (5) Lastly. there have now been many reports that
to saline-pretreated contro1 animals. Similar findings a single injection of AMPH can produce a very long-
have been obtained in other studies where rotational lasting enhancement in a variety of AMPH-induced
behavior, stereotypy or locomotion were meas- behaviors’“.‘“‘.‘“~,‘h4. lt is difficult to imagine that
ured’T.67.2”. For example. Kobinson24” compared conditioning could account for these enduring effects
 169

of one exposure to AMPH, since most conditioning cific neurotransmitter systems. Most researchers
phenomena require repeated pairing of the CS and have studied brain DA systems, and SO evidente for
UCS. Furthermore, as pointed out by one of the changes in nigrostriatal, mesolimbic and mesocorti-
anonymous reviewers of this paper, ‘sensitized re- tal DA systems will be reviewed first. There is only
sponses grow with the passage of time . whereas limited evidente that behavioral sensitization is ac-
conditioned responses should decline with companied by changes in other neurotransmitter sys-
*lh.17.Ihl
time tems, and SO this will be reviewed second. Since the
The conclusion to be drawn from the evidente just literature is large and there are multiple hypotheses
summarized is clear; drug-environment conditioning as to the nature of neural changes. studies proposing
cannot fully account for behavioral sensitization. It a primarily postsynaptic vs presynaptic basis to sensi-
needs to be emphasized, however, that even though tization will be dealt with separately.
drug-environment conditioning does not explain be-
havioral sensitization, it is probably a major factor in- 5.3.1. The nigrostriatal dopamine system
fluencing many studies of behavioral sensitization. If Most attempts to identify a neural correlate of be-
animals are repeatedly and frequently tested in a havioral sensitization have focused on the nigrostria-
unique environment , it is very likely that drug-envir- tal DA system. This is to be expected because AMPH
onment conditioning will occur1”‘~21s~25”~29’.It is causes striata1 DA releasely2, and many of the behav-
therefore difficult to interpret and evaluate studies of iors that are sensitized by AMPH (e.g. stereotypy,
behavioral sensitization that are confounded by con- rotation) are thought to be caused by the release of
ditioning variables because the extent to which DA from nigrostriatal neurons”~“y~‘y’.‘y~.~~‘O.
changes in behavior can be attributed to sensitization 5.3.1.1. Evidente for postsynaptic changes. In one
vs conditioning is unclear. It is probable that some of of the earliest papers on behavioral sensitization Kla-
the apparent discrepancies in the literature are due to wans and Margolin’“’ proposed that the repeated ad-
differences in the extent to which conditioning varia- ministration of AMPH produces postsynaptic DA re-
bles predominate in any particular study (see below). ceptor supersensitivity. They based this idea on an
Nevertheless, neither drug-dispositional nor condi- experiment showing that guinea pigs sensitized to
tioning hypotheses can fully explain behavioral sensi- AMPH were also hypersensitive to apomorphine
tization. and SO other hypotheses must be enter- (APO), a direct-acting DA receptor agonist. In a lat-
tained. er paper they provided neurochemical evidente for
striata1 DA receptor supersensitivity in AMPH-pre-
5.3. Neural hypotheses treated guinea pigs’54.
Further studies to examine the hypothesis that
It has been suggested that the repeated intermit- postsynaptic DA receptors are supersensitive in
tent administration of AMPH causes a long-lasting AMPH-sensitized animals have largely utilized one
change in neural systems that mediate the motor of two approaches. (1) If AMPH-pretreated animals
stimulant effects of AMPH, and that this is responsi- have supersensitive postsynaptic DA receptors they
ble for the heightened behavioral response seen upon should be hypersensitive to the behavioral effects of
subsequent exposure to the drug152.‘86.267.The idea direct-acting DA receptor agonists, as reported by
that a centra1 change is involved is supported by the Klawans and Margolin ls2 However. these data are
observation that rats given repeated systemic injec- equivocai. Table 1 shows that in the majority (12 out
tions of AMPH are hypersensitive to the locomotor- of 20) of studies of this type (albeit a small majority)
enhancing effects of a subsequent intraventricular in- it was found that AMPH-pretreated animals are not
jection of AMPH225. Research on the neural corre- hypersensitive to APO.
lates of behavioral sensitization has addressed two (2) The second approach has been tu study DA re-
basic questions: (1) what is the locus of the ceptor binding. However, studies on DA receptor
change(s), and (2) what is the nature of the binding do not support the contention that striata1
change(s)? Because of the character of this research, postsynaptic DA receptors are up-regulated in
the locus of change is largely defined in terms of spe- AMPH-sensitized animals; and in fact. most of these
170

TABLE 1

The effea of ampheramine sensirization on hehavior induced hy a suhsequenr injecrion of apomorphine

APO, apomorphine; M, male; F. female; D, o-AMPH; M, meth-AMPH; L. L-AMPH: mk. mg/kg;

- - d. dav: mo. month; inj. ‘njections:
wk, week: h. hours; m, minutes; +. increasing doses.

Referente Species sex A-&PH Iniecrron schedule Wirhdrawal Rehavror

period

Antelman and Chiodo” Rats ? D 4mk;d x 6d Il d locomotior’

Bailey and Jacksor? Mice M D 4 mk;d X 20 d r( d locomotion
Conway and Uretsky4’ Rats M 5mk3xldX5d 3d stereotyp-
Hitzemann et al.“’ Rats M I> 3-+l?mk?X:dX3wk I-30d stercotypy
Hitzemann et al.“’ RafS F D hmk? Xid x l-4d Ih-.20h stereotypi
Jackson et al.“’ Rats M D 5 mk:d x 25 d 7 (1 stereotyp‘
Jenner et al.“’ Mice M D 2.5- 20 mkid x 3 mo I wk--3 mo rotation
Kilbey and Ellinwood’“h Rats F D 7 mk!d x l4d 5 <I \tcrcotyp!
Rebec and SegaI*” Rats M D 5 mk:d x 1 d Id stcreotypy
Robinson’“’ Rats F D 3 mk.‘3-4 d x 5 inj ’ (1 rotation
Weston and 0verstreet31h Rats M D ?orXmk/d x 3-l7d I d locomot’on and
sniffing
hor Ihmk/d X 3%l7d I ti locomot’on and
sniffing
Wilcox et al.“” Micc M D -l mk:d x 20 d 4d cage clin’h’r’g

Bailey and Jackson” Mice M D 1 mkid x 20 J Hd Iocomot’o”

Echols” Mice M D 1 mk;wk x 3 wk I wk rotation
Klawans and Margolin’“’ Guinea M D 1-5 mkid X 21 d 3-IOd stcreotvp\
pigx
Martres et al.‘* Mice M D 5 mk%l min x 4 inj 70 h cagc climh’ng
Nelson and Ellison“” Rats M D 3.2-3.7 mk/d x 7-30 d I or 30 d stereotyp!
Nishikawa et al.z02 Rats M M 6mkid x l4d 14 d stereotypy
Weiner et al.“’ Guinea M D S mk:d x 21 d IOLI stcrcotyp\
pigs
Wilcox et al. “’ Mice M D 4 mk;d x 20 d Sor l2d cagc cl’mh’ng

’ Also added AMPH to drinking water: DA depleted and rotation depresscd. ‘ No if 4 d withdrawal. yes il X- 12 d withdrawal. ’ Ke-
duction in oral stereotypy. ’ No with 0.25 or 0.5 mg/kg and yes with 1-4 mg!kg APO. ’ Ycs with some treatments. but not others. ’ No
with 1 mg/kg APO: small effect on onset of stereotypy with 3 mg/kg huf no effect on intenxitv.

studies report that in AMPH-pretreated animals crease in striatal [-‘H]spiroperidol binding in AMPH-
there is either a decreuse in DA receptor binding, or pretreated rats. Attempts to identify changes in LIA-

no change (Table Il). In only 4 of the 24 experiments stimulated adenylate cyclase activity in sensitized an-
summarized in Table 11 were AMPH-pretreated ani- imals have also been negative7~‘1’~!‘J~“i.
mais found to have increased DA receptor binding. In conclusion. the idea that behavioral sensitiza-
These 4 reports differ somewhat from the rest in that tion is due to hypersensitive striatal postsynaptic DA
in 3 of them [3H]DA or [“HJADTN were used as the receptors is not supported by most of the available
ligand. In contrast, [“H]spiroperidol was used in most evidente. In fact. much of the evidente suggests the
studies reporting a decrease or no change in binding. opposite, that is, a small down-regulation of postsyn-
Furthermore, the Klawans et al.15’ study is unusual aptic DA receptors in AMPH-pretreated animals.
because they reported an increased affinity for The idea that postsynaptic DA receptors are actually
13H]DA at ‘high affinity’ sites with no change in B,,,. hyposensitive in AMPH-pretreated animals is fur-
but an increase in the number of receptors at ‘low af- ther supported by a recent electrophysiological ex-
finity’ sites (see also ref. 98). This is difficult to inter- periment by Kamata and Rebec17” (see also refs. 8.
pret. The only report of increased [‘Hlspiroperidol 295). who found that the ability of iontophoretically
binding is an abstract by Robertsonz3*. but in two applied DA to inhibit glutamate-induced striatal unit
subsequent papers Robertson237*2’Y reports a de- activity was reduced in AMPH-pretreated rats.
 171

TABLE 11

The effecl of amphetamine sensitization on striata1 dopamine receptor binding

Abbreviations: as in Table 1. NC, no change; ADTN, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene.

Referente Species Sex AMPH Injection schedule Withdrawai Ligand Competitor Bind--
period ing

Akiyama et al.6 Rats M M 4 mk/d 14 d

x 7 d + 4 mk2 [3H]spiperone spiperone Down
Akiyama et al.’ Rats M M 4 mkid 14 d
x 7d [‘Hlspiperone butaclamol Down
Daiguji and Meltzer”’ Rats M D 5+15mk2/dx20d1 17-20 h [3H]spiroperidol ADTN Down
Hitzemann et al.“’ Rats F D 6mk2 xld x 1-4d 16-20 h .[3H]spiroperidol
._ . butaclamol or Down
sulperide
Howlett and Nahorski” Rats M D 5+15mk2x/dx20d1 17-20h [3H]spiroperidol butaclamol or Down
dopamine
Howlett and Nahorski’lJ Rats M D 5-+15mk2x/dx20d’ 17-20h [‘Hlspiperone ? Down
Kaneno and Shimazono”” Rats M M 6 mkld x 14 d 10d [3H]spiroperidol in vivo’ Down
Muller and Seeman”j Rats M ? 10 mkid x 14 d (oral) 1d [‘Hlapomorphine apomorphine Down
Riffee et al.z3’ Mice M D 4 mk/d x 14 d 3d [3H]spiroperidol apomorphine Down
or butaclamol
Robertson’s’ Rats M D 5-lOmk2xidx21d Id [3H]spiroperidol domperidone Down
Robertson’“’ Rats M D lOmk2 xid x 21d 24-36 h [3H]spiroperidol domperidone Down

Akiyama et al.’ Rats M M 4mkid x 14d 7d [‘Hlspiperone ADTN NC

Algeri et al.’ Rats M D 10mkid x 7d Id [‘Hlhaloperidol haloperidol NC
Burt et al.” Rats ? D 5mkid x 3wk 5-7 d [‘Hlhaloperidol dopamine NC
Howlett and Nahorski” Rats M D 5+ 15mk2 xid x 4d’ 17-20h [3H]spiroperidol butaclamol or NC
dopamine
Howlett and Nahorski” Rats M D 5-9 15mk2 xid x 4d’ 17-20h [3H]spiperone ‘? NC
Jackson et al.“’ Rats M D 5 mkld x 25 d 7d [‘Hlspiperone butaclamol NC
Muller and Seeman’9’ Rats M 7 10 mkid x 14 d (oral) 1d [“Hlhaloperidol pimozide NC
Owen et al.2”J Vervet M D 4+12mk/dx35d 1d? [‘Hlspiperone butaclamol NC
and F
Riffee et al.‘35 Mice M D 4mkid x 14d lor5d [‘Hlspiroperidol apomorphine NC
or butaclamol

Borison et al.” Rats M D 3.75 mkld x 5 wk 5d [‘Hldopamine butaclamol Up

Klawans et al. Ii’ Guinea M D 5mkidx4wk 7d [3H]dopamine apomorphine Up
pigs or butaclamol
Robertson’s’ Rats M D 10 mk 2 xid x 21 d 24-36 h [3~]~~~~ dopamine UP
Robertson’ss Rats M D 5 mkid x 22 d 2d [‘Hlspiroperidol ‘? UP
’ Also added 25 + 75 mgiml to drinking water. ‘ Given 4 mgikg of AMPH 1 h before kill. ’ Cerebellum used to estimate non-specific
binding.

Since the weight of the evidente is strongly against AMPH with a unique test environment even an injec-
the DA postsynaptic receptor supersensitivity hy- tion of saline will produce many of the behaviors pre-
pothesis, it is curious that there are SOmany studies in viously associated with only AMPH administration
which ‘cross-sensitization’ to AP0 was found (Table (see above for references). It is therefore possible
1). It is not clear what differentiates the studies in that the enhanced behavioral response to AP0 that is
which cross-sensitization to AP0 was found from sometimes observed in AMPH-pretreated animals is
those in which it was not. The most obvious varia- due to drug-environment conditioning, and not to an
bles, such as treatment regimen or withdrawal peri- up-regulation of postsynaptic striata1 DA receptors.
od, do not account for the discrepancies. One hy- It should also be noted briefly that there have been
pothesis, that unfortunately is impossible to test post- no studies of striata1 DA receptor binding in animals
hoc, is that apparent cross-sensitization to AP0 is ac- treated with a relatively conservative AMPH injec-
tually due to drug-environment conditioning effects. tion regimen (for example, every 4-7 days for a tota1
It is known that AMPH can act as an unconditioned of 5-10 injections), and then withdrawn for longer
stimulus, such that after the repeated pairing of than 7 days. Therefore, despite the many studies on
172

DA receptor binding shown in Table Il, it is not of AMPH neurotoxicity (as indicated by the use of
known whether the behavioral sensitization pro- high doses of AMPH with accompanying DA deple-
duced by intermittent injections of AMPH is consis- tion). Studies on the effects of chronic AMPH admin-
tently accompanied by a small down-regulation, or istration that were excluded on the basis of these cri-
any other change in DA binding. teria include refs.: 90. 91, 113. 142. 155. 193. 231.
5.3.1.2. Evidente for presynapric changes. Upon 269. and others discussed above in regard to AMPH
cursory examination the evidente for presynaptic neurotoxicity. There is considerably more consensus
changes in the nigrostriatal DA system of sensitized as to the nature of presynaptic changes accompany-
animals appears to be contradictory and confusing. ing behavioral sensitization when only those studies
But much of this confusion is because different relevant to the phenomenon of behavioral sensitiza-
AMPH treatment regimens produce different effects tion are examined.
on presynaptic indices of DA function. As discussed The following review includcs experiments in
above, AMPH is neurotoxic if elevated brain concen- which presynaptic DA function was estimated by
trations are sustained for very long, either by contin- either: (1) measures of DA concentrations; (2) meas-
uous administration or frequent multiple injections ures of DA synthesis; and/or (3) measures of DA uti-
of high doses. AMPH neurotoxicity is manifested by lization or reiease. Each of these will be discussed in
many presynaptic histopathological and neurochem- turn. These measures were obtained under either
ical changes. including degeneration of nigrostriatal steady-state (resting) conditions, or following an ad-
DA terminals and striata] DA depletion. However. it ditional ‘challenge’ injection of AMPH. and this is
will be shown below that robust behavioral sensitiza- also noted.
tion can be produced by a regimen of repeated inter- (1) DA concentrations. Tahle III lists studies in
mittent AMPH injections that does not result in DA which striata1 DA concentrations were measured in
depletion secondary to degeneration of striatal DA animals sensitized to AMPH. It is clear from Tablc
terminals. Furthermore, behavioral sensitization II1 that AMPH pretreatment can produce robust be-
persists for months following the withdrawal of havioral sensitization without causing a reduction in
AMPH, in the absence of damage to nigrostriatal the steady-state concentrations of striata1 DA (e.g.
DA neurons. Therefore, to realistically evaluate refs. 43. 167, 202 and unpublished studies by the au-
whether behavioral sensitization is accompanied by thors). Following a challenge injection of AMPH.
changes in presynaptic striata] DA function it is im- pretreated animals sometimes show a slightly greater
perative to exclude studies in which the AMPH treat- decline in striatal DA concentrations than contro1 an-
ment regimen may have been neurotoxic. and where imals?O’; but this is not always foundlh7. Two studies
measures were made without having withdrawn ani- in which whole brain concentrations of DA were
mals from the drug. Othcrwise. the neurotoxic ef- measured are also included in Table 111. hecause
fects of AMPH. or the well known presynaptic com- striatal DA would comprise the largest fraction ot
pensatory responses that occur following partial whole brain DA. Again. AMPH pretreatment had
damage to dopaminergic systems3.‘04.2ss, could easily no effect on the whole brain concentrations of DA.
be mistaken for neural correlates of behavioral sensi- On the basis of the studies listed in Tabie 111 we
tization. would argue that a long-lasting depletion of DA in
It is sometimes difficult to determine from a paper AMPH pretreated animals, over-and-above the tran-
whether the AMPH treatment regimen used was sient changes that might occur following enhanced
neurotoxic. Some multiple injection regimens may DA release (e.g. ref. 202), is prima facie evidente for
produce a mix of toxic and sensitization effects. TO AMPH neurotoxicity.
avoid mistaking the neural correlates of behavioral (2) DA synthesis. Table IV lists studies in which
sensitization with those associated with AMPH neu- striatal (or whole brain) DA synthesis was estimated
rotoxicity. studies were excluded from the following in AMPH-pretreated and contro1 animals. The most
analysis if: (1) AMPH was given more than two times consistent finding is that AMPH sensitization is not
per day; (2) animals were withdrawn from AMPH for accompanied by changes in striata] DA synthesis un-
less than one day; or (3) there was clear evidente der steady-state conditions. or tollowing a suhse-
 173

TABLE 111

The effect of amphetamine sensitization on striata1dopamine concentrations’

Abbreviations: as in previous Tables.

.~
Referente Injection schedule Ejfect
.~
A. Steady-state (resting) conditions
Alloway and Rebec” lmk2xidX6d Id NC
Alloway and Rebec” Smk2xidx6d Id Down
Camp and Robinsonn 2-3 mki4 d x 10 inj 8-13 d NC
Eichler et al.“’ 2-12 mkid X 65 d Id NC
Jackson et al.“’ 5 mkld x 25 d 7d NC
Kuczenski and Leithlh’ 3 mkid x 6 d 2d NC
Lynch et al. “’ 0.5+2mk/d x 14d 36 h-7 d NC
Nishikawa et al.“” 6mkid x 14d 15d NC
Pearl and Seiden”” (note 2) 2.5 mkid x 60 d 28 h NC
Pearl and Seider? (note 2) 2.5 mkid x 60d 28 h NC
Riffee and Gerald”’ (note 2) 2.5 mkid x 7 d l-2 d NC

B. After challenge’
Kuczenaki and Leithlh’ 3 mkld x 6 d 2d NC
Nishikawa et al.‘“’ 6mkid x 14d 15d Down
’ Excludes studies in which: (a) AMPH was given more than two times per day; (b) animals were withdrawn for less than 1day; (c) wry
high doses of AMPH were used (see text for rationale). ’ Whole brain. ’ After a subsequent challenge injection of AMPH.

quent challenge injection of AMPH34,‘67.2u’. None of tivity. Although Algeri et al.’ and Taylor and Ho2”’
the studies in which whole brain206.23”.273 or fore- found a decline in tyrosine hydroxylase activity in
brain”s DA synthesis was estimated report any effect AMPH-pretreated animals, it should be noted that
of prior AMPH treatment (Table IV). Besson et a1.34 they used a very large dose of AMPH (10 mgikg) and
did report a small decline in the formation of withdrew animals for only one day. It is unlikely that
[“H]DOPA in AMPH- pretreated rats, but the same this latter effect is related to behavioral sensitization,
paper reports no change in tyrosine hydroxylase ac- but may be due to AMPH neurotoxicity. The only re-

TABLE IV

The effect of amphetamine sensitization on striata1dopamine syathesis

Abbreviations: as in previous Tables.

Referente Injection schedule Withdrawal Measure Effect

period

A. Steady state (resting) conditions

Algeri et al? lOmkldx7d Id Tyrosine hydroxylase Down
Besson et a1.j” 1 mkid X 8 d Id Tyrosine hydroxylase NC
Besson et al.‘” 1 mkid x 8 d Id [‘HIDOPA formation Down
Hulme et al.“‘(note 1) 11.7mk/d x 3-7d ? Tyrosine hydroxylase NC
Kuczenski and Leithlh’ 3 mkid x 6 d 2d [‘HJTyrosine -ì [‘HJDA UP
Nishikawa et al.“” hmk/d x l4d 15d Tyrosine hydroxylase NC
Pearl and Seiden”‘h (note 1) 2.5 mkid x 60 d 28 h DOPA accumulation NC
Riffee and Gerald’” (note 1) 2.5 mkld x 7 d 2d [“H]Tyrosine + [‘H]DA NC
Tavlor and Ho’“’ lOmkidx5d Id Tyrosine hydroxylase Down

B. After challenge
Kuczenski and Leithlh7 1+12mk3x/dx4d 2d [jH]Tyrosine -) [‘H]DA NC
Nishikawa et al.‘“? 6mkid x 14d 15 d Tyrosine hydroxylase NC
Short and Shusterz73 (note 1) lOmk2xidx5d 3-25 d Tyrosine hydroxylase NC
~~
’ Whole brain or forebrain.
174

port of an increase in striata1 DA synthesis following mostly formed from DA after re-uptake into the pre-
AMPH-pretreatment is by Kuczenski and Leithlh7. synaptic terminal 162.‘74.187,246
(but see ref. 47). Table
They found a small (ll-18%) enhancement in the V also includes experiments in which the decline in
conversion of [3H]tyrosine to [3H]dopamine in DA concentrations following inhibition of tyrosine
AMPH-pretreated rats. However, they also point hydroxylase was used to estimate LIA utilization3”. It
out that the effect is not strong because. ‘a statistical- should be noted that both of these measures of DA
ly significant increase is only observed when the num- ‘turnover’ are sensitive to changes in release.
ber of animals is large’ (p. 407). It would be informa- It is clear from Table V that there is little evidente
tive to know if this effect persists for longer than the for a change in striata1 DA utilization in AMPH-sen-
two-day withdrawal period used by Kuczenski and sitized animals when they are tested under steady-
,Leith16’. In contrast, Kuczenski and Leith’67 did not state conditions lh7.183,1’)1.20?,233,
ln addition, sensitiza-
find that AMPH-pretreatment enhanced DA synthe- tion does not alter the basa1 rate of endogenous DA
sis following a subsequent challenge injection of efflux from striata1 tissue in vitro’h’.‘42~244, although
AMPH (Table IV). the physiological significante of basa1 DA efflux in
(3) DA utilization/release. Table V lists studies in vitro is questionable because it is both temperature-
which the concentration of DA metabolites andior and calcium-independent*“. In contrast to these neg-
the metabolite to transmitter ratios were used to esti- ative findings, Camp and RobinsonJ3 recently found
mate DA utilization. Dihydroxyphenylacetic acid significantly higher striata1 DOPAC to DA ratios in
(DOPAC) concentrations are thought to provide a AMPH-pretreated than in contro1 rats, suggesting
good estimate of DA utilizationirelease because it is enhanced DA release. However. this was only infe-

TABLE V

The effect of amphetamine sensitization on striata1 dopamine utilizationlrelease

Abbreviations: as in previous Tables. DOPAC, dihydroxyphenylacetic acid; HVA, homovanilhc acid; MPT, alpha-mcthyl-p-tyroaine

Referente Injection schedule Withdrawal Measure

period

A. Steady-state (resting) conditions

Camp and Robinson (M)43 3 mki4 d x 1 0 inj 8-13d DOPACIDA N(‘
Camp and Robinson (F)” 2.6mk/4d x IOinj 8-13 d DOPACIDA 1’P
Jackson et al.‘2’ (note 1) 5 mkid x 25 d ?d Decline in DA after MPT NC
Kolta et al. Ih’ Smk2xidxSd 3-30 d Endogenous DA release NC
Kuczenski and Leitht6’ 3 mkid x 6 d 2d DOPAC; HVA NC
Lynch et al.‘sa 0.5 -+ 2 mkid x 14 d 7d DOPAC NC
Lynch et al.“’ 0.542mkid X 14d 12-48 h DOPAC Down
Mittleman et al.“’ 3 mki3 d x 9 inj l-2 mo DOPACDA NC
Nishikawa et aL2” 6mkid x 14d 1Sd DOPAC; HVA; DOPAUDA NC
Robinson and Becker’“’ Smk2xidx5d 10 d Endogenous DA release NC
Robinson et al.‘@ 1.25 mk once 3-5 wk Endogenous DA release NC
Robinson et al.?” 3 mkid x 7 d Sd Decline in DA after MPT NC
Robinson et al.‘@ 3 mk/3-4 d x 9 inj 10d Decline in DA after MPT N<‘

B. After challenge
Jori and Bernardi12’ 5 mk/d x 4-10 d (mice) 1d Elevation in HVA NC
Jori and Bernardi12’ 5 mk/d x 4 d (rats) Id Elevation in HVA Down
5 mk/d x 10 d (rats) Id Elevation in HVA NC
Kolta et al.“” 5mk2x/dxSd 3d Endogenous DA release NC
Kolta et al.“’ 5mk2x/dxSd 15-30 d Endogenous DA release Up
Kuczenski and Leith”j’ 3 mkld x 6 d 2d Decline in DOPAC and HVA UP
Nishikawa et aL’O hmk/d x 14d 15d DOPACIDA LJP
Robinson and Becker242 Smk2x/dxSd 10d Endogenous DA release UP
Robinson et a1.‘44 1.25 mk once 3-5 wk Endogenous DA release UP
Robinson and Becker (note 2) 3 mk/3-4 d x 10 inj 10d DOPAC; HVA UP
’ Whole brain minus cerebellum; ’ Dnpublished observations - footshock stress challenge.
 17.5

mule, but not male rats (Table V). Studies in which AMPH stimulated more DA release in sensitized
male rats were used report no effect of AMPH-pre- than in contro1 animals. Furthermore, Kuczenski and
treatment on steady-state (resting) DA utiliza- Leith16’ found that a challenge injection of AMPH
tion’h7.‘y’~2”2. This sex differente may be related to was more effettive in decreasing DA metabolite lev-
the sex differente in behavioral sensitization’“,240~244. els in AMPH-pretreated than in contro1 rats; an ef-
Perhaps because female rats show more robust be- fect that could be due to a leftward shift in the AMPH
havioral sensitization than males, the neural corre- dose-response curve. In contrast, Jori and Bernar-
lates of behavioral sensitization will be more appar- di”’ found that AMPH pretreatment did not alter the
ent in females. On the other hand, AMPH-pre- effect of a challenge injection of AMPH on HVA
treated female rats did not show a greater decline in concentrations. However, this could be because Jori
striata1 DA following tyrosine hydroxylase inhibition and Bernardi12’ withdrew animals from AMPH for
than contro1 female rat?“. It is not clear what ac- only one day, and there is evidente to suggest that
counts for the differente between the two methods more robust behavioral sensitization results if ani-
for estimating DA utilization. Perhaps the effect is mals are withdrawn for more than one day’6,1’2,‘6’.
small and the former method is more sensitive to the Considering the tendency of behavioral sensitization
neural consequences of repeated intermittent to ‘grow’ over time following the withdrawal of
AMPH administration than the latter. Also, in the AMPH16.‘7.1h’, it is important to note that Kolta et
Robinson et a1.‘43 study only one point in time was al.“’ found that AMPH-stimulated striata1 DA re-
sampled after tyrosine hydroxylase inhibition, and a lease was not significantly enhanced 3 days after the
more complete analysis of the rate of decline of DA is last AMPH treatment, but was enhanced 15 and 30
required to more accurately estimate DA utilization, days later. This latter finding underscores the impor-
especially given the low rate of striata1 DA turnover. tante of withdrawing animals from AMPH for a few
In contrast with the paucity of evidente for days in studies concerned with the biologica1 basis of
changes in DA utihzationirelease under steady-state behavioral sensitization.
conditions, there are a number of reports of en- In conclusion, there is strong evidente that the be-
hanced striata1 DA utilizationirelease in AMPH-pre- havioral sensitization produced by the repeated in-
treated animals given a subsequent challenge injec- termittent administration of AMPH is accompanied
tion of AMPH (Table V). Robinson and Becker242 by an enduring enhancement in the release of striata1
first reported that repeated intermittent injections of DA produced by re-exposure to AMPH (Table V).
AMPH in vivo produce an enduring enhancement (at (It should be noted that a neurotoxic regimen of
least 10 days) in the AMPH-stimulated release of en- meth-AMPH administration does not enhance DA
dogenous striata1 DA in vitro, and more recent stud- release, but may actually decrease meth-AMPH
ies suggest this effect persists for at least 30 days fol- stimulated DA release2’“.)
lowing the last AMPH treatment’61*244. In addition, As an aside, there is an interesting differente be-
Robinson et a1.‘44 found that even a single injection tween the reports of Kuczenski and Leith’67 and Ni-
of 1.25 mgikg of AMPH enhanced the AMPH-stimu- shikawa et al. 202 which deserves comment .
lated release of striata1 DA measured in vitro 3-5 Kuczenski and Leith”’ found that an acute injection
weeks later. An enhancement in AMPH-stimulated of D-AMPH decreased striata1 DA metabolite con-
striata1 DA release in sensitized rats has now been centrations, but Nishikawa et al.“’ reported that an
obtained in 5 different studies conducted in two dif- acute injection of meth-AMPH increased DOPAC
ferent labs45.‘61~‘42~244,
and therefore it would appear levels in AMPH-pretreated rats. The former effect
to be a robust phenomenon. would be expected if D-AMPH also blocked DA re-
The effects of AMPH sensitization on DA release uptake into presynaptic terminals, thus reducing
in vitro are consistent with a number of in vivo studies DOPAC (and HVA) formation”‘. The latter effect
(Table V). Nishikawa et al.2o2 reported that the el- would be expected as a consequence of enhanced DA
evation of DOPAC to DA ratios produced by a chal- release, but only if meth-AMPH did not prevent the
lenge injection of meth-AMPH was enhanced follow- re-uptake of DA into presynaptic terminals and its
mg meth-AMPH pretreatment, suggesting that conversion into DOPAC. Perhaps meth-AMPH is
176

not as potent a re-uptake blocker as D-AMPH, and tors (Table 11). It is possible this reflects a change in
therefore DOPAC formation is enhanced following presynaptic DA receptors.
meth-AMPH, but decreased by D-AMPH. Unfortu- Much of the evidente for DA autoreceptor subsen-
nately, we know of no direct comparison between the sitivity in sensitized animals comes from electrophys-
re-uptake blocking vs release enhancing properties iological studies. These are summarized in Table VI,
of meth-AMPH and D-AMPH (e.g. ref. 89 and R.M. The firing rate of most mesencephalic DA neurons is
Ferris and K.E. Moore, personal communication). decreased by the systemic application of either
Because behavioral sensitization is accompanied AMPH or APO, and this is thought to reflect nega-
by an enduring enhancement in the utilization/re- tive feedback mediated by DA autoreceptors22”. In
lease of striata1 DA produced by re-exposure to animals previously exposed to repeated intermittent
AMPH, it seems reasonable to hypothesize that pre- injections of AMPH, both AMPH and AP0 are less
synaptic changes in striata1 DA neurons are at least effettive than norma1 in reducing the discharge rate
partially responsible for the behavioral phenome- of dopaminergic cells in the substantia nigra, zona
non. Of course, this would not exclude changes in compacta (SNC16,13311”4 ) and ventral tegmental area
other neural systems as well. But before reviewing (VTA135,3’7). In fact, the firing rate of some DA cells
evidente for changes in other neural systems, ideas is actually enhanced by AMPH or AP0 in AMPH-
concerning the cellular basis of enhanced striata1 DA sensitized rats, an effect never seen in contro1 ani-
release in sensitized animals will be discussed. In mals16,‘33. Furthermore, the spontaneous firing rate
doing SO, it should be kept in mind that hypotheses of SNC and VTA units is increased1”4.317 (although
regarding the nature of the cellular change(s) respon- see also refs. 133, 134, 135 and Table VI), and the
sible for enhanced DA release are constrained by ev- ability of iontophoretically applied DA to inhibit
idence that it occurs in the absence of changes in VTA unit discharge decreased in AMPH-sensitized
striata1 DA concentrations (at least under steady- rats317. These effects could be due to subsensitive DA
state conditions; Tables 111, IV). autoreceptors. The experiment with iontophoretical-
5.3.1.3. Dopamine autoreceptor subsensitivity. ly applied DA”” suggests that DA autoreceptors lo-
One hypothesis is that the repeated exposure to ab- cated on the cell bodies andior dendrites of VTA cells
normally high concentrations of DA produced by re- are hyposensitive in sensitized animals. In contrast.
peated AMPH administration causes DA autorecep- the sensitivity of nigral zona reticulata neurons to
tors to become subsensitive16~26~18~‘9s~2s9. It is AMPH is increased following repeated AMPH ad-
thought that autoreceptors on the presynaptic termi- ministration’“‘. as is the sensitivity of SNC neurons to
nals, celI body and/or dendrites of DA neurons con- AP0 following a neurotoxic regimen of AMPH ad-
trol DA synthesis, release and the discharge rate of ministration7x.
the celi via negative feedback86+314. Subsensitivity of Although electrophysiological studies have sup-
these autoreceptors would result in a reduction in this ported the DA autoreceptor subsensitivity hypothe-
negative feedback and enhanced DA release. In sup- sis, biochemicalipharmacologicat studies designed to
port of this hypothesis, Muller and Seeman”’ report- test the same hypothesis have not (Table VI). One
ed that repeated AMPH administration produced a biochemical approach has been to study the ability of
decrease in [3H]apomorphine binding, but no change low doses of AP0 to reduce the formation of the DA
in [3H]haloperidol binding (Table 11). They argued metabolites, DOPAC and HVA, an effect thought to
that the low concentrations of [3H]apomorphine used be due to the selettive stimulation of DA autorecep-
in their study reflected presynaptic DA receptor tors49.168. However, the repeated intermittent admin-
numbers. There is some question about this conclu- istration of AMPH does not alter the ability of AP0
sion, however, for as White and Wang317 pointed out. to reduce striata1 DA metabolite levels. BS would be
[3H]apomorphine may not selectively label DA auto-
receptors175~261. Nevertheless, the most consistent
finding from striata1 DA receptor binding studies is
that repeated AMPH administration produces a
small down-regulation (or no change) of DA recep-
 177

this is not altered in sensitized animals either49. A Wilcox234 reported that sensitization to AMPH does
third approach involves behavioral estimates of DA not alter the ability of AP0 to inhibit the locomotion
autoreceptor sensitivity. These have produced mixed produced by challenge injection of AMPH in mice
support for the subsensitive autoreceptor hypothesis. (also R.E. Wilcox, personal communication).
At very low doses AP0 produces a decrease in loco- It is not clear why the electrophysiological and bio-
motion, presumably because DA autoreceptors are chemical estimates of DA autoreceptor sensitivity
selectively stimulated and this reduces DA release. If are SO discrepant. Perhaps one should disregard the
DA autoreceptors were subsensitive in AMPH-pre- biochemicalipharmacological studies for the moment
treated animals, low doses of AP0 should be less ef- and ask how well the available electrophysiological
fective in reducing locomotion, as reported by Antel- evidente accounts for behavioral sensitization. The
man and Chiodo’7. However, using a very similar answer is, not that well; as illustrated in the following
paradigm, Conway and Uretsky”’ found no evidente examples. One problem is raised by the studies of
for DA autoreceptor subsensitivity in AMPH-pre- Kamata and Rebec1”“,‘“4, who pretreated rats with
treated animals (Table VI). Furthermore, Riffee and either 1 or 5 mgikg of D-AMPH two times a day for 6

TABLE VI

Evidente relevant to the dopamine autoreceptorsubsensitivity huporhesis

Abbreviations: as in previous Tables. SNC, substantia nigra, zona compacta; VTA, ventral tegmental area; GBL. gamma-butyrolac-
tone; U p , some cells showed an increase.

Measure Challenge Injection schedule Withdrawal Effect Referencr

drug period

A. Electrophysiological evidente
1. Ability of AMPH or AP0 to AP0 4 mkid X 6-15 d 2-11 d Down Antelman and ChiodoIh
inhibit SNC unit discharge AP0 Smk2xidx6d Id Down Kamata and Rebec”’
AMPH 5mk2xidx6d Id Down Kamata and Rebec”’
AP0 4 mk once 7-16d NC Antelman and ChiodoIh
AP0 lmk2xidxhd Id NC Kamata and Rebec13’
AMPH 2.5-Smk2x/dxS-16d Id NC Staunton et aI.‘s3
AMPH lmk2xidx6d Id UP Kamata and Rebec”’
2. Change in spontaneous discharge - 5mk2xldx6d Id UP Kamata and Rebec’jJ
rate of SNC cells lmk2xidxhd Id NC Kamata and Rebec’“’
_ l-5mk2 x/d x 6d Id NC Kamata and Rebec’j’
1.5-5mk2 x/d x X-16d 1d NC Staunton et al.“’
3. Ability of AMPH or AP0 to AMPH and AP0 l-5 mk 2 xid x 6 d Id Down Kamata and‘Rebec”’
inhibit VTA unit discharge AMPHandAPO 5mklor2xidx7d Id Down White and Wangӓ
AMPH and AP0 5 mk 2 xid x 7 d Ud Down White and Wangj”
AMPH and AP0 5 mkid x 7 d Xd NC White and Wang”’
AMPH and AP0 5 mk once Id NC White and Wang3’-
4. Change in spontaneous discharge - 5mk2xldx7d Id UP White and Wang”’
rate of VTA cells l-Smk2xidx6d Id NC Kamat,r ‘ ‘,md Rebec“’
5. Ability of iontophoretic DA to
inhibit VTA unit discharge DA Smk2x/dx7d Id Down White and Wang”-

B. Biochemical/pharmacological evidente
1. Ability of AP0 to reduce striatal AP0 5mk2xidxSd 3d NC Conway and Uretaky”’
metabolite levels AP0 3 mkid x 6 d 2d NC Kuczenski et al.‘hX
2. Ability of AP0 to inhibit GBL-
induced DA synthesis AP0 Smk2xidxSd 3d NC Conway and Urctsky””
3. Ability of a low dose of AP0
to decreasc:
- locomotion 6 mkid X 6 d 2-11 d Down Antelman and Chiodo”
Smk2x/dx5d 3-10d NC Conway and Uretsky’”
5mk2xidx5d 3d NC Riffee and Wilcox”’
- rotation 3 mkid x 5 d 7d NC Robinson””
178

days, and then tested them after one day of withdra- evidente of DA autoreceptor subsensitivity after X
wal (Table VI). Pretreatment with either 1 or 5 days of withdrawal. These results suggest that in the
mg/kg of AMPH produces behavioral sensitization. VTA the electrophysiological signs of autoreceptor
However, when subsequently challenged with APO, subsensitivity do not persist sufficiently long to ac-
only those animals pretreated with the 5 mg/kg dose count for behavioral sensitization. More studies will
of AMPH showed evidente of DA autoreceptor sub- be required to ciearly establish whether the electro-
sensitivity134. In animals pretreated with 1 mgikg physiological signs of autoreceptor subsensitivity in
there was actually a significant increase in the ability the SNC persist longer than in the VTA, as suggested
of AMPH to inhibit SNC unit discharge’s3 (Table by Antelman and Chiodo’“.
VI). This latter effect is opposite to that predicted by There is a third feature of behavioral sensitization
the DA autoreceptor subsensitivity hypothesis. not accounted for by the electrophysiological evi-
A second problem with the electrophysiological dente for DA autoreceptor subsensitivity. It is clear
studies concerns their ability to account for the per- that enduring behavioral sensitization is produced by
sistence of behavioral sensitization. Animals remain a single injection of AMPH’7.40*24”~‘6X.as are endur-
hypersensitive to the motor stimulant effects of ing changes in striata1 DA release“‘. However. both
AMPH for months after the cessation of treat- Antelman and Chiodolh and White and Wang”’ re-
ment1x,240. As mentioned above, there is even evi- ported that a single injection of AMPH does not alter
dente to suggest that for some period of time follow- the ability of AP0 to inhibit SNC or VTA unit dis-
ing withdrawal from AMPH there is a progressive in- charge (Table VI).
crease in sensitivity’6~“2~‘6’.~“. The enhancement in A fina1 argument against the DA autoreceptor
AMPH-stimulated striata1 DA release in AMPH- subsensitivity hypothesis is provided by studies on
sensitized animals is also very persistent, being evi- the role of DA terminal autoreceptors in the regula-
dent weeks to months following withdrawal’h1~71’.2”‘. tion of AMPH-stimulated striata1 DA release. Auto-
It is therefore unfortunate that in SOmany of the elec- receptors on the presynaptic terminals of nigrostria-
trophysiological studies animals were withdrawn for tal DA cells are thought to regulate the depoIariza-
only one day before testing (Table VI). This not only tion-induced, calcium-dependent release of DA via
decreases the probability of observing changes re- negative feedback 92.‘72 However, it has been report-
lated to behavioral sensitization, given that the be- ed that AMPI-stimulated striatai DA release, ;i
havioral effect and effect on AMPH-stimulated stria- process that is calcium-independent and may involve
tal DA release is larger with longer withdrawal peri- an exchange-diffusion process”. is nor modulated by
. 3 but does not allow an evaluation of the per-
ods’(” presynaptic DA autoreceptors”^. It is difficult tn
sistence of electrophysiological changes that are oh- imagine how the increase in striata1 DA release in vit-
served. ro produced by sensitization could be due to a change
Antelman and ChiodoI did report that the de- in presynaptic DA autoreceptors if these receptors
crease in the ability of AP0 to inhibit SNC unit dis- do not normally modulate AMPH-stimulated DA re-
charge seen in sensitized rats persisted for at least 11 lease”‘.
days. However, White and Wang”” found that in the In summary, the DA autoreceptor subsensitivity
VTA this effect was greatly attenuated after only 8 hypothesis initially seems to provide an attrattive ex-
days of withdrawal. White and Wang”” gave rats 5 planation of behavioral sensitization and enhanced
mg/kg of AMPH for 7 days. either daily or twice striata1 DA release in animals given repeated inter-
daily, and then withdrew them for one or 8 days be- mittent injections of AMPH, but it is not without
fore testing (Table VI). Both of these pretreatment problems. First. the electrophysiologicaì evidencc
rcgimens produce behavioral sensitization. In rats does not account for a number of critica1 features of
pretreated twice daily and withdrawn for 8 days. the behavioral sensitization. These include: (1) the be-
decrease in the ability of AMPH or AP0 to inhibit havioral and neurochemical effects persist for weeks
VTA unit discharge was only 50% of that observed to months and, at least in the VTA, the electrophys-
after one day of withdrawal. More importantly, in iological effects dissipate quickly-‘“: (2) behavioral
animals pretreated daily with AMPH there was no sensitization and enhanced striatal DA release art
 179

produced by a single injection of AMPH, but there is ily releasable pool, and a concomitant decline in the
no evidente for DA autoreceptor subsensitivity after size of the storage pool, there might be an en-
a single injection (Table VI); and (3) pretreatment hancement in AMPH-stimulated DA release without
with low doses of AMPH result in electrophysiologic- changes in overall DA concentrations.
al effects opposite those predicted by the DA autore- Another possibility is that the primary effect of
ceptor subsensitivity hypothesis’“3. Second. the bio- AMPH sensitization is on neurons afferent to striata1
chemical studies do not support the electrophysiolog- DA terminals, and these presynaptically facilitate
ical evidente for DA autoreceptor subsensitivity, DA release by hyperpolarizing DA terminals. This
and the pharmacologicalibehavioral studies are could also increase the rate of DAIAMPH transport.
equivocal. Third. AMPH-stimulated DA release in and thereby enhance AMPH-stimulated DA re-
vitro appears not to be modulated by presynaptic DA leasey’~““. TO date there is no evidente for such an
autoreceptors 173 It is concluded that the available hypothesis. But it is an intriguing one, especially
evidente does not provide strong support for the hy- since the sensitization to electric shock in Aplysia de-
pothesis that either behavioral sensitization or the scribed by Kandel and his colleagues is thought to be
enhanced striata1 DA release produced by repeated due to the facilitory effect of a hyperpolarizing pre-
intermittent AMPH treatment is caused solely by synaptic serotonergic input on subsequent transmit-
subsensitive DA autoreceptors. Of course, it is possi- ter release’“‘. It would be very interesting if a similar
ble that there is a cascade of cellular changes that mechanism was involved in the behavioral sensitiza-
leads to the enduring behavioral and neurochemical tion described here. There is only limited evidente
signs of sensitization. and that changes in DA autore- for changes in serotonergic activity in AMPH-sensi-
ceptors represent but one stage in this process. tized animals (e.g. ref. 281 and unpublished obser-
5.3.1.4. Other hypotheses. If subsensitive DA au- vations by the authors), and this requires further in-
toreceptors are not directly responsible for the en- vestigation. There is also very little known about the
during effects of sensitization, there must be other influente of serotonin on striata1 DA releasej15. and
ways that repeated intermittent AMPH treatment we know of no studies on the effects of serotonin spe-
produces an enhancement in AMPH-stimulated cifically on AMPH-stimulated striata1 DA release.
striata1 DA release”‘.“‘. These alternative hypoth- In conclusion. there is good evidente for changes
eses remain to be tested, but a couple deserve men- in the nigrostriatal DA system of sensitized animals.
tion here for the sake of completion. but considerably more work is required in even this
One possibility is that there is simply more DA most extensively studied system. Although it has
available for release in AMPH-sensitized animals. been shown that striata1 DA releaseiutilization is en-
This could occur, in the absence of changes in overall hanced following an AMPH challenge in sensitized
DA concentrations, if there was a shift in the distri- animals, the cellular basis of this effect is not known.
bution of DA between two hypothesized intracellular and its relationship to behavioral sensitization needs
‘pools’ of DA. It is thought that striata1 DA is distrib- to be further clarified. Furthermore, the nigrostriatal
uted in two functional pools within the presynaptic DA system is probably not the only brain DA system
terminal - a newly synthesized, readily releasable altered by the repeated intermittent administration
pool with a rapid turnover rate, and a storage pool of AMPI-I. Evidente for changes in other DA sys-
that turns over more slowlyy7~‘92. AMPH may stimu- tems is discussed next.
late DA release from the more readily releasable
pool, because the behavioral response to AMPH is 5.3.2. The mesolimbic and mesocortical dopamine
not depressed by depletion of vesicular DA stores systems
with reserpine, but the motor stimulant (and euphor- There are a number of reasons for suspecting that
ic) effects are depressed by synthesis inhibition with AMPH sensitization might alter mesolimbic or me-
a_methyl_p_tyrosine",~~~,'y~,2~9.313,
The fact that socortical DA systems. First, according to the cur-
AMPH-induced DA release is calcium-independent rent Zeitgeist it would be expected that any treat-
supports this idea 2y~260~3’x.
Therefore, if AMPH sensi- ment known to produce severe cognitive and affec-
tization produced an increase in the size of the read- tive disturbances in humans would also produce ab-
normalities in one or many limbic and cortical struc- tor binding (Table VII). It should be noted that in
tures. Second, there is indirect experimental evi- most of these studies extreme AMPH pretreatment
dente suggesting that mesolimbic or mesocortical regimens were used, and animals were withdrawn
DA systems are involved in behavioral sensitization. from AMPH far only one day’q.‘tt.tt”,l”j.:“7.“‘y. As
For example, Eichler and Antelman’” reported that previously mentioned, it is doubtful that this para-
electrical self-stimulation in mesolimbic or mesocor- digm provides information relevant to the neural ba-
tical pathways sensitized rats to a subsequent injec- sis of behavioral sensitization. As in the case of the
tion of AMPH. AMPH pretreatment also enhanced striaturn (Table II), it is concluded that there is no
electrical self-stimulation at media1 prefrontal cortex consistent evidente for changes in mesolimbic DA
sites236. Sega1 et al. 266found that 6-OHDA lesions of receptor binding in association with behavioral sensi-
the nucleus accumbens attenuated the development tization.
of behavioral sensitization, further implicating the In the two studies on DA receptor binding in the
mesolimbic DA system in sensitization’“. In spite of frontal cortex that were found. a decline in in vivo
this indirect evidente, there is not much direct evi- [3H]spiroperidol binding was reported in one’j’, and
dente for changes in either mesolimbic or mesocorti- no change in [“Hlspiperone binding in the otherh. It is
tal DA systems in animals repeatedly exposed to difficult to compare these studies because in the lat-
AMPH. This should not be taken to indicate that ter one the animals were challenged with AMPH 1 h
such changes do not exist, because it will become ob- prior to being killed. Obviously, there is not suffi-
vious in the following discussion that there have been cient evidente to draw any conclusions about
very few attempts to identify neural changes in these changes in mesocortical DA receptors in sensitized
structures using paradigms relevant to the phenome- animals. Nevertheless, the decrease in frontal cortex
non of behavioral sensitization. DA binding reported by Kaneno and Shimazono”” is
Studies on mesolimbic DA receptor binding in ani- interesting in relation to evidente that AMPH sensi-
mals pretreated with AMPH are equivoca1 (Table tization enhances frontal cortex DA utilization’“‘
VII). There are 4 reports of an increase, 3 of no (see below). This may be similar to the situation in
change and 5 of a decrease in mesolimbic DA recep- the striatum, where there appears to be a small

TABLE VII

‘The effect of amphetamine sensitization on mesolimbic (accumbens or accumbens plus tubercle) dopamine receptor binding

Abbreviations: as in previous Tables.

Referente Species Sex Drug Injection schedule Withdrawal- Ligand C‘ompetitor Bind-
period ing
.~~
Daiguji and Meltzer”’ Rat M D S+ lSmk2 xid x20d’ 17-20h [3H]spiroperidol ADTN Down
Hitzemann et al.“’ Rat F D 6mk2 xld x l-4d 16-20 h [3H]spiroperidol hutaclamoi or Down
sulperide
Kaneno andShimazono”9 Rat M M 6mkld x 14d 10 d [‘Hlspiroperidol in vivo’ Down
Robertson”” Rat M D lOmk2 x!d x 21 d 24-36 h [3H]spiroperidot domperidone Down
[‘H]ADTh’ dopamine Down

Akiyama et al.’ Rat M M 4mkid x 14d 7d [‘Hlspiperone ,ADTN NC

Howlett and Nahorski1’4 Rat M D 5- 15mk2 x/d x 20d’ 17-20h [‘Hlspiperone ” N(
Owen et al.2”4 Vervet M D 4-+12mWdx35d Id? [3H]spiperone butaclamol N<
and F

Akiyama et al.’ Rat M M 4mk/d x 14d 7d [3H]spiperone butaclamol L’P

Akiyama et aLh Rat M M 4mkld x 14d 7 -+ 4 mk 1h [3H]spiperone <@perone UP
prior to kill
Howlett and Nahorski’14 Rat M D 5+15mk2xld~4d 17-20h [3H]spiperone ! “P
Robertsonz3s Rat M D 5mkldx22d 2d [3H]spiroperidol ‘I UP
’ Also added 2.5+ 75 mg/ml to drinking water. * Cerebellum used to estimate non-specific activity.
 181

down-regulation of DA receptors in response to en- sensitized and contro1 animals (Table VIII). There
hanced DA release in sensitized animals. was a similar discrepancy between the reports of
Evidente that behavioral sensitization is accompa- Kuczenski and Leith”‘, who used D-AMPH. and Ni-
nied by presynaptic changes in mesolimbic DA struc- shikawa et al.““, who used meth-AMPH, in regards
tures is also quite limited (Table VIII). There is a striata1 DA utilization (Table V). In conclusion,
consensus that the steady-state concentrations of me- more work is required to determine if AMPH sensiti-
solimbic DA are not altered by repeated intermittent zation produces changes in mesolimbic DA activity.
injections of low doses of AMPH’67’183.202 (and un- They may very well occur, but are only apparent in
published studies by the authors), although sensi- female animals, or when sensitized animals are sub-
tized animals may show a greater decline in DA lev- sequently challenged with a stimulus that increases
els than contro1 animals when subsequently chal- dopaminergic activity (e.g. see the discussion of
lenged with meth-AMPH’“*. The only study to exam- opiate-DA interactions below).
ine mesolimbic tyrosine hydroxylase activity reports We are aware of only one report that repeated in-
no change in sensitized rats, suggesting mesolimbic termittent injections of AMPH produce enduring ef-
DA synthesis is not altered’O*. AMPH sensitization fects on DA neurons projecting to the neocortex
also does not seem to influente mesolimbic DA utili- (Table VIII). In two independent experiments, Rob-
zation under steady-state conditions, as indicated by inson et a1.2”3found an enduring enhancement in me-
DA metabolite levels’h7~‘83~202,or the rate of the de- dia1 prefrontal cortex DA utilization in OVX female
cline in DA after tyrosine hydroxylase inhibition”’ rats previously exposed to AMPH, as indicated by an
(Table VIII). However, Camp and Robinson”” have increase in the rate of decline of DA following tyro-
obtained preliminary evidente for enhanced nucleus sine hydroxylase inhibition. The significante of these
accumbens DA metabolite levels (utilization?) in enduring changes in mesocortical DA neurons to be-
sensitized female. but not male rats. When sensitized havioral sensitization, and how they are related to
rats were subsequently challenged with meth- similar changes in the striatum (Table V) will be ex-
AMPH, Nishikawa et al.“’ found that mesolimbic plored in future studies. Nevertheless. it is encourag-
DA utilization was enhanced, but in a similar study ing that there is enhanced frontal cortex DA utiliza-
Kuczenski and Leithi6’ found no differente between tion in this anima1 mode1 of AMPH psychosis. be-

TABLE VI11

The effecr of amphetamine sensirization on presynaptic indices of mesolimbic and mesocortical dopamine acfivity

Abbreviations: S, steady-state (resting) conditions; C, after a challenge injection of AMPH

Referente Strutture Injection schedule Withdrawal Condition Measure Effecr

period

Alloway and Rebec’ Accumbens 1-5 mk 2 xld- x 6 d Id s DA concentrations NC

Eichler et al.hy Accumbens 2-12 mkid x 65 d Id S DA concentrations NC
Kuczenski and Leithlh7 Mesolimbic 3 mk/d x 6 d 2d SorC DA concentrations NC
Lynch et al.“’ Amygdala 0.5+2mg/mUd x 14d l-7d s DA concentrations NC
Nishikawa et al.‘“’ Mesolimbic 6 mk/d x 14 d 15 d S DA concentrations NC
Nishikawa et al.‘“2 Mesolimbic 6 mkid x 14 d 15 d C DA concentrations Down

Alloway and Rebec’ Accumbens l-5 mk 2 xid x 6 d Id S DOPAC NC

Camp and Robinson (F)” Accumbens 2.6 mki4 d x 10 inj 8-13 d S DOPAC; HVA LJP
Kuczenski and Leith16’ Mesolimbic 3 mk/d x 6 d 2d SorC DOPAC; HVA NC
Lynch et al.“’ Amygdala 0.5-2 mgimlid x 14 d l-7d S DOPAC NC
Nishikawa et al.‘“’ Mesolimbic 6 mkid x 14 d 15 d S or C Tyrosine hydroxylase NC
Nishikawa et al.?“’ Mesolimbic 6 mkid x 14 d 15d S DOPAC; HVA; DOPACIDA NC
C DOPAC; DOPACIDA UP
Robinson et al,2’3 Accumbens 3 mkil-4 d x 7-9 inj S-10d S Decline in DA after MPT NC

Robinson et al.“’ Frontal cortex 3 mkil-4 d X 7-9 inj 8-10d S Decline in DA after MPT “P
182

cause dysfunction in the frontal lobe has been impli- tization to DALA, which is similar to the situation
cated in the manifestation of AMPH psychosis and following AMPH sensitization (Tables 111, V). Fur-
schizophrenia33,‘60~zo1,3~. thermore, animals sensitized by intra-VTA DALA
are hypersensitive to the motor stimulant effects of
5.3.3. Other neurotransmitter systems systemically administered AMPH or intra-VTA neu-
5.3.3.1. Opiate peptide-dopamine interactions. rotensin, effects thought to be mediated by mesotc-
Although the effects of repeated AMPH administra- lencephalic DA neurons. They are not hypersensi-
tion on brain opiate peptide systems have not re- tive to the motor stimulant effects of caffeine, which
ceived much attention there is accumulating evi- are thought to be non-dopaminergic’*‘. Kalivas””
dente that some of the enduring changes in behavior also presented evidente that neither changes in
produced by the repeated administration of opiates opioid nor postsynaptic DA receptors underlie intra-
may be mediated via changes in dopaminergic activ- VTA DALA-induced sensitization. It is concluded
ity. As with AMPH, tolerante develops to many of that both AMPH and opiate peptides may produce
morphine’s effects, but its motor stimulant effects are some of their enduring effects on behavior by altering
progressively enhanced upon repeated intermittent the presynaptic activity of mesotelencephalic DA
administration, either systemically*’ or into the ven- neurons.
tra1 tegmental area (VTA’**T~~~). The sensitizing ef- 5.3.3.2. Norepinephrine. The effects of repeated
fects of systemic morphine are also very persistent. intermittent injections of AMPH on indices of brain
lasting for months following withdrawa12”25. Mor- norepinephrine (NE) activity are summarized in
phine-induced sensitization of motor activity is prob- Table 1X. Some researchers have reported a smail
abiy due to morphine’s action on an endogenous mes- decline in brain NE concentrations after repeated
encephalic opiate system, because the daily adminis- AMPH adm i n i st rat i on ' . I8" , ~0~ , ~7~
, hut in al1 instances
tration of a peptidase-resistant enkephalin analog animals were treated at least twice a day, t’or ver-
(DALA; D-Ala*-D-Me?-enkephalinamide) into the long periods of time, and/or with relatively high
VTA also produces a progressive and enduring en- doses of AMPH. Certainly AMPH treatment regi-
hancement in the motor stimulant effects of a subse- mens that are toxic to DA neurons may also deplete
quent intra-VTA DALA challenge131. This DALA- NE”“~22”*29Y.When a less extreme treatment regimen
induced behavioral sensitization is blocked by nalox- is used, or when animals are withdrawn for a longer
one; and morphine or D-Ala”-D-Leu”-enkephalin, period of time, repeated AMPH administration does
but not dynorphin, partially substitute for DALA'j' not alter brain NE concentrati<)ns9.69.““,‘2’.“3 (and
On the basis of this evidente Kalivas et al.13’ have unpublished studies by the authors). There is alscr
suggested that delta or mu, but not kappa opiate re- little evidente for changes in NE synthesis or release
ceptors are probably involved in DALA-induced in AMPH sensitized rats”‘,“‘: although admittedly
sensitization. there has been insufficient effort LO identify such
Behavioral, eiectrophysiological and neurochem- changes. One exception comes fxom studies on the
ical studies suggest that some of the motor stimulant noradrenergic input to cerebellar Purkinje cells. So-
effects of opiates are due to opiate-DA interactions, renson et a1.Z7’ reported that SO days following with-
and therefore the sensitizing effects of opiates could drawal from repeated AMPH treatment the dis-
also be due to opiate-DA interactions (see refs. 129, charge rate of Purkinje cells was abnormally low, and
131 for references). In support of this, Kalivas’*” has disruption of the NE input to these cells from the lo-
shown that in animals sensitized by daily intra-VTA cus coeruleus partially reversed this effect”*. Fur-
DALA injections a subsequent challenge injection of thermore, cerebellar cortex 3-methoxy-4-hydroxy-
intra-VTA DALA produces a greater enhancement phenyl glycol (MHPG) concentrations were elevated
in nucleus accumbens DOPAC and HVA concentra- 10 days after withdrawal from AMPH, perhaps indi-
tions than in non-sensitized controls, and that this ef- cating enhanced NE release. MHPG levels had re-
fect persists for at least 7 days. Interestingly. the turned to contro1 levels by 30 days of withdrawal”‘.
steady-state concentrations of nucleus accumbens The authors concluded that sensitization to AMPH
DA, DOPAC and HVA are not influenced by sensi- enhances NE neurotransmission in the cerebellum.
 183

However, this cannot completely account for the ef- ratory), there is one intriguing report of altered sero-
fect on Purkinje cells because removal of the NE in- tonergic activity in AMPH-sensitized rats. Sparber
put only partially reversed the effect278. and Tilson2s1 reported that AMPH-stimulated
The evidente for enduring changes in NE recep- [“Hlserotonin release into the lateral ventricle was
tors is largely negative (Table 1X). For example, Ba- significantly enhanced in rats treated with 2.5 mg/kg
nerjee et al.24 reported an increase in [3H]DHA bind- of AMPH each day for S-12 days and withdrawn for
ing after 1-2 days of withdrawal, but norma1 levels of one day. In contro1 animals AMPH failed to stimu-
[3H]DHA binding by 4 days of withdrawal. late significant [3H]serotonin release.
5.3.3.3. Serotonin. Serotonin-containing neurons 5.3.3.4. Amino acids. It has been suggested that
modulate both brain DA activity and the behavioral glutamate release is decreased in schizophrenics’4y,
effects of stimulant drugs, and therefore could be in- and therefore the effects of sensitization on amino
volved in the development of behavioral sensitiza- acid transmitters is of interest. The repeated inter-
tion. However, there is very little direct evidente for mittent administration of meth-AMPH (4 mg/kg
changes in serotonergic systems in AMPH-sensitized daily for 14 days) did reduce [3H]kainic acid binding
animals. Again, this may be due to insufficient effort in rat cerebral cortex, when measured 8 days after
to identify such changes. Although steady-state brain the last AMPH treatment. This suggests a reduction
5hydroxytryptophan activity and serotonin concen- in glutamate receptors 143 Unfortunately, it is diffi-
trations are not influenced by the repeated intermit- cult to assess how relevant studies on presynaptic in-
tent administration of non-toxic doses of dices of amino acid transmitter function are to behav-
AMPH’~‘y~“8~7y”(and unpublished studies in this labo- ioral sensitization, because in two studies animals

TABLE 1X

The qfyect ofamphetamine sensitization on indices ofbrain norepinephrine activitv

Abhreviations: as in orevious Tables. NE, norepinephrine; ctx, cortex; .. .

hpc, hippocampus, ot., olfactory tubercle: cAMP, cyclic
AMP: MHPG. 3 methoxy,4-hydroxy-phenyl-glycol. .

Referente Injection schedule Withdrawal Measure Effect

period

Alloway and Rebec’ striatum 5mk2xldx6d Id NE concentrations Down

Alloway and Rebec’ striatum lmk2xidx6d Id NE concentrations NC
Eichler et al.h’ neocortex 2-4 mkid x 65 d Id NE concentrations NC
Eichler et al.h” neocortex S-12mkid x 65d Id NE concentrations Down
Herman et al.“‘” cerebellum 3mk/dx9mo 3d NE concentrations Down
Herman et al.“” ctx. striatum, thalamus 3mk/dx9mo 1-3d NE concentrations NC
Jackson et al.“’ whole brain, minus cerebellum 5 mk/d x 25 d ld NE concentrations NC
Lynch et al.“’ hpc, striatum, brainstem O.S-+2mg/ml x l4d ?d NE concentrations Down
Lynch et al.‘X’ ot., amygdala, midbrain 0.5 -t 2 mgiml x 14 d 7d NE concentrations NC
Pearl and Seiden”” whole brain 2.5 mk/d x 60 d Id NE concentrations Down
Riffee and Gerald”‘ whole brain 2.5 mk/d x 7 d l-2d NE concentrations NC
Short ‘,md Shuster”’ whole brain lOmk2xidxSd 3-25 d’ NE concentrations Down

Jackson et il.” whole brain, minus cerebellum 5 mk/d x 25 d 7d NE decline after MPT NC
Sorenaen ei al,“’ cerebellum 2 mkid x 21 d IO d MHPG concentrations “P
Sorensen et al.‘7h cerebellum 2 mkid x 21 d 30 d MHPG concentrations NC
Sparber and Tilsor?’ perfuse lateral ventricle 2.5 mkid x X-12 d Id [~H]NE release NC

Banerjee ct al.” whole brain, minus cerebellum 10 mkid x 6 wk 3d 13H]DHA binding’ NC

Banerjee et al.zJ whole brain, minus cerebellum 10 mkid x 6 wk l-2 d [‘H]DHA binding’ “P
Chanda et al.‘h whole brain, minus cerebellum 10 mk/d x 6 wk 4d NE stimulated cAMP NC
Chanda et aI.Jh whole brain, minus cerebellum 10 mkid x 6 wk 4d [‘H]DHA binding’ NC
Howlett and Nahorski”’ striatum. limbic forebrain S+lSmk2x/dx4-20d’ Id [lH]DHA binding? NC
’ NE concentrations steadily increasing to near norma1 by 25 d. ’ Additional AMPH added to drinking water. ‘DHA = dihydroalpre-
nol. displaced with NE.
184

were not withdrawn from AMPH for even one tized animals is not known. A number of possibilities
day 148,163,and in the other AMPH was provided con- are schematically illustrated in Fig. 2B. One possibil-
tinuously in the drinking waterls4. ity is that the autoreceptors regulating DA release or
discharge rate are subsensitive (‘3’). However, as
5.4. The neural basis of behavioral sensitization: con- discussed above, the available evidente for autore-
clusions and a hypothesis ceptor subsensitivity is equivocai, and fails to account
for many of the characteristics of behavioral sensiti-
Despite many attempts to identify an enduring zation and the persistente of enhanced DA release.
neural change associated with repeated intermittent Other possibilities include presynaptie facilitation by
AMPH administration perusal of Tables I-1X re- hyperpolarization of the DA terminal via a presynap-
veals that the neural basis of behavioral sensitization tic input (‘4’), or a shift in the distribution of DA from
has not been thoroughly characterized. Neverthe- a ‘storage pool’ to a more readily releasable pool
less, the available evidente does provide some prom- (‘5’). There is no evidente for a change in tota1 DA
ising leads. The section of this review on ‘neural hy- concentrations, at least during the resting state (note
potheses’ began with two questions: (1) what is the that the number of DA ‘molecules’ illustrated in Fig.
locus of the neural change(s) underlying behavioral 2A and B is the same), or in DA synthesis rate (‘6’).
sensitization; and (2) what is the nature of the Future research on the nature of presynaptic changes
change(s)? In answer to the first question, there is in mesotelencephalic DA systems, and on changes in
sufficient evidente to conclude that repeated inter- other neurotransmitter systems that influente dopa-
mittent exposure to AMPH alters mesotelencephalic minergic activity will be required to further elucidate
DA systems. Of course. other neural systems are the neural basis of behavioral sensitization. In partic-
probably involved as well, but only DA systems have ular. it will be important in future studies to try and
been studied in any detail. In answer to the second relate changes in specific neural systems (e,g. the
question, we propose that behavioral sensitization to mesolimbic, mesocortical or nigrostriatal DA sys-
AMPH is at least partly due to presynaptic changes tems) to changes in specific behaviors (e.g. locomo-
characterized by enhanced DA release. tion. the various components of stereotypy. rotation-
Fig. 2 schematically illustrates some of the changes al behavior).
in brain DA neurons that could occur following the One fina1 point to be made here concerns the ambi-
repeated intermittent administration of AMPH. Fig. guity created in the literature whcn studies involving
2A illustrates the release of DA induced by AMPH in neurotoxic AMPH treatment regimens are cited as
an anima1 exposed to AMPH for the first time. Note being relevant to the neural basis of behavioral sensi-
that DA release can be modulated by autoreceptors tization. and vice versa. This should be avoided.
on the presynaptic terminal (autoreceptors on the Some of the problem is simply because the same
ce11body and dendrites are not illustrated), andior by terms are frequently used to refer to different phe-
a presynaptic hyperpolarizing input (indicated by nomena. For example, the phrase repeated AMPH
‘-‘). Fig. 2B illustrates the same terminal after the an- administration’ is used to refer to both: (1) treatment
ima1 has been repeatedly and intermittently exposed paradigms in which very high doses are repeatedly
to AMPH, and then after a withdrawal period (weeks given. which in effect continuously elevates brain
to month later) is again challenged with AMPH. It is concentrations of AMPH and produces neurotoxici-
known that there is an enhanced behavioral response ty; and (2) paradigms retevant to hehavioral sensiti-
to this challenge injection of AMPH, and the best ev- zation, in which repeated but intermittent injections
idence available to date suggests it is due to enhanced of non-toxic low doses are used. lt is suggested that
DA release (item no. 1 on Fig. 2B). There is no con- individua1 researchers make a greater effort to iden-
vincing evidente for changes in postsynaptic DA re- tify whether the paradigm they use is more relevant
ceptors (indicated by ‘2’ on Fig. 2B), except perhaps to the ‘AMPH neurotoxicity syndrome’, or the phe-
a small down-regulation that we propose is secondary nomenon of behavioral sensitization; and to be care-
to enhanced DA release. The nature of the cellular fu1 about citing evidente relevant to only one phe-
change underlying enhanced DA release in sensi- nomenon as being relevant to the other.
 185

A NORMAL B SENSITIZED hances many of the centra1 and behavioral conse-

quences of subsequent stressJ~‘3.‘J~‘7.44.~K~.
Of direct
relevance to the behavioral sensitization produced by
stimulants is evidente that daily injections of cocaine
produce a progressive enhancement in plasma nor-
epinephrine (NE) and epinephrine concentra-
tions’“‘, and in particular that repeated exposure to
stress sensitizes brain DA systems’x~“‘“~“h. It has
even been suggested that some of the enduring ef-
fects of stimulant drugs on brain and behavior are
Fig. 2. A schematic illustration of possible changes in dopa- due to their action as stressors’7.‘9.“‘.
minergic neurons following the repeated intermittent adminis-
Much of the evidente for an association between
tration of amphetamine. A: an illustration of the release of DA
from a dopamine terminal the first time it is exposed to amphet- AMPH sensitization and sensitization to stress comes
amine. The black dots represent DA ‘molecules’ that are local- from a series of experiments by Antelman and his
ized either in a ‘storage pool’ (enclosed circles), or a more colleagues, who studied the effect of a variety of
‘readily releasable pool’ (freely distributed in the cytoplasm).
Postsynaptic DA receptors are black, presynaptic autorecep- stressors on the stereotyped behavior produced by a
tors are white and a presynaptic receptor receiving a hyperpo- subsequent injection of AMPH (for review see ref.
larizing input from another cell is striped. B: an illustration of 17). Exposure to stressors such as tail pinch, food
the same terminal after the anima1 has been sensitized to am-
phetamine. It is known that there is an enhanced behavioral re- deprivation or footshock ali enhance the stereotypy
sponse to amphetamine in a sensitized animal, and it is sug- (or polydipsia) produced by an injection of AMPH
gested that this is due to enhanced DA release (item no. 1). given weeks 1ater”~“~‘“~‘“. Studies by other research-
Numbers 2-6 illustrate other possible changes. including
changes in postsynaptic receptors (2), presynaptic autorecep- ers have subsequently shown that immobilization or
tors (3). a hyperpolarizing presynaptic input (4), the intracellu- footshock stress also produce an enduring en-
lar distribution of DA (5), or DA synthesis (6). See the text for hancement in AMPH-induced locomotion’“x and ro-
a discussion of each of these possibilities.
tational behavior’“’ (see also ref. 105).
Not only does previous exposure to stress enhance
6. GENERALIZABILITY OF SENSITIZATION AMPH-induced behavior, but previous exposure to
AMPH may influente the effects of subsequent
6.1. Stimulants and stress stress. For example, Antelman et al.” reported that
rats previously exposed to AMPH are more sensitive
Thus far behavioral sensitization has been de- to the activational effects of tail pinch. The effects of
scribed as a special kind of behavioral plasticity, footshock stress on indices of brain DA activity are
where a relatively short-term pharmacological ma- also altered by sensitization to AMPH (unpublished
nipulation (exposure to AMPH) produces a very studies by the authors). Mild footshock stress is
long-lasting change in the response induced by subse- known to enhance DA utilization in a number of
quent exposure to the same stimulus. However, it is brain regions, as indicated by increased DOPAC
worth noting at this time that behavioral sensitization concentrations, or DOPAC to DA ratios’74.“7 (cf.
is not unique to the psychopharmacology of psycho- ref. 291). We have found that 5 min of mild footshock
motor stimulant drugs, but can be produced by non- produces a greater elevation in the ratio of DOPAC
pharmacologic environmental stimuli as well. For ex- to DA in the media1 prefrontal cortex and hypothala-
ample, there are many studies showing that repeated mus of sensitized female rats than in saline-injected
intermittent stress can sensitize the hypothalamo-pi- or non-handled contro1 animals, perhaps due to en-
tuitary-adrenal (HPA) axis. Daily immobilization or hanced DA release (unpublished studies). Thus, it
footshock stress produces a dramatic and progressive appears that AMPH and stress may be to some extent
increase in plasma corticosterone concentra- interchangeable in producing sensitization.
tions’06.2R”. and in adrenal tyrosine hydroxylase and Evidente that sensitization to stress may involve
phenylethanolamine-N-methyl-transferase activity enduring changes in mesotelencephalic DA systems
(PNMT”‘). Repeated intermittent stress also en- is also suggested by recent studies by Kalivas et al. ‘x’
1X6

on the effects of intra-VTA injections of the enkeph- release of ACTH to a 3 min ‘psychological’ stress is
alin analog, DALA. When injected into the VTA. also greater in femalc than in malr ratsI’*.
DALA produces hyperactivity. an effect that i\ These sex differenccs may be related to the cffects
thought to be due to the DALA-induced release of of gonadal hormones on bra’n 1>A activity and the
DA in the nucleus accumbens’“‘. Furthermore. the HPA axis. Gonadal hormones ;u-c known to mod-
repeated intermittent administration of DALA pro- ulate striatal and hypothalamic I>A releasr and re-
duces a progressive sensitization of motor activity. ceptors in ;I sexually dimorphic manner’“,“‘.’ “‘.““.
and this is accompanied by sensitization of mesolim- and male and female gonadal hormones different’al-
hic DA Int erestingly. expo- Iy cffect the HPA axis. For cxamplc. Kita!“-“” has
sure mild footshock also sensitizes shown that ovariectomv (0V.X) decreasrs both the
to the stimulant effects intra-VTA DALA. pituitary secretion of ACTH and plasma corticostcr-
animals sensitized DALA show exagger- one”. prcsumably due to a reduct’on in ACTH syn-
ated response to stress”” thesis and the sensitivity of the pituitary to corticotro-
In there is cvidence to pin-releasing factor (C’RF). In sharp contrast. castra-
gest that repeated intermittent to either tion (CAST) of male rats increases plasma ACTH at
or environmental that attivate rcst or aftcr stress. and this is rekersed by testoster-
DA systems produce enduring in one replacement“.‘5”. Kitay”” ha> suggested that en-
DA and that changes are dogenous gonadal hormones in males and females in-
ized by to stimuli subsequent- tluence HPA activity in an opposing fashion.
ly brain DA (b) Chronic cffects. As discussed abovc. fcmalcs
show much more robust sensitization to repeated in-
6.2. Sex differences, stimulants and stress termittent injections of AMPH than males. and this i\
not affected hy 0VX’4”.L4J. In contrast. CAST male\
It was mentioned above that there are robust sex show greater sensitization tc) IIMPH than intact
differences in the sensitization to AMPH. If sensiti- malcs and art comparable to fcmales. We know cit
zation to AMPH and stress are to some extent inter- only onc study on sex diffcrencek in the responso ot
changeable, as just suggested. it follows that there the HPA axis to repeated interm’ttent stress. but the
should also be sex differences in the sensitization to similarity to the pattern of >cx d’ffercnccs seen with
stress. Although the evidente is limited. a review of AMPH sensitization is striking”“’
the literature reveals that there are remarkably simi- Hennessy el al. ““’ (ser far rev1c.w re!‘. 107) show&
lar sex differences in both the acute and chronic cf- that in gonadally intact femalr m’ce the plasma corti-
fects of AMPH and stress. costerone response to footshock stress is sensitizcd
(a) Acute effects. Female rats show a much greater by daily footshock sessions. OVX produced a general
behavioral response to an acute injection of AMPH decline in the circulating levels ot corticosteronc in
than males. as indicated by measures of locomotor all groups. but OVX rats stili showed a clear sensiti-
activity IxxYstereotyped activity” or rotational behav- zation of the corticosterone rrsponse with repeatecl
i <)~71 . 3h . ~44 . ?45 .
This sex differente in AMPH-induced stress. In contrast. gonadallv intact male micc did no{
behavior is not due to sex differences in the metaho- sensitize to repeated stress. That 1s. in intact male>
lism of AMPH1O’~‘U~‘Xy. because it persists when the elevation in plasma corticostc‘ronc was the samc
males are given considerably higher systemic doses after the 10th shock session as ir was after the first.
of AMPH than femalesJ6. or when doses are titrated On the other hand, CAST male m’cc did show scnsl-
SO males and females have equivalent brain levels of tization. having significantly higher plasma cortico-
AMPH”.4”. There is a similar sex differente in the sterone levels after the 10th than after the first shock
response of the HPA axis to acute stress. Female rats session”h.
show a much greater and more persistent elevation of In summary. the available evidente suggests that:
plasma corticosterone than males in response to (1) females show more robust sensitization in rc-
either immobilization, footshock or forced running spanse to repeated AMPH or stress than do malcs:
stress’“‘.‘“‘. or to a direct injection of ACTH”‘. The (2) removal of the ovaries has no (or little) effect on
 1x7

the sensitization produced by repeated AMPH or neurochemical alterations. Perhaps with the devel-
stress; and (3) removal of the testes enhances the de- opment of new non-invasive techniques for imaging
velopment of sensitization to both repeated AMPH neural activity in humans (e.g. PET, NMR) some of
or stress. It is therefore possible that a testicular hor- these issues will be resolved. Nevertheless, it is inter-
mone directly or indirectly retards the development esting to note in this regard that plasma HVA levels
of enduring changes in brain and behavior produced are elevated in schizophrenics. There is also a strong
by the repeated intermittent application of either positive correlation between the severity of the psy-
AMPH or stress. chosis and HVA levelsh’,“‘X (see also ref. 295), and
the reduction in psychosis produced by neuroleptic
7. CONCLUSIONS treatment is correlated with a reduction in plasma
HVA 1evels’“s. Enhanced plasma HVA levels could
In conclusion, we agree with previous suggestions be due to elevated levels of DA release, but unfortu-
that the hyperdopaminergic state and resultant nately there are many other possible explanations for
changes in behavior produced by an acute injection these results (e.g. ref. 47).
of moderate to high doses of AMPH provides a rea- There is growing evidente to support the sugges-
sonable mode1 of some changes in brain and behavior tion that sensitization is not unique to the psycho-
associated with some forms of schizophrenia’“‘, pharmacology of stimulant drugs”~‘“~“‘, but can be
“y.Z1”,lM. That is, amphetamine psychosis, and possi- produced by any stimulus that greatly increases brain
bly paranoid schizophrenia, are associated with, catecholamine activity, including environmental
‘high concentrations of DA at the synapse’“” (p. stimuli. For example, we discussed evidente that the
216). Lower doses of AMPH do not usually produce repeated administration of AMPH, an enkephalin
the perseverative stereotyped behavior SO similar to analog or stress al1 sensitize brain DA systems. It re-
that seen in AMPH psychosis and schizophrenia. mains to be determined if the sensitization produced
However. when low doses of AMPH are repeatedly by different agents has the same cellular basis, but
and intermittently administered they also come to thus far the sensitization produced by AMPH and
produce high DA concentrations at the synapse, stress seems to be quite interchangeable. Animals
which we propose is due to a progressive en- that have been previously exposed to AMPH or
hancement in DA release. This enhancement in DA stress often show an exaggerated response when sub-
release is manifested as behavioral sensitization in sequently challenged with an injection of AMPH, or
non-human animals and AMPH psychosis in hu- further stress. In fact, it may be that sensitized ani-
mans. Furthermore, in individuals sensitized to mais are hyperresponsive to any stimulus that activates
AMPH other stimmi (e.g. stressors), that do not nor- brain catecholamine systems, and that the effects of
mally cause a large release of DA, may come to do sensitization are not obvious in the absence of such
SO, thereby also producing symptoms associated with stimuli. This may help explain why psychosis only
psychotic disorders. tends to recur in former AMPH addicts following re-
It will require considerably more research with exposure to AMPH or exposure to ‘physical or psy-
new techniques to establish whether schizophrenia chological stress’“‘?. and why stress is considered a
and AMPH psychosis are accompanied by enhanced precipitating agent in psychiatric disorders thought
DA release. The fact that the neurochemical effects to involve brain catecholamine dysfunction’“~‘7~1x~
39 . 63 . 103 . 210
of sensitization have been difficult to identify under
steady-state conditions, but are often apparent only Lastly, it should be noted that there is great indi-
following a ‘challenge’ to the system, may help ex- vidual variation in the susceptability to sensitization.
plain why evidente for presynaptic changes in schizo- just as there is in the acute effects of stimulants and
st reSS12 . 42 . 99 . 191 , 221
phrenics has been to elusive’“3.30h. Not only is it diffi-
cuh to obtain valid measures of presynaptic activity I t was discussed how sex-related hormonal varia-
in human subjects, but matters are further comph- bles may influente the development of sensitization
cated because it may be necessary to ‘challenge’ sub- to AMPH or stress, and some researchers have be-
jects just prior to analysis in order to easily detect gun to explore genetic influences”‘,“‘,““. But for the
188

most part, factors that account for individua1 varia- cused on mesotelencephalic DA systems. and sug-
tion in the responsiveness to stimulants and stress gestions that behavioral sensitization is accompanied
have received very little attention. Increased knowl- by: (1) an increase in postsynaptic DA receptors; (2)
edge of these will be important in understanding the an increase in DA synthesis; (3) an increase in DA
etiology of stimulant-induced psychosis and the ma- utilization and/or release; and (4) u decrease in DA
jor endogenous psychoses, especially given the com- autoreceptors. are cvaluated. Ir is concluded that
plex interplay between environmental and biologica1 there is not convincing evidente far an increase in
variables in the development of psychoses’~.‘x,99.“h. postsynaptic DA receptors or m DA synthesis in am-
Research on how genetic, hormonal and environ- mals sensitized to AMPH. In contrast. there is strong
menta1 factors influente sensitization to stimulants evidente to support the notion that behavioral sensi-
and stress will be valuable in this regard. tization is due to enhanced mesotclencephalic DA
release, especially upon re-exposure to the drug. The
8. SUMMARY evidente that this enhancement in DA release is due
to autoreceptor subsensitivity was found to be equiv-
Some people who repeatedly use stimulant drugs. ocal, and therefore other hypotheses should be cn-
such as amphetamine (AMPH), develop an AMPH- tertained.
induced psychosis that is similar to paranoid schizo- Lastly. evidente is discussed in support of the idea
phrenia. There has been, therefore, considerable in- that behavioral sensitization is not unique to the ps’-
terest in characterizing the effects of chronic stimu- chopharmacology of stimulant drugs. but may he
lant drug treatment on brain and behavior in non-hu- produced by many environmental stimuli that direct-
man animals, and in developing an anima1 mode1 of ly or indirectly attivate brain catecholaminc systcms.
AMPH psychosis. A review of this literature shows For example. there are many studies showing that
that in non-human animals chronic AMPH treatment AMPH and stress are to some extent interchange-
can produce at least two different syndromes. and able in producing both behavioral sensitization and
both of these have been proposed as anima1 models long-term changes in brain DA sysrcms. 11 is con-
of AMPH psychosis. The first syndrome is called cluded that sensitized animals may hc hypcrrespon-
‘AMPH neurotoxicity’. and is produced by maintain- sive to any stimulus that activates brain catechola-
ing elevated brain concentrations of AMPH for pro- mine systems. and that the effects ofsensitization are
longed periods of time. AMPH neurotoxicity is char- not obvious in the absence of such stimuli. This ma>
acterized by what has been termed ‘hallucinatory- be related to the fact that psychosis only tends to re-
like’ behavior, which occurs in association with brain cur in former AMPH addicts following re-cxposurc
damage resulting in the depletion of striatal DA and to AMPH or stress. and that stress i> considered :I
other brain monoamines. The second syndrome ilr precipitating factor in psychiatric disorders thought
called ‘behavioral sensitization’. and is produced by to involve brain catecholamine dysfunction.
the repeated infermittent administration of lower
doses of AMPH. Behavioral sensitization is charac-
terized by a progressive and enduring enhancement ACKNOWI.EDGEMENl-S

in many AMPH-induced behaviors. and is not ac-

companied by brain damage or monoamine deple-
tion. It is argued that the changes in the brain and bc-
havior associated with the phenomenon of behavior-
al sensitization provide a better ‘model’ of AMPH
psychosis than those associated with AMPH neuro-
toxicity.
Much of the review involves a critica1 analysis of
hypotheses regarding the biologica1 basis of behav-
ioral sensitization. Research on this question has fo-
Research hy the authors descrihed herein was
partly supported by grant no. 37377 from the NIMH
and Research Career Development Award no. 00844
from the NINCDS to T.E.R. We thank E. Castane-
da. M. Washburn. an anonymous reviewer. and cs-
pecially I.Q. Whishaw for their vcry helpful com-
ments on an earlier version of the manuscript. Kathr
Davids deserves thanks for her paticnt secretarial
services.
 189

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