European Neuropsychopharmacology (2013) 23, 9991009

www.elsevier.com/locate/euroneuro

REVIEW

Schizophrenia and dopamine receptors

Philip Seemana,b,n
a

Department of Psychiatry, University of Toronto, 260 Heath Street, West, Unit 605, Toronto, Ont., Canada M5P 3L6
Department of Pharmacology, University of Toronto, 260 Heath Street, West, Unit 605, Toronto, Ont., Canada M5P 3L6

Received 7 November 2012; received in revised form 6 April 2013; accepted 24 June 2013

1.

KEYWORDS

Abstract

Striatum;
Caudate nucleus;
Putamen;
Dopamine supersensitivity;
Psychosis

Schizophrenia patients are behaviorally supersensitive to dopamine-like drugs such as amphetamine or methylphenidate, meaning that patients respond to such drugs with increased
psychotic symptoms, as compared to control subjects. A basis of such supersensitivity may be
an increased pre-synaptic release of dopamine or a post-synaptic elevation of D2 receptors or of
D2High receptors in active stages of schizophrenia. While the pre-synaptic release of dopamine
is normal in stable patients with schizophrenia, brain imaging studies nd that D2 receptors are
increased by an average of 5.8% in antipsychotic-free schizophrenia patients. It is possible that
the behavioral supersensitivity may stem from more D2High receptors in schizophrenia.
Although the antipsychotic/dopamine D2 receptor can exist in vitro in a state of high afnity
for dopamine (as D2High), or in a state of low afnity for dopamine (as D2Low), there is no clear
evidence that D2High states can be selectively labeled or stably exist in vivo. Nevertheless, two
studies revealed an 80% increase in apparent D2High receptors in schizophrenia patients after
reducing endogenous dopamine. The elevation in apparent D2High receptors in vivo in
schizophrenia matches the elevation in D2High receptors in vitro in animal models of psychosis,
including dopamine-supersensitive animals pretreated with amphetamine, marijuana, or
phencyclidine, or animals with gene knockouts in various neurotransmitter pathways, including
those for glutamate receptors. The elevation of D2High receptors in vitro and the increased
apparent D2High receptors in vivo is consistent with behavioral dopamine supersensitivity in
schizophrenia patients.
& 2013 Elsevier B.V. and ECNP. All rights reserved.

Introduction

The dopamine hypothesis of schizophrenia is based on the

idea that dopamine neurotransmission is increased in this

disease. Van Rossum (1967) worded his original hypothesis as

follows:
When the hypothesis of dopamine blockade by neuroleptic
agents can be further substantiated it may have fargoing

Tel.: +1 416 486 3456.

E-mail address: Philip.Seeman@utoronto.ca

0924-977X/$ - see front matter & 2013 Elsevier B.V. and ECNP. All rights reserved.
http://dx.doi.org/10.1016/j.euroneuro.2013.06.005

1000
consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could then be part of the
aetiology. Obviously such an overstimulation might be caused by
overproduction of dopamine, production of substances with
dopamine actions (methoxy derivatives), abnormal susceptibility of the receptors, etc.
Van Rossum's hypothesis that antipsychotic drugs may act
by blocking dopamine receptors was nally substantiated
in vitro by direct binding assays (Seeman et al., 1975, 1976).
Nevertheless, while the dopamine receptor-blocking action
of antipsychotics supports the dopamine hypothesis of schizophrenia, it is not known which of the mechanisms that Van
Rossum listed might account for the overstimulation of
dopamine receptors. That is, it is not clear whether the
overstimulation of dopamine receptors is based on more
synthesis and release of dopamine or a higher susceptibility
or sensitivity of brain dopamine receptors to dopamine itself.
The purpose of this mini-review is to examine whether
the hypertransmission of dopamine in schizophrenia resides
in the increased susceptibility of the receptors to dopamine.
More specically, in order to determine the molecular basis
of a possible dopamine supersensitivity in schizophrenia,
the present perspective and critique raises questions relating to dopamine supersensitivity and dopamine D2High
receptors. The questions are:
A. What are dopamine D2High receptors? Although the
antipsychotic/dopamine D2 receptor can exist in vitro
in a state of high afnity for dopamine (as D2High), or in
a state of low afnity for dopamine (as D2Low), there is
no clear evidence that D2High states can be selectively
labeled in vivo or actually exist in a stable state in vivo.
This is in contrast to the parathyroid hormone receptor
that can be specically labeled as a stable entity, albeit
in vitro (Dean et al., 2008). Do D2High states exist
in vivo? Are they as difcult to detect as the Higgs
Boson? Are they functional?
B. Are the number of dopamine D2High receptors increased
in schizophrenia?
C. Are dopamine D2High receptors related to behavioral
dopamine supersensitivity or psychosis?

2. Dopamine supersensitivity in
schizophrenia
A majority of patients with schizophrenia are behaviorally
supersensitive to dopamine-like drugs such as amphetamine,
methamphetamine, cocaine, or methylphenidate, whether
or not they are taking antipsychotics (Lieberman et al.,
1987). As reviewed by Lieberman et al. (1987), 7478% of
patients with schizophrenia revealed new symptoms or
experienced an increase of psychotic symptoms after being
given amphetamine or methylphenidate. Psychotic symptoms
could also be elicited in this way in control subjects, but only
in approximately 25% of individuals. The worsening of
symptoms caused by the psychostimulants occurred even
when the patients were taking antipsychotic medication.
A review by Curran et al. (2004) generally supports the
ndings of Lieberman et al. (1987). Curran et al. reported
that Experimental studies show that a single dose of a

P. Seeman
stimulant drug can produce a brief increase in psychosis
ratings (a response) in 5070% of participants with schizophrenia and pre-existing acute psychotic symptoms, unaffected by the presence of antipsychotic medication. Those
with schizophrenia who do not have acute psychotic symptoms respond, but less frequently (30%).

3.

Dopamine release in schizophrenia

Because amphetamine increases the release of dopamine

from dopamine neuron terminals, the increase of psychosis
caused by amphetamine in schizophrenia could arise from
an enhanced release of dopamine (Laruelle, 2000a). In fact,
a review by Howes et al. (2012) indicates that presynaptic
abnormalities (with increased dopamine content, increased
dopamine synthesis, or increased dopamine release) are the
major abnormalities in dopamine transmission in schizophrenia with a Cohen effect size of d= 0.79.
However, while the amphetamine-induced release of dopamine in schizophrenia is generally twice that of control
subjects, this is found in patients who are in an acute psychotic
episode but not in patients during a remission between
psychotic episodes (Laruelle et al., 1999). This type of measurement has recently become more complicated, because
future work on amphetamine-induced release of dopamine in
patients may need to examine whether there is also a
contributing role of GABA (gamma-amino-butyric acid) that is
simultaneously released with dopamine (Tritsch et al., 2012).
While the release of endogenous dopamine from presynaptic terminals by amphetamine is increased in schizophrenia (Laruelle, 2000a), the density of presynaptic
dopamine D2 receptors (so-called dopamine autoreceptors)
is normal in schizophrenia (Fusar-Poli and Meyer-Lindenberg, 2013a). However, there is a 14% increase in the
dopamine synthesis capacity in schizophrenia (Fusar-Poli
and Meyer-Lindenberg, 2013b). While most schizophrenia
patients with an increased dopamine synthesis capacity
respond to antipsychotic treatment, other patients with a
low level of dopamine synthesis capacity appear resistant to
antipsychotic medication (Demjaha et al., 2012).
Demjaha et al. (2012) have reasonably suggested that
such treatment resistance may arise because of breakthrough dopamine supersensitivity that occurs after prolonged antipsychotic medication (Samaha et al., 2007,
2008). Furthermore, as stated further on, the general
increase of 5.8% in dopamine D2 receptors (see later) could
actually account for a disproportionate increase in the
sensitivity of dopamine D2 receptors in antipsychotictreated patients, as based on a previous analysis (List and
Seeman, 1980), thereby partly accounting for the breakthrough dopamine supersensitivity.
While the D2Short form of the D2 receptor is associated
with dopamine autoreceptors (Usiello et al., 2000), haloperidol targets the D2Long form of the D2 receptor, which is
associated with post-synaptic receptors (Usiello et al., 2000).

4. Post-synaptic dopamine supersensitivity in

schizophrenia
Hence, the increased psychotic effect of dopamine-like
drugs in schizophrenia could occur by enhanced stimulation

Schizophrenia and dopamine receptors

1001

of supersensitive post-synaptic dopamine receptors, especially D2 receptors, the common target of antipsychotics
(Seeman, 2006; see also Laruelle, 2000b). In fact, Thompson
et al. (2012) have found clinical evidence for supersensitivity of post-synaptic dopamine receptors in patients who
have both schizophrenia and substance dependence; they
found that amphetamine released lower than normal
amounts of dopamine, yet the patients had an increase in
their psychotic symptoms with the amphetamine challenge.
Therefore, while D2 receptors may be a main target of
antipsychotic action, the following question arises: Are the
D2 receptors more numerous in schizophrenia, or is there
some other property of D2 receptors that is abnormal and
that is being targeted by the antipsychotic medication?

5. Dopamine supersensitivity in
schizophrenia: More D2 receptors?
If individuals with schizophrenia were generally supersensitive to dopamine-like stimulant drugs, one would expect
some aspect of dopamine neural transmission to be
increased in such individuals. Early work on the molecular
basis of dopamine supersensitivity in schizophrenia focused
on the total density of dopamine D2 receptors in the human
striatum (Seeman et al., 1987). The post-mortem control
striata from neurologically normal humans who died of
pneumonia, cardiac infarcts, or accidents showed a D2
density of about 13 pmol/g. Individuals who died with
schizophrenia had a bimodal pattern, where one group
had a normal density of about 14 pmol/g and the second
group had an elevated density of about 26 pmol/g (Seeman
et al., 1987). However, many or most of these schizophrenia
individuals, though not all, had been treated with antipsychotics during their lifetime. Therefore, it is likely that the
group showing 26 pmol/g had been extensively medicated
with antipsychotics that would have induced the synthesis
of additional D2 receptors. It is also possible that some of
the schizophrenia patients in the bimodal distribution of
dopamine receptors had abnormal amounts of dopamine D2
receptors that may have been secondary to factors not
related to schizophrenia.
While such an increase in the number of D2 receptors
could account for behavioral dopamine supersensitivity in
patients, subsequent brain imaging of striatal dopamine D2
receptors in control subjects and schizophrenia patients,
using a variety of radioligands (Talvik et al., 2006; Knable
et al., 1997; Kessler et al., 2009; Pilowsky et al., 1994;
Martinot et al., 1991, 1994; Yang et al., 2004; GraffGuerrero et al., 2009; Farde et al., 1990; Crawley et al.,
1986; Corripio et al., 2006, 2011; Kegeles et al., 2010a,
2010b; Nordstrm et al., 1995; Wong et al., 1986), found
that the density of dopamine D2 receptors was raised by
5.8% (Fig. 1, which omits Wong et al. (1986), because the
value from that publication markedly skewed the overall
average).
As shown in Fig. 1, at least 13 brain imaging studies found
that the overall increase in dopamine D2 receptors in the
striata of non-medicated schizophrenia patients, as compared to control subjects, was between 6% and +33%,
averaging 5.872.7% (mean7s.e.). Therefore, while there is

Figure 1 Average increase in dopamine D2 receptors in schizophrenia striatum, as monitored by 13 brain imaging studies, was
5.872.7% (mean7s.e.). Each point represents a change in the
binding potential or density of dopamine D2 receptors as labeled
by a radioactive ligand in antipsychotic-free (mostly antipsychotic-nave) schizophrenia patients, as compared to control subjects. References are: (a) Talvik et al. (2006), (b) Knable et al.
(1997), (c) Kessler et al. (2009), (d) Pilowsky et al. (1994), (e)
Martinot et al. (1994), (f) Yang et al. (2004), (g) Martinot et al.
(1991), (h) Graff-Guerrero et al. (2009), (j) Farde et al. (1990),
(k) Crawley et al. (1986), (m) Corripio et al. (2011), (n) Kegeles
et al. (2010a, 2010b), (p) Corripio et al. (2006), and (q)
Nordstrm et al. (1995).

no overwhelming increase in the density of striatal dopamine D2 receptors, an increase of 5.8% could actually
account for a disproportionate and non-linear increase of
possibly 50% in the sensitivity of dopamine D2 receptors in
antipsychotic-treated patients, as based on a previous analysis (assuming no spare D2 receptors; List and Seeman, 1980).

6.

Dopamine D2High receptors

The dopamine D2 receptor is a typical G-protein-linked

receptor that can exist in a state of high afnity for
dopamine, D2High, or in a state of low afnity for dopamine, D2Low. Experimentally, the two states are readily
detected in vitro when dopamine is competed against a
radioactive antipsychotic drug such as [3H]raclopride or
preferably [3H]domperidone, using brain tissue as the

1002
source of receptors. Such competition reveals two distinct
phases, one at low concentrations of dopamine, D2High, and
one at high concentrations of dopamine, corresponding to
D2Low (Seeman et al., 2005, 2006). Such high- and lowafnity states can rapidly convert into each other in a
matter of seconds or less, as worked out for the formyl
peptide receptor (Wu et al., 2007). In vitro, the addition of
a guanine nucleotide fully converts all the D2High receptors
into D2Low receptors.
In vivo, however, there is no direct evidence that D2High
receptors actually exist in a stable state or can be selectively labeled. Indirect evidence for the existence of D2High
in vivo is that the concentration in human plasma of a
radioactive dopamine-like agonist such as [11C]naxagolide is
approximately 2 nM (Graff-Guerrero et al., 2009), which
matches the approximate afnity of this drug for D2High
receptors in vitro. Furthermore, the plasma concentration
of the radioactive naxagolide is about 1000 times lower than
the concentration needed to occupy the D2Low receptors
(Seeman, 2007).
Although the high-afnity and low-afnity states of the
D2 receptor can be detected in homogenized tissues, the
transient existence of D2High states in vivo is not clearly
established. For example, Skinbjerg et al. (2010) could not
detect D2High sites in intact cells, although such sites could
be detected in intact cells by others (Seeman, 2009). In
particular, Skinbjerg et al. (2010) found that dopamine
inhibited the binding of [3H]sulpiride at a single binding
site in intact tissue culture cells, but only detected
D2High with [3H]methylspiperone after the cells were
homogenized.
A search to detect stable D2High states in vivo by means
of positron emission tomography is encountering inconsistencies. For example, intravenous amphetamine inhibited
the binding of agonists (methoxy-NPA and radioactive (+)
PHNO) more than it inhibited the binding of an antagonist
(raclopride) (Ginovart et al., 2006).
In contrast, Ross and Jackson (1989) simultaneously coinjected a dopamine agonist and the radioligand intravenously to measure D2 in vivo. By this in vivo method, Ross
and Jackson successfully identied high-afnity and lowafnity D2 receptors occupied by the ligand but displaced
by the agonist (such as pergolide), similar to the pattern
obtained in vitro.
Using the co-injection method, therefore, it was found
that an intravenous injection of the agonist NPA inhibited the
binding of [3H](+)PHNO more than the D2 antagonist [3H]
raclopride (Seeman, 2009) as measured ex vivo. This nding
supports the idea that the sites for the binding of agonist and
antagonist may differ and that D2High sites exist in vivo.
The major biological difference between the preinjection method and the co-injection method (Ross and
Jackson, 1989) is that the co-injection method ensures that
the arrival of the ligand and the NPA agonist occur at
precisely the same moment. Considering that a receptor
agonist can rapidly desensitize a receptor or internalize
receptors within seconds or minutes (von Zastrow and
Kobilka, 1992; Insel et al., 1983), the arrival of NPA prior
to that of [3H](+)PHNO would reduce the amount of D2High
receptors available to [3H](+)PHNO.
In addition, the injection of a G-protein inhibitor directly
into the striatum to block the G protein (that mediates the

P. Seeman
D2-associated dopamine-inhibited cyclase) attenuated
apomorphine-induced stereotyped behavior (Fujita et al.,
1985), demonstrating that the high-afnity state of D2 may
be the functional state in the nervous system.
Finally, it has also been possible to demonstrate directly
that an agonist ligand such as [3H](+)PHNO actually binds to
D2High sites in vivo. For example, following an in vivo
injection of [3H]PHNO and an immediate removal of the
striatum, the addition of a guanine nucleotide accelerated
the release of [3H]PHNO from the striatal tissue (Seeman,
2009). This indicated that there was a signicant amount of
this ligand attached to D2High receptors in vivo moments
before the striatum was removed.
Although dopamine D2 receptors have been covalently
labeled in vivo by radioactive chlorethyl-norapomorphine
(Costall et al., 1980; Guan et al., 1984), there is no
evidence that the labeling was selective for dopamine
receptors or that D2High receptors were selectively labeled.
Apparently, the only high-afnity state of any G-linked
receptor that has been selectively labeled in vitro is the
parathyroid hormone receptor (Okazaki et al., 2008).
While the gene for the dopamine D2 receptor continues
to be one of the top 16 genes that are statistically
signicantly associated with schizophrenia (Zhang et al.,
2007; Allen et al., 2008; Bertolino et al., 2009), the gene for
the D2 receptor refers to the entire receptor rather than to
either the D2High or D2Low state of the receptor. A detailed
analysis of the association between the D2 receptor gene
and schizophrenia is discussed elsewhere (Allen et al., 2008;
Bertolino et al., 2009).

7. Are dopamine D2High receptors

functional?
If the D2High receptor exists in vivo, the question immediately arises as to which of the two states is the functional
state, D2High or D2Low? This question continues to be
difcult to answer, considering that the two states rapidly
convert into each other. At present, evidence suggests that
D2High may be the functional and physiological state
related to the action of dopamine.
For example, the data in Fig. 2 (top) shows that the
inhibition by dopamine-like drugs on the release of prolactin
from intact pituitary cells in culture best match the drug
dissociation constants at the D2High receptor (George et al.,
1985). Once again, however, although the prolactin-releasing
cells are physiologically functional, these data are in vitro
and not in vivo.
In addition, the data in Fig. 2 (bottom) indicates that the
therapeutic concentrations of dopamine-like drugs that are
used to treat Parkinson's diseased patients (Seeman, 2007)
match the dissociation constants for the D2High state.
Although such data suggest that D2High might be the
functional state of the D2 receptor, there are many drawbacks to this view. For example, the free concentrations of
the therapeutic drugs in the plasma have a wide range,
depending on the clinical dose, the dosing schedule, and the
clinical state of the patient. Given the wide range of plasma
concentrations, one could equally make the argument that
D2Low is the functional state of the receptor for the

Schizophrenia and dopamine receptors

1003

8. Dopamine D2High receptors in

schizophrenia

Figure 2 Functional state of the dopamine D2High receptor. The

agonist drug concentrations that are effective in inhibiting the
release of prolactin from anterior pituitary cells in culture (top) or
are effective in treating Parkinson's disease (bottom) match the
drug concentrations (dissociation constants) that act at the highafnity state of the dopamine D2 receptor, or D2High. These data
suggest that the D2High state of the D2 receptor is the functional
state of D2 in presynaptic D2 receptors (similar to D2 in the
anterior pituitary cells) and postsynaptic D2 receptors that
respond to therapeutic concentrations of anti-Parkinson drugs.
1, (+)Epinephrine; 2, ()epinephrine; 3, ()norepinephrine; 4,
(+)-3-PPP; 5, ()-3-PPP; 6, dopamine; 7, RU-24213; 8, RU-24926;
10, ()apomorphine; 11, bromocriptine; 12, dihydroergocriptine;
13, -ergocriptine; 14, pergolide; 15, (7)-N-propylnorapomophine (NPA)(IC50 value for prolactin inhibition (84 nM) was taken
as twice that for ()NPA (42 nM); 33, (+)-norepinephrine; 34,
()-N-propylnorapomorphine. (Top: adapted from George et al.
(1985); bottom: redrawn from Seeman (2007), with permission
from Wiley & Sons, Inc.).

therapeutic action of anti-Parkinson drugs. Clearly, additional evidence is needed to establish the functional roles of
the D2High and D2Low states.

While the summary in Fig. 1 shows that the density of D2

receptors is essentially normal in non-medicated schizophrenia patients, is it possible that within the general
population of D2 receptors there is a component of D2High
receptors that is altered in schizophrenia?
In an attempt to answer this question and in order to
measure high-afnity D2 receptors in vivo with a radioligand, one approach has been to deplete endogenous
dopamine by pre-medicating the subject with alphamethyl-paratyrosine (Laruelle, 2000a; Abi-Dargham et al.,
2000; Kegeles et al., 2010a, 2010b). The ndings of the
latter two studies are summarized in Fig. 3. The report by
Abi-Dargham et al. (2000) showed that after depletion of
endogenous dopamine by alpha-methyl-paratyrosine, the
binding of [123I]IBZM increased by 971.65% (mean7s.e.)
in 18 control volunteers, but increased by 1972.6%
(mean7s.e.) in 18 patients with schizophrenia (with a
statistically signicant difference of p= 0.003). These extra
D2 sites labeled by [123I]IBZM represent unmasked sites with
high afnity for dopamine, and might represent D2High
receptors, unmasked by the fall in endogenous dopamine.
The difference of 199% for the apparent D2High sites in the
two sets of individuals represented a 110% increase of
apparent D2High receptors in schizophrenia, compared to
the control subjects.
The ndings of Kegeles et al. (2010a, 2010b) were similar.
After premedication with alpha-methyl-paratyrosine, they
found that the binding of [11C]raclopride increased by
1071.65% (mean7s.e.) in control humans, but increased
by 1571.65% (mean7s.e.) in the associative region of the
striatum in schizophrenia patients (Fig. 3). Hence, the
difference of 1510%, or 5%, in the apparent D2High sites
between the control and schizophrenia subjects represented a 50% elevation of apparent D2High receptors in
schizophrenia.
The increased amounts of D2High receptors in these
studies (Abi-Dargham et al., 2000; Kegeles et al., 2010a,
2010b) were also viewed as an increase in the baseline
occupancy of D2 receptors by dopamine in schizophrenia
(Abi-Dargham et al., 2000) or as an increased synaptic
function in schizophrenia (Kegeles et al., 2010a, 2010b).
Essentially, these phrases reect the same biological meaning that schizophrenia is associated with an increased
amount of apparent D2High receptors that are occupied
by endogenous dopamine.
These reports (Abi-Dargham et al., 2000; Kegeles et al.,
2010a, 2010b), however, may not truly reect D2High
receptors, but may rather indicate D2 receptors that remain
occupied by endogenous dopamine after the dose of alphamethyl-paratyrosine. While these apparent D2High sites
have a high afnity for dopamine, because they retain some
endogenous dopamine, it is not obvious that they are
D2High sites in the sense used in the in vitro work, and it
is not known whether these apparent D2High sites are
convertible to D2Low sites.
The same method of pre-medication with alpha-methylparatyrosine was used in cocaine-dependent subjects
(Martinez et al., 2009), but the apparent D2High receptors

1004

P. Seeman

Figure 3 Elevation of apparent D2High receptors in schizophrenia patients (left side), but reduction of apparent D2High receptors
in cocaine-dependent subjects (right side). The apparent D2High receptors in these individuals were unmasked by pre-medication
with alpha-methyl-paratyrosine (MPT). The study by Abi-Dargham et al. (2000) found that the binding potential of [123I]IBZM
increased in control subjects, but that the increase in schizophrenia subjects was 110% higher. The study by Kegeles et al. (2010a,
2010b) found that the binding potential of [11C]raclopride increased in control subjects, while the increase in schizophrenia subjects
was 50% higher. These apparent D2High receptors may not be the same as the in vitro D2High receptors in animal studies. In cocainedependent subjects, however, pre-medication with MPT elevated the binding potential of [123I]IBZM about 5.9% less than the
elevation found in the control subjects, indicating a reduction in the density of the apparent D2High receptors in the cocainedependent individuals (Martinez et al., 2009). Dashed lines indicate s.e.

were actually found to be lower in these subjects (Fig. 3,

right).
A preliminary conclusion, therefore, is that an elevation
of apparent D2High receptors may occur in schizophrenia,
but to test this hypothesis additional research must be done
on other diseases and related psychoses.
Would an elevation in these apparent D2High receptors
be an index of a pre-psychotic clinical episode? This
question has been examined (Bloemen et al., 2013). After
depleting endogenous dopamine with alpha-methylparatyrosine in fourteen individuals at high risk for psychosis, Bloemen et al. found that the binding of [123I]IBZM
increased in proportion to the presence of positive symptoms. However, for the entire group of 14 individuals, the
increased binding of [123I]IBZM after dopamine depletion
was not different than that of 15 control subjects. Nevertheless, the increased level of apparent D2High sites in
those with more pre-psychotic symptoms indicates a possible new avenue of research on the clinical signicance of
these high-afnity dopamine receptors.

9. Post-synaptic dopamine supersensitivity in

schizophrenia with drug dependence
It is known that the rate of dopamine synthesis progressively
increases as patients develop psychosis (Howes et al.,
2011). This process is apparently the basis for the action
of amphetamine which releases more endogenous dopamine

in patients with schizophrenia than in control subjects

(Laruelle, 2000a).
While these two pre-synaptic events (synthesis and
release of dopamine) no doubt contribute to the onset of
psychosis, the post-synaptic action of dopamine on postsynaptic supersensitive dopamine D2 receptors must also
occur. For example, as already noted above, Thompson
et al. (2012) found a group of patients who had both
schizophrenia and drug dependence who showed less
amphetamine-induced release of dopamine as compared
to normal controls. Despite this very low release of endogenous dopamine by amphetamine, the low level of
released dopamine still triggered positive psychotic symptoms at an intensity similar to that found in schizophrenia
without drug dependence. Therefore, Thompson et al.
suggested that in substance-dependent patients with schizophrenia, hypersensitivity of D2 receptors to dopaminergic stimulation is the predominant dopaminergic alteration,
as opposed to excess presynaptic release.

10.

Is it possible to label D2High selectively?

For clinical purposes, therefore, it would be desirable if

there was a radioligand that would unequivocally label
D2High receptors. At present, however, there is no consensus as to whether it is feasible to selectively label
D2High receptors. There are numerous publications using
radioactive N-propylnorapomorphine (NPA) and related

Schizophrenia and dopamine receptors

radioactive congeners as ligands for D2High receptors
in vitro and proposed for use in vivo. However, while some
researchers accept the premise that radioactive versions of
(+)naxagolide, N-propylnorapomorphine (NPA; Costall et al.,
1980; Guan et al., 1984), or methoxy-NPA (Skinbjerg et al.,
2010) may label D2High receptors, others view these radioactive compounds as not selective but can label both D2High
and D2Low receptors (Seeman, 2012). This may be because
these agonist ligands are slow to dissociate from the D2
receptor. For example, the half-time for these compounds to
dissociate from the D2 receptor is between 100 and 600 s
(Seeman, 2012). These long time periods are much slower
than the sub-second dissociation of the G-protein that maintains the high-afnity state of the D2 receptor (Wu et al.,
2007). Therefore, these compounds remain attached to both
the high- and low-afnity states of the D2 receptor (Fig. 4,
bottom). Such long periods of association with the D2
receptors would be expected to lead to non-selective labeling
of both D2High and D2Low receptors (Seeman, 2012), especially in vivo.
For example, mice that are decient in dopamine hydroxylase are supersensitive to dopamine-like agonists
(Skinbjerg et al., 2010), and have an elevated number of
D2High receptors when using the dopamine/[3H]domperidone competition method in vitro (Seeman et al., 2005).
However, when using [11C]methoxy-NPA to measure the
binding potential of this radio-ligand (Skinbjerg et al.,
2010), the binding potential was found to be normal. Such
discordant data between the in vitro and in vivo results may
arise from the fact that [11C]methoxy-NPA labels D2High and
D2Low in vivo, as discussed above in connection with Fig. 4.
At the same time, the in vitro data show a relative increase
of 200% in D2High receptors (Fig. 5), using the dopamine/
[3H]domperidone competition method, but only a relative
increase of 27% when using the dopamine/[3H]spiperone
method (Skinbjerg et al., 2010), the latter ligand being less
selective for D2 receptors.
However, in contrast to the clinical in vivo experiments,
the proportions of D2High and D2Low receptors are more
readily measured in vitro, because the long period of
incubation (2 h) permits the added dopamine to equilibrate
with the receptor and the radioligand (Fig. 4, top). Moreover, the various exogenous dopamine concentrations added
will determine whether the high-afnity or low-afnity
state of the D2 receptor is being targeted, as shown in
Fig. 4 (top).

11. Future selective labeling of D2High

receptors?
In attempting to D2 receptors selectively with irreversible
compounds such as ()-N-(chloroethyl)norapomorphine
(Costall et al., 1980; Guan et al., 1984), no selectivity had
been shown for dopamine D2 receptors to the exclusion of
other related receptors. Recently, however, the new compound MCL-524 (R-()-2-uoroethoxy-N-propyl-norapomorphine) has been found to label D2High preferentially
(Sromek et al., 2011, 2012). This will enable the synthesis
of an alkylating derivative of MCL-524, using a chloro-ethyl
group to replace the N-propyl group on MCL-524, in order to
label D2High selectively.

1005

Figure 4 Comparison of in vitro and in vivo methods to measure

D2High receptors. Top: in vitro method provides sufcient time
during the incubation period of two hours for the exogenously
added dopamine and the radioligand (agonist or antagonist) to
compete and equilibrate with the dopamine D2High and D2Low
receptors. The D2High state of the receptors occurs at dopamine
concentrations less than 1,000 nM dopamine, while the D2Low
state of the receptors occurs at dopamine concentrations higher
than 1,000 nM. In this experiment, the cocaine-dependent rats
exhibited almost 3-fold more D2High receptors, as compared to the
control animals. (Adapted and redrawn from Seeman et al. (2005)).
Bottom: non-selective labeling of D2High and D2Low by an agonist
radioligand. A problem in selectively labeling D2High receptors
in vivo by means of a radioactive agonist ligand such as [11C](+)
PHNO or compounds related to [11C]MNPA is that these ligands
remain bound to the D2 receptor for 100600 s, much longer than
the life-time of the high-afnity state of D2. As with related
receptors, it is considered that the D2 receptor constantly oscillates
between the high- and low-afnity states. The high-afnity state of
the D2 receptor converts to the low-afnity state as soon as the
G-protein dissociates from the D2 receptor protein, a matter of less
than a second in another G-protein-linked receptor (Wu et al.,
2007), while the radioligand remains bound to the receptor (middle
panel). In effect, therefore, the agonist radioligand ends up nonselectively labeling both D2High and D2Low (from Seeman (2012),
with permission).

1006

P. Seeman

Figure 5 Animals that were behaviorally supersensitive to dopamine-like drugs (amphetamine, methylphenidate, and cocaine)
revealed higher proportions of dopamine D2 receptors in the brain striata that were in the high-afnity state for dopamine, D2High
(left side) (Seeman et al., 2005, 2006). The right side shows that there was either no elevation or a minor elevation of D2High receptors in
animals that were not behaviorally sensitive to dopamine-like drugs. These latter animals had knockouts in the genes for glycogen
synthase kinase (GSK3beta), metabotropic glutamate receptor mGluR5, dopamine D1 or D3 receptors, histamine H1, H2 or H3 receptors,
and adenosine A2A receptors. (Adapted and redrawn from Seeman et al. (2006), with permission from Wiley & Sons, Inc.).

12. Elevated D2High receptors in animal

models of psychosis: Is dopamine
supersensitivity related to D2High receptors?
The elevated levels of the apparent D2High receptors found
in schizophrenia (Fig. 3) are supported by extensive data on
many animal models of psychosis (Seeman et al., 2005,
2006), as summarized in Fig. 5. The left side of this gure
shows the elevation of dopamine D2High receptors in
animals that were behaviorally supersensitive to
dopamine-like drugs (e.g., apomorphine, cocaine, methylphenidate, amphetamine). As already mentioned, it is not
clear whether the elevation in D2High receptors found
in vitro in the animal models of psychosis corresponds to
the elevations in the apparent D2High receptors found in
the brain imaging experiments.
Moreover, there is a major discrepancy between the human
data on cocaine-dependent individuals with their reduction in
the apparent D2High receptors (Fig. 3) and the animal model
of cocaine dependence, where an elevation in D2High
receptors was found (Figs. 3 and 5) (Briand et al., 2008).
Such different results from in vivo and in vitro methods are

not surprising, considering the different factors involved, as

discussed in connection with Fig. 4.
The right side of Fig. 5 shows data for animals that were
not behaviorally supersensitive to dopamine-like drugs. The
post-mortem striata showed either a lack of elevation, a
minor elevation, or an actual fall in the proportion of
D2High receptors in mice with knockouts in the genes for
glycogen synthase kinase (GSK3beta), metabotropic glutamate receptor mGluR5, dopamine D1 or D3 receptors,
histamine H1, H2 or H3 receptors, and adenosine A2A
receptors. Gene knockout mice with no behavioral supersensitivity did not reveal any elevation in the proportion of
D2High receptors (Seeman et al., 2005, 2006).
It is important to note that deletions of genes that are
not related to the dopamine system also resulted in animal
models of behavioral dopamine supersensitivity, and at the
same time revealed marked elevations in D2High receptors,
as illustrated in Fig. 5. These genes include those for the
metabotropic glutamate mGlu2 and mGlu3 receptors, PostSynaptic Density protein 95 (PSD95), G-Protein Receptor
Kinase 6 (GPRK6), the Trace Amine-1 receptor, and Regulator of G protein Signaling 9-2 (RGS9-2)(Fig. 5).

Schizophrenia and dopamine receptors

1007

Many gene knockouts, of course, do not result in dopamine supersensitivity, because knockouts of some genes,
such as those for adenosine A2A receptors, lead to dopamine sub-sensitivity (Fig. 5). In keeping with this reduction
in dopamine sensitivity, the D2High receptors were reduced
by 75% in the striata of adenosine A2A knockout mice.
Similarly, mice with knockouts of the metabotropic glutamate receptor-5 (mGluR5) were not supersensitive, and the
proportion of D2High receptors did not increase (Fig. 5).

striata from patients who had schizophrenia (Perreault

et al., 2010). Here, too, some or many of the D2 units
within the D1D2 dimer are likely to exist in the
D2High state.
3. A decrease in the afnity between monomers that
constitute each D2 protein, such that more of the
monomers can now exist in the high-afnity state and,
therefore, bind more dopamine.

13. Other psychosis models: Caesarian birth

with anoxia; psychostimulants; social isolation;
steroids

In summary, the elevated D2High receptors in animal

models of psychosis, and the elevations in the apparent
D2High recepotrs in the human brain imaging data may be
related to the clinical signs and symptoms of psychosis. Such
a relation will need to be tested when selective imaging of
D2High in patients becomes possible by radioactive D2Highselective agonists.
There are presumably many detailed steps in the antipsychotic pathway after an antipsychotic targets dopamine
D2High receptors. The intracellular proteins and factors
that regulate D2High need to be determined, because they
may provide better drug target sites for treatment of
schizophrenia.

In another model for schizophrenia, adult rats that were

born by Caesarian section (with anoxia) exhibited dopamine
supersensitivity. Striata from these rats revealed an elevation in the proportion of D2High receptors (Fig. 5), but no
increase in the total population of D1 or D2 receptors.
Rats that have been sensitized by amphetamine, phencyclidine, quinpirole or caffeine also become supersensitive to
dopamine agonists. The striata from such supersensitive rats
did not reveal any increase in the total population of
dopamine D2 receptors, but showed an elevation in the
proportion of D2High receptors (Fig. 5).
Social isolation is a risk factor for psychosis, and rats
isolated from birth reveal dopamine supersensitivity and
elevated D2High receptors (Fig. 5) (King et al., 2009).
Consistent with the hypothesis of D2High being the
convergent target for various psychoses is the fact that
most psychoses, but not all, respond to treatment with D2
antagonists (Alzheimer psychosis may be less responsive to
antipsychotics, although the clinical doses used must be
kept low to prevent side effects).
Because D2High receptors are elevated in the animal
models of the various human psychoses, it appears reasonable to consider D2High a common target for the convergence of the various psychosis pathways in animals at least.
In addition, although haloperidol can itself induce an
elevation of D2High receptors, haloperidol effectively
reversed the amphetamine-induced elevation of D2High
receptors (Seeman, 2009). Moreover, it is reasonable to
hypothesize that risk factors or altered genes that lead to
dopamine supersensitivity can also increase the risk for
psychosis or schizophrenia.

14. Molecular mechanisms of D2High

supersensitivity
There are at least three molecular components underlying
the basis of dopamine supersensitivity. These include:
1. An increase in D2D2 dimers that is known to occur in
amphetamine-sensitized rat striata, as well as in postmortem striata from patients who had schizophrenia
(Wang et al., 2010). Some or many of the D2 units within
the D2D2 dimer are likely to exist in the D2High state
(Wang et al., 2010).
2. An increase in D1D2 dimers that is known to occur in
amphetamine-treated rats, as well as in post-mortem

Conicts of interest
There are no relevant nancial conicts of interest.

Contributors
This work was prepared and written by P.S.

Role of funding sources

I thank the Karolina Jus Estate, the Medland family and the O'Rorke
family for their support, the funds of which were used for supplies.

Acknowledgments
Supported by the Karolina Jus Estate, and by the John William
Medland Fund donated by Pamela H. and Desmond O'Rorke, Janet
Marsh Frosst, and David Medland.

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