Neuroscience and Biobehavioral Reviews 27 (2004) 693701

www.elsevier.com/locate/neubiorev

Review

LSD, 5-HT (serotonin), and the evolution of a behavioral assay

James B. Appela,*, William B. Westa, James Buggyb
a
Behavioral Pharmacology Laboratory, Department of Psychology, University of South Carolina, 1512 Pendleton Street, Columbia, SC 29208, USA
b
Department of Pharmacology and Physiology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA

Abstract
Research in our laboratory, supported by NIDA and facilitated by Roger Brown, has indicated that serotonergic neuronal systems are
involved in the discriminative stimulus effects of LSD. However, the only compounds that fully antagonize the LSD cue act at both serotonin
(5-HT) and dopamine (DA) receptors. In addition, substitution for LSD in standard drug vs. no-drug (DND) discriminations does not
necessarily predict either similar mechanisms of action or hallucinogenic potency because false positives occur when animals are given
drugs such as lisuride (LHM), quipazine, or, possibly, yohimbine. These effects can be greatly reduced by using drug vs. drug (D D), drug
vs. drug vs. no drug (D ND), or drug vs. other drug (saline, cocaine, pentobarbital) training procedures. Additional studies, in which drugs
were administered directly into the cerebral ventricles or specific brain areas, suggest that structures containing terminal fields of serotonergic
neurons might be involved in the stimulus effects of LSD.
q 2003 Elsevier Ltd. All rights reserved.
Keywords: LSD; Serotonin (5-HT); Lisuride (LHM); Drug discrimination; Rats

Contents
1. Antagonism of the LSD cue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
2. False positives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
3. Neuroanatomical substrates of the LSD cue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700

Not long before Roger Brown became Chief of the
Neuroscience Research Branch at NIDA, we argued that
drug discrimination is a reliable, robust, sensitive, and
selective behavioral assay, which has been used with
considerable success to analyze the mechanism(s) of action
underlying the subjective effects of hallucinogenic drugs
[1]. This argument was based on the results of many
experiments conducted in our own and other laboratories
involving two-lever, drug vs. no-drug (D ND) or, in one
case, drug vs. drug (D D) discrimination procedures; that
is, situations in which animals were trained to press one
lever after receiving a systemic (i.p.) injection of a training
drug such as LSD and a second lever, after a control
injection of saline vehicle (0.9% NaCl) or another
psychoactive substance such as the LSD congener, lisuride
hydrogen maleate (LHM). Substitution (generalization),
combination (antagonism) and various kinds of pre-treat-
* Corresponding author. Tel.: 1-803-777-2685; fax: 1-803-777-9558.
E-mail address: appel@sc.edu (J.B. Appel).
0149-7634/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2003.11.012
ment tests following such training indicated that: (1) the
assay is very sensitive in the sense that doses as low as
0.0025 mg/kg of LSD can be discriminated from saline; (2)
all compounds known to cause hallucinations at relatively
low doses (in humans) and act primarily, if not exclusively,
through serotonergic mechanisms appear to have LSD-like
effects (in rats) and, (3) both drugs and physiological
interventions that alter the functional activity of serotoner-
gic neuronal systems can either mimic or, when given in
combination with LSD, antagonize the LSD cue [1]. (4)
Substances that act through other monoaminergic neuronal
systems (e.g. dopaminergic systems) do not alter the
stimulus properties of LSD either when they are given
alone or in combination with LSD.
Since 1983, we continued to use drug discrimination to
study the mechanisms of action of LSD and several other
abused substances including cocaine, MDA, MDMA, PCP,
and marihuana (D9-THC) with the support of NIDA
(USPHS Research Grants R01 DA02543 and R37
DA02543) and the active encouragement and assistance of
694 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701

Roger Brown. This is largely because of at least two major

problems, the first of which concerns the occurrence of
socalled false positives [2 4] and the second is that
putatively site-selective serotonin (5-HT) antagonists (5-
HT1, 5-HT2, 5-HT3) do not appear to block the LSD cue as
well as substances that act at both 5-HT and dopamine (DA)
receptor sites [5 7]. We will discuss the antagonism
problem first because the methods used to study it are
probably more familiar in that they involved standard, two
lever (D ND) discrimination training [8]. We will then
discuss some more complex procedures we have been using
to analyze the false positive problem and will conclude by
reviewing an experiment in which test drugs were injected
directly into the cerebral ventricles (i.c.v.t.) or specific areas
of the brain (i.c.) thought to contain relatively high
concentrations of serotonergic neurons.

1. Antagonism of the LSD cue

When a variety of 5-HT antagonists were given 1-h
before the training dose of LSD to rats trained to
discriminate LSD (0.08 mg/kg, i.p.) from saline, Fig. 1
shows that methiothepin blocked the stimulus effects of
LSD cue completely (20% of control), according to criteria
suggested by Appel et al. [1]. The structural congeners of
LSD, BOL and methysergide (UML) blocked the LSD cue
partially (30% of control) as did another centrally acting
5-HT antagonist, cyproheptadine; the peripherally acting
5-HT antagonist xylamidine had no effect at any dose tested.
Even more impressive results were obtained with more
recently synthesized 5-HT antagonists (Fig. 2), particularly
those developed and studied extensively at Janssen
Pharmaceutica in Belgium [5,6]. Both pirenpirone and
ritanserin blocked the LSD (0.08 mg/kg) cue completely
Fig. 2. Effects of six more recently developed 5-HT receptor antagonists
given i.p. 1-h prior to LSD in rats trained to discriminate LSD (0.08 mg/kg,
i.p.) from saline.
and dose dependently; metergoline, Ly 53857, and pizotifen
(BC 105), blocked the cue partially.
The situation was complicated when, in an effort to
determine the 5-HT receptor subtype most involved in the
stimulus effects of LSD, we gave site-selective antagonists
in combination with LSD to animals trained to discriminate
LSD from saline [7]. Fig. 3 shows that the putative 5-HT2
antagonists SR 46349B and LY 237733 blocked the cue
only partially (40 50%) and that neither the 5-HT1
antagonist WAY 100635 nor the 5-HT3 antagonist MDL

Fig. 3. Effects of putatively site-selective 5-HT receptor subtype

Fig. 1. Effects of six putative 5-HT antagonists given i.p. 1-h prior to LSD antagonists given i.p. 1-h prior to LSD in rats trained to discriminate
in rats trained to discriminate LSD (0.08 mg/kg, i.p.) from saline. LSD (0.08 mg/kg, i.p.) from saline.
 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701 695

Fig. 4. Effects of four DA antagonists given i.p. 1 h prior to LSD in rats

trained to discriminate LSD (0.08 mg/kg, i.p.) from saline.

72222 had any effect at all. Assuming that sufficient

amounts of these compounds reached the brain following
their systemic (i.p.) administration, the data do not support
Fig. 5. False positives. Three drugs, which are not hallucinogenic (in
the idea that activity at any of these receptor sites is humans) substitute completely (lisuride, quipazine) or partially (yohim-
critically or uniquely involved in the LSD cue; however, bine) for LSD in rats trained to discriminate LSD (0.08 mg/kg, i.p.) from
they do reinforce the hypothesis that activity at 5-HT2 is saline.
more important than activity at either 5-HT1 or 5-HT3
receptor subtypes [8,9]. them in a two-lever, D D (LSD LHM) situation [11 13].
While it is certainly possible that other monoaminergic However, systematic manipulation of agonists and antag-
systems in addition to 5-HT play a role in the behavioral and onists in both LSD- and LHM-trained animals is time-
subjective effects of LSD, it is clear from Fig. 3 that, in consuming and the two-lever D D procedure has some
contrast to compounds that have affinity for both 5-HT and important disadvantages: (1) it requires a prolonged training
DA receptors (Fig. 2), drugs that act primarily by blocking period during which active substances must be injected
DA receptors do not alter the LSD cue (Fig. 4). almost every day and, (2) it can result in relatively flat
generalization gradients when dissimilar drugs are tested
[14,15]. We therefore trained a single group of animals to
discriminate both LSD (0.08 mg/kg) and LHM (0.04 mg/
2. False positives
kg) from saline in a three-lever, D D ND procedure,
which, because it combines D ND and D D procedures,
The problem of false positives arises when drugs, might have some of the advantages of both [16,17].
which are not known to be hallucinogenic or may not act Fig. 7 shows the results of dose-response tests with the
primarily through serotonergic mechanisms, substitute for two training drugs. When animals were given LSD
LSD (Fig. 5). Such effects are important because they cast (left panel), they responded in a dose-related fashion on
doubt on the hypotheses that substitution for LSD predicts
hallucinogenic potency in humans, similarity in neuronal or
receptor mechanisms, or both [1,4,10]. We therefore
devoted a considerable amount of time and effort to
comparing the stimulus effects of LSD to those of perhaps
the most interesting false positive, the LSD congener
lisuride (LHM; Fig. 6).
In a series of experiments conducted by F. J. White in our
laboratory, it was possible to demonstrate that LSD and
LHM could be differentiated either by extensive treatment
with both 5-HT and DA agonists and antagonists in standard
D ND situations (LSD-saline and LHM-saline discrimi- Fig. 6. Structures of LSD and its non-hallucinogenic congener, lisuride
nations) or by training animals to discriminate between hydrogen maleate (LHM).
696 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701
Fig. 7. Results of dose-response tests with LSD, lisuride (LHM) and saline
in rats trained to discriminate LSD (0.08 mg/kg, i.p.) from LHM
(0.04 mg/kg, i.p.) and saline in a three-lever (D D ND) drug discrimi-
nation task. (Reprinted from [16, p. 15], with the permission of Springer-
Verlag).
the LSD-appropriate lever; interestingly, most mistakes
occurred on the saline-appropriate lever, suggesting that
the stimulus effects of LSD are more similar to those of
saline (ND) than they are to those of LHM. When the same
animals were tested with LHM (right panel), they
responded on the LHM-appropriate lever in a dose-related
manner; once again, mistakes occurred predominantly on
the saline-appropriate lever.
During substitution tests with the DA agonist apomor-
phine, responding occurred on the LHM-appropriate lever
Fig. 8. Results of substitution tests with apomorphine, quipazine and pentelene tetrazol (PTZ) in rats trained to discriminate LSD (0.08 mg/kg, i.p.) from LHM
(0.04 mg/kg, i.p.) and saline in a three-lever (D D ND) drug discrimination task. (Reprinted from [16, p.15], with the permission of Springer-Verlag).
(Fig. 8); very little responding occurred on the LSD lever.
Similar tests with quipazine, a 5-HT agonist, engendered
responding on the LSD-, but not the LHM-appropriate lever;
saline-appropriate responding occurred following injections
of pentylene tetrazol (PTZ), a substance that has little effect
at either DA or 5-HT receptors.
When given in combination with LSD, the 5-HT
antagonist pizotifen (BC105) reduced the amount of
responding on the LSD-appropriate lever (Fig. 9). Interest-
ingly, as this antagonism occurred, the percent of alternative
choices was divided between the LHM and the saline levers.
Pizotifen had no effect on the LHM cue (data not shown).
Pirenpirone proved to be a more effective antagonist of LSD
than pizotifen (Fig. 9) in that this substance not only dose-
dependently reduced, but also completely eliminated
responding on the LSD-appropriate lever at the highest dose
tested (1 mg/kg). Pirenpirone also antagonized the LHM cue
(when given in combination with LHM), but did so only
partially and at doses 10 times higher than doses that
completely blocked the LSD cue (Fig. 10). The DA antagonist
haloperidol blocked the LHM, but had no effect on the LSD
cue (Fig. 10).
Thus, the results of studies involving both two-lever D
D and three-lever D D ND discrimination procedures
suggest that, while the effects of LSD and LHM may be
similar in some D ND situations, the mechanisms of action
of these compounds are, in fact, quite different; LSD acts
primarily as an agonist at 5-HT receptors while LHM acts
primarily at DA receptors [18].
More recently, we used another two-lever training
situation in an attempt to eliminate or reduce the incidence
of false positives; namely, a drug-other (D O) procedure
first described by Overton [19]. In this experiment, animals
were trained to discriminate LSD from a group of other
 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701
Fig. 9. Results of combination tests with Pizotifen (BC 105) and
pirenpirone given i.p. 1-h prior to LSD, in rats trained to discriminate
LSD (0.08 mg/kg, i.p.) from LHM (0.04 mg/kg, i.p.) and saline in a three-
lever (DD ND) drug discrimination task. (Reprinted from [16, p.16],
with the permission of Springer-Verlag).
substances, which consisted of cocaine (10 mg/kg), pento-
barbital (5 mg/kg) or saline [2]. Dose-response or substi-
tution tests with various hallucinogens or putative false
positives were then given to both D O and D ND (control)
trained animals.
Unlike the three-lever procedure, which required an
average of 72 days to learn to criterion, Fig. 11 shows that
the D O discrimination was acquired rapidly (34 days)
compared with controls (31 days).
Fig. 10. Results of combination tests with haloperidol (Haldol) and
pirenpirone given i.p. 1-h prior to LSD, in rats trained to discriminate LSD
(0.08 mg/kg, i.p.) from LHM (0.04 mg/kg, i.p.) and saline in a three-lever
(D D ND) drug discrimination task. (Reprinted from [16, p. 17], with the
permission of Springer-Verlag).
697
Fig. 11. (Top) Acquisition of discrimination between LSD (0.08 mg/kg,
i.p.) and saline (0.9% NaCl) using a standard drug-no drug (D ND)
training procedure. Criterion (at least 80% of the responses occurring
before the first FR was completed for seven consecutive sessions) was
attained in 26 days. (Bottom) Acquisition of discrimination between LSD
(0.08 mg/kg, i.p.) and a set of other compounds (D-Other) consisting of
saline, cocaine (10 mg/kg, i.p.) and pentobarbital (5 mg/kg). Criterion
(above) was attained in 31 days. (Reprinted from [2, p. 354], with the
permission of Elsevier Scientific Publishers).
As we expected, LSD and the indole-amine hallucino-
gens DOM and DMT substituted for the training drug
(0.08 mg/kg of LSD) in a dose-dependent manner in both
D O and D ND trained animals (Fig. 12). However, the
non-hallucinogenic false positives LHM, quipazine and
yohimbine, which mimicked LSD at least partially when
tested following standard DND training, engendered
saline-appropriate responding following D O training
(Fig. 13).
Thus, the two-lever D O procedure seems to be as
selective as, and more efficient than the D D ND, three-
lever procedure.
3. Neuroanatomical substrates of the LSD cue
The final variation on the drug discrimination procedure
I will discuss involved the administration of drugs into the
cerebral ventricles or various regions of the brain that have
been postulated to play a role in the behavioral effects of
LSD. In these experiments, which were conducted in
collaboration with Dr James Buggy (University of South
Carolina School of Medicine), W. B. West, and others, rats
698 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701

Fig. 12. Results of substitution tests with three indole-amine hallucinogens (LSD, DOM and DMT) in rats trained to discriminate LSD (0.08 mg/kg, i.p.) from
either saline (left panels) or a group of other drugs (saline, cocaine and pentobarbital; right panels). (Reprinted from [2, p. 355], with the permission of Elsevier
Scientific Publishers).

trained to discriminate LSD from saline were implanted
with chronic, indwelling cannulae in either the third or
lateral ventricles, or, bilaterally in the dorsal raphe, nucleus
accumbens (NAc), or fimbria striatum. The extent to which
a series of intracerebroventricular (icvt) or intracebral (i.c.)
injections of small amounts of LSD (mg) or, in one
instance LHM, delivered over a 1 h period through these
cannulae, substituted for LSD (0.08 mg/kg, i.p.) was then
determined.
Fig. 14 shows that injections of LSD directly into the
third ventricle substituted completely (left panel), while
injections into the lateral ventricle substituted partially for
systemic (i.p.) LSD.

Fig. 13. Results of substitution tests with three false positives (lisuride,
quipazine and yohimbine) in rats trained to discriminate LSD (0.08 mg/kg,
i.p.) from either saline (left panels) or a group of other drugs (saline,
cocaine and pentobarbital; right panels). (Reprinted from [2, p. 357], with
the permission of Elsevier Scientific Publishers).
Fig. 14. Results of substitution tests with LSD injected through cannulae
implanted into the cerebral ventricles in rats trained to discriminate LSD
(0.08 mg/kg, i.p.) from saline.
 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701
Fig. 15. Results of substitution tests with LSD injected through cannulae
implanted into the dorsal raphe (left panels) or fimbria striatum (right
panels) in rats trained to discriminate LSD (0.08 mg/kg, i.p.) from saline.
Direct administration of LSD into the dorsal raphe
substituted partially for i.p. LSD while injections into the
fimbria striatum induced responding primarily on the saline-
appropriate lever (Fig. 15).
The results of tests in which drugs were injected directly
into the NAc were interesting in that LHM produced more
responding on the LSD lever than did LSD itself (Fig. 16);
Fig. 16. Results of substitution tests with LSD or lisuride (LHM) injected
through cannulae implanted into the nucleus accumbens (NAc; left panels)
or given systemically (i.p.; right panels) in rats trained to discriminate LSD
(0.08 mg/kg, i.p.) from saline.
699
however, since neither substance substituted for systemi-
cally administered LSD completely, these results should be
interpreted with caution.
Since the doses of LSD or LHM administered i.c.v.t. or
i.c. were 100 1000 times less than those usually given
systemically, it is unlikely that that their effects were caused
by diffusion into the circulation or other tissue. However, it
is certainly possible that i.c.v.t. injections mimicked the
LSD cue most readily because substances administered in
this manner do tend to diffuse within the brain and therefore
stimulate a variety of structures in close proximity to actual
injection sites. Thus, injections of LSD into the third
ventricle might have affected the habenular nuclei, hippo-
campus, and para-ventricular nuclei, all of which receive
input from serotonergic terminals of neurons originating in
the dorsal raphe [20]. It is also interesting that the highest
concentration of 5-HT2C receptors, for which LSD has a
high affinity, is found in the non-neuronal choroid plexus of
the third ventricle [9]. Since structures adjacent to the lateral
ventricle, such as the NAc and caudate-putamen, are more
dopaminergic than serotonergic [21], it is not surprising that
LSD injected into this region substituted less than when
injected into the third ventricle.
The dorsal raphe has been implicated as a possible site of
action of LSD for many years [22]. Both direct adminis-
tration of LSD and electrical stimulation of this region have
been found to substitute for i.p. injections of LSD [23,24].
However, in the present experiment, LSD substituted only
partially when injected into the raphe. In addition, it should
be mentioned that i.p. LSD did not induce FOS expression
in this area but rather, caused intense FOS expression in
regions such as the cortex, hippocampus, and habenula,
which, as mentioned previously, contain projections from
neurons that originate in the dorsal raphe. Thus, the present
results support the hypothesis that 5-HT terminal fields are
more likely responsible for the physiological effects of LSD
than are 5-HT cell bodies [25].
Injections of LSD into the NAc, an area involved in the
reinforcing stimulus effects of many, if not most abused
drugs [26], did not substitute for i.p. LSD. While this may
appear to contradict previously reported findings [27], the
dose used in the earlier experiment (1.0 mg) was almost two
times higher than that used herein. Perhaps more impor-
tantly, the sites within the NAc differed in the two studies:
Nielsen & Scheel Kruger [27] used the NAc core and the
present study used the NAc shell, an area with significant
DA innervation [21]. Perhaps for this reason, i.c. LHM
produced more responding on the LSD-appropriate lever
responding than did i.c. LSD. It should be noted, however,
that LHM is about twice as potent as LSD, at least when
given systemically (i.p.).
The fimbria striatum is one of the few regions of the brain
that is reported to have higher concentrations of 5-HT2C
than 5-HT2A receptors [20]. Since direct injections of LSD
into this area substituted only partially for i.p. LSD, it might
be argued that 5-HT2A is the primary receptor involved in
700 J.B. Appel et al. / Neuroscience and Biobehavioral Reviews 27 (2004) 693701
the LSD cue and that 5-HT2C serves as a modulator [28].
However, this hypothesis should be made with caution
because 5-HT2C receptors in other areas of the brain could
play a critical role in the action of these drugs [9].
4. Conclusions
Indole- and phenylethyl-amine hallucinogens substitute
for LSD in two-lever DND procedures. Under similar
conditions, other false positives such as lisuride, quipazine
and yohimbine that are not known to be hallucinogenic (in
humans) and, in some instances, may not act primarily at
5-HT receptor sites, also substitute for LSD.
Substances such as ritanserin and pirenpirone that
antagonize the stimulus effects of LSD most consistently
act at 5-HT, but also at other receptor sites. Among
putatively more site-selective drugs, 5-HT2 antagonists
block the LSD cue to a greater extent than either 5-HT1 or
5-HT3 antagonists but do not block it completely. Thus, it is
likely that neuronal or receptor systems in addition to 5-HT2
may be involved in the complex, in vivo effects of LSD.
Since D D, D D ND, and D O procedures appear to
reduce or eliminate false positives such as lisuride, it
might be profitable to use them in future studies of the
neuronal and receptor mechanisms underlying the stimulus
and other subjective effects of drugs such as LSD.
The results of studies involving the administration of
drugs directly into the brain must be considered preliminary
because so few areas have been explored and even fewer
drugs have been studied; however, they do at least suggest
that it might be profitable to examine structures that contain
terminal fields of serotonergic neurons (cortex, habenular
nuclei, hippocampus, and para-ventricular nuclei) in the
search for the neuronal substrates of in vivo effects of LSD.
Finally, it appears that at least one lifetime of research
with LSD and 5-HT gives us little reason to question either
of the following conclusions that were made at the end of
the last century: Serotonin gave birth to the field of
neuroscience [29]; in spite of, or perhaps, because of the
fact that this substance is an enigma; it is at once
implicated in virtually everything but responsible for
nothing [30].
Acknowledgements
Supported by USPHS Research Grants DA R01 02543
and R37 DA 02543, from the National Institute on Drug
Abuse. We thank the many graduate and undergraduate
students who participated in the activities of the Behavioral
Pharmacology Laboratory during its 30 years of existence:
most especially, Donald M. Kuhn, Francis J. White, Kathryn
A. Cunningham, Patrick M. Callahan, Barbara B. Simon,
Walter G. Rolandi, and Tevfic Alici. Without their
assistance and hard work, none of the research reported
herein would have been conducted.
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