Serotonergic Mechanisms in

Schizophrenia: Evolution and

Current Concepts
Herbert Y. Meltzer, MD, Zhu Li, PhD, Mei Huang, PhD, and Adam Prus, PhD

Corresponding author Introduction

Herbert Y. Meltzer, MD
Vanderbilt University School of Medicine Psychiatric Hospital at
Serotonin (5-hydroxytryptamine, 5-HT) was one of the first
Vanderbilt, 1601 23rd Avenue South, Nashville, TN 37215, USA. neurotransmitters implicated in schizophrenia, even before
E-mail: herbert.meltzer@vanderbilt.edu dopamine (DA), which was, and still is, the main neurotrans-
Current Psychosis & Therapeutics Reports 2006, 4:12 –19 mitter thought to be involved in the etiology of core aspects
Current Science Inc. ISSN 1545-8083 of schizophrenia, including delusions and hallucinations
Copyright © 2006 by Current Science Inc. (positive symptoms), negative symptoms (withdrawal,
anergia, flat affect, avolition, and anhedonia), and cognitive
impairment. The DA hypothesis was based on the evidence
Serotonin (5-HT) was once thought to have a role in visual
that amphetamine or methamphetamine, which enhance
hallucinations based on the findings that lysergic acid dieth-
the concentration of synaptic DA through effects on the DA
ylamide was found to be a serotonin agonist. This led to a
transporter, could induce paranoid psychoses when given
search for endogenous indole hallucinogens in schizophre-
repeatedly, and that the first effective antipsychotic, chlor-
nia, which ultimately proved unsuccessful. Studies of 5-HT
promazine, was a DA receptor antagonist. The D2 receptor,
receptor subtypes opened up the issue in several ways, with
which signals mostly through inhibition of adenylate cyclase,
the 5-HT2A, 5-HT2C, and 5-HT1A receptors seeming to
was the DA receptor identified as the site of action of chlor-
be of greatest importance, and 5-HT6 and 5-HT7 recep-
promazine and was one of five that were eventually identified
tors of secondary importance. Linkages between 5-HT,
and cloned. Numerous other D2 receptor antagonists were
dopamine (DA), glutamate, acetylcholine, and brain-derived
found to be effective antipsychotic drugs with a high correla-
neurotrophic factor, have provided some important leads as
tion between average clinical dose and D2 receptor affinity
to how 5-HT may be involved in schizophrenia. It has been
being noted. The inability to find another pharmacologic
found that 5-HT2A rather than 5-HT2C receptor stimula-
principle that could reliably produce an antipsychotic drug or
tion is the most likely basis for the hallucinogenic effects
enhance the effectiveness of D2 antagonists heightened the
of lysergic acid diethylamide, but recent neurochemical and
interest in dopaminergic mechanisms for more than 40 years.
genetic studies have raised the possibility that the 5-HT2C
That two major side effects of this generation of antipsychotic
receptor may also be important in psychosis based on its
drugs, extrapyramidal symptoms and hyperprolactinemia,
ability to regulate tonic dopaminergic function. The dis-
could be traced to blockade of D2 DA receptors also was a
covery that 5-HT2A receptor blockade was an important
major contributing factor to diminishing interest in the role of
component of the action of clozapine and other atypical
other neurotransmitters and modulators. The discovery that
antipsychotic drugs also restored interest in a primary role
glutamate antagonists, which block the N-methyl-D-aspartate
of 5-HT2A receptors in the etiology of psychosis. 5-HT1A
class of glutamate receptors, produced psychosis and cognitive
receptors also have been found to enhance DA release in
impairment in normal subjects and patients with schizophre-
the cortex and hippocampus and are primary factor in the
nia produced a major shift. However, no agents have yet been
regulation of DA release in both of these regions. Postmor-
introduced that are effective to treat schizophrenia by revers-
tem studies have found some evidence of non–drug-induced
ing a hypothesized deficit in glutamatergic function.
increased density of 5-HT1A receptors. Genetic studies
are ongoing to link single nucleotide polymorphisms of the
5-HT2A, 5-HT2C, and 5-HT1A receptors to some schizo-
Lysergic Acid Diethylamide, Indole
phrenia phenotypes. It is likely that serotonergic function
will become even more important in developing genetic and
Hallucinogens, and the Serotonergic
other markers for schizophrenia novel therapies, particu-
Hypothesis of Schizophrenia
As with DA and glutamate, interest in the role of 5-HT
larly for psychosis and cognition.
in schizophrenia originated in the discovery that lysergic
 Serotonergic Mechanisms in Schizophrenia Meltzer et al. 13
acid diethylamide (LSD), mescaline, peyote, and psilo-
cybin were structurally related to 5-HT and could cause
visual hallucinations, although rarely the more common
form of reality distortion found in schizophrenia (audi-
tory hallucinations). This was the starting point for the
theory that schizophrenia may be attributable to an
abnormality of the serotonergic system. Gaddum [1••]
reported that LSD was a 5-HT antagonist suggesting that
inhibition of serotonergic function could lead to psycho-
sis. However, subsequent evidence indicated that a more
potent and generalizable effect of LSD and other indole
hallucinogens was their agonist action at 5-HT2A and 5-
HT2C receptors, two of the 14 5-HT receptors that have
now been identified. The 5-HT2A and 5-HT2C receptors
belong to the G-protein-coupled receptor superfamily. G-
protein-coupled receptors transduce extracellular signals
to the interior of cells through their interaction with G-
proteins. The 5-HT2A receptor is negatively coupled to
adenylate cyclase, whereas the 5-HT2C receptor is nega-
tively coupled to phosphatidyl inositol hydrolysis [3].
It was found that a significant correlation (r = 0.938)
existed between the 5-HT2 binding affinities of LSD
and other hallucinogens and their ED50 values as
determined in tests of stimulus generalization using
1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane as
the training drug. A significant correlation (r = 0.924)
was found for 15 of these agents where human data were
available, and their 5-HT2 binding affinities and their
hallucinogenic potencies in humans [4]. The hallucino-
genic effect of indole hallucinogens has been related to
stimulation of 5-HT2A rather than 5-HT2C receptors on
the basis of behavioral studies [5]. These studies led to
the search for an endogenous indole or indole-like hal-
lucinogens that may be the basis for schizophrenia. Some
possibilities were explored in great depth, such as dime-
thoxyphenethylamine (pink spot), but no claims could
be substantiated in the long term.
Numerous studies have examined the density of 5-
HT2A receptors in various cortical regions of patients
with schizophrenia with decreased [6,7], increased [8],
or normal levels reported. Recent PET studies have not
found decreased 5-HT2A receptors in the cortex of never
medicated or unmedicated patients with schizophrenia
[9]. This will be discussed in more detail. 5-HT2 receptor
antagonists such as ketanserin and ritanserin were found
to lack psychotomimetic properties. That LSD did not
produce auditory hallucinations or, at least superficially,
the cognitive dysfunction of schizophrenia, diminished
interest in the role of 5-HT2A receptor stimulation in the
etiology of schizophrenia. However, recent research from
Umbricht et al. [10] and Hasler et al. [11••], based on
administration of psilocybin to normal volunteers, has
shown disruptive effects of this prototypical hallucino-
gen on cognitive functions that are abnormal in patients
with schizophrenia, such as attention, as assessed with
the continuous performance test, and measures of execu-
tive function. As will be discussed, the 5-HT2A receptor
has an important regulatory effect on glutamatergic neu-
rotransmission, serving to depolarize the glutamatergic
pyramidal neurons that are central to cognitive function.
Therefore, it is not surprising that excessive stimulation
of these neurons may be disruptive of cognitive function.
There has been extensive discussion of the role of
5-HT2A versus 5-HT2C receptors in the action of the
indole hallucinogens to cause hallucinosis. There are few
drugs that are selective for each of these receptors. Recent
neurochemical studies have suggested that the indole
hallucinogens act more via stimulation of the 5-HT2A
than the 5-H2C receptors. Therefore, Gresch et al. [12]
provided evidence that the tolerance that accompanies
repeated LSD administration in rat brain is blocked by a
selective 5-HT2A, but not a 5-HT2C antagonist. The effect
of LSD on gene activation in rat brain has been reported
to be mediated by 5-HT2A receptor stimulation [13]. The
5-HT2A/2C agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-
aminopropane (DOI), a potent hallucinogen has been
proposed to act by targeting 5-HT2A heteroceptors on
thalamocortical neurons and eliciting release of glutamate
from these cells, which in turn drives cortical neurons.
Scruggs et al. [14] showed that systemic administration
and intracortical administration of DOI significantly
increased extracellular glutamate levels in the somatosen-
sory cortex using microdialysis. The increase in glutamate
levels elicited by intracortical DOI was blocked by treat-
ment with the selective 5-HT2A antagonist M100,907.
They concluded that these data support the hypothesis
that 5-HT2A receptor-mediated regulation of glutamate
release is the mechanism through which hallucinogens
activate the cerebral cortex. However, common single
nucleotide polymorphisms of the 5-HT2A and 5-HT2C
receptors have been associated with auditory hallucina-
tions in patients with Alzheimer’s disease [15•].
Serotonin Receptor Genetic Studies
and Schizophrenia
A recent meta-analysis of whole-genome linkage scans
found that the T102C single nucleotide polymorphism
(SNP) of the gene HTR2A, which codes for the 5HT2A
receptor, and is located on the long arm of chromosome
13, is associated with schizophrenia in patients from
European, but not Asian, countries. The C-allele form of
HTR2A is significantly less frequent than that of the T-
allele form in patients with schizophrenia and in normal
control subjects in the European sample. Although data
pooled from five family-based association studies did not
show significant evidence for association of the C allele
with schizophrenia, the pooled OR was 1.3 (95% CI,
0.9 to 1.8; z = 1.47; P = 0.14), which is consistent with
the results of the case-control studies [16]. Masellis et al.
[17] reported that a -1438 A-->G SNP in the putative pro-
moter and a silent T102C substitution in HTR2A were in
14 Schizophrenia
almost complete linkage disequilibrium, and neither was
associated with response. However, a his452tyr HTR2A
polymorphism was found to be associated with cloza-
pine response (his452tyr allele: χ2 = 6.43, 1 df, P = 0.01
[P = 0.04, Bonferroni corrected]; genotype: χ2 = 6.54, 2
df, P = 0.04 [P = 0.16, Bonferroni corrected]). No HTR2A
haplotype was associated with response.
Castensson et al. [18] found decreased levels of mRNA
for the HTR2C and increased levels for the monoamine
oxidase B genes in schizophrenia brain (P = 0.001), but
no change in 14 other genes proposed to be differentially
expressed in schizophrenia in brain samples from 55
patients with schizophrenia and 55 control subjects. In
a subsequent study, the decrease in HTR2C mRNA was
reported to be present in neuroleptic treated individuals
and in patients untreated at death, indicating that the
lower expression was not attributable to treatment.
Three promoter polymorphisms were used to construct
haplotypes. No SNP showed genotypic or haplotypic asso-
ciation with the disease. Gene expression of HTR2C was
not affected by haplotype and the expression decrease in
patients with schizophrenia was similar in all haplotype
combinations (diplotypes). It was concluded that the
decrease in HTR2C expression in schizophrenia could be
related to etiology rather than to drug treatment [19].
Petronis [20] has suggested that epigenetic factors (eg,
imprinting and RNA editing), rather than inherited SNPs,
may be involved in the role of the HTR2A and other genes
in schizophrenia and be partially responsible for the
discrepancies between association and family studies. 5-
HT2C receptor RNA undergoes editing to produce several
receptor variants, some with biological differences from
the unedited form. In a small sample of patients with
schizophrenia and control subjects, RNA was extracted
from frontal cortex and reverse-transcriptase polymerase
chain reaction products of the edited region were cloned
and sequenced (n = 100). Reduced RNA editing, increased
expression of the unedited 5-HT2C-INI) isoform in
schizophrenia (P = 0.001), and decreased expression of the
5-HT2C-VSV) and 5-HT2C-VNV) isoforms were observed
in the patients with schizophrenia. It was suggested that
the reduced RNA editing could be caused by altered activ-
ity of the editing enzyme(s) rather than a mutation in
the HTR2C. Because the unedited 5-HT(2C-INI) is more
efficiently coupled to G proteins than the other isoforms,
its increased expression in schizophrenia may lead to
enhanced 5-HT(2C)R-mediated effects. An association
has been reported between the C allele of a -759C/T
polymorphism in the promoter of the HTR2C gene and
antipsychotic-induced weight gain. Buckland et al. [21]
cloned six HTR2C promoter haplotypes constructed from
four HTR2C promoter SNPs into a luciferase reporter
gene plasmid. Their transcriptional activities then were
compared in two human cell lines. They found that all
haplotypes containing the -759C allele showed less tran-
scriptional activity than haplotypes containing the -759T
allele. They suggested that the -759C allele is functional
and results in relative underexpression of HTR2C and
that reduced expression of HTR2C mRNA may underlie
vulnerability to weight gain with atypical antipsychotic
drugs such as clozapine and olanzapine.
None of the other 5-HT receptors have been impli-
cated in the etiology of schizophrenia per se but as will
be discussed, some, as well as the 5-HT2A and 5-HT2C
receptors have been implicated in the mechanism of
action of clozapine and related antipsychotic drugs.
The Role of Serotonin in the Mechanism of
Action of Atypical Antipsychotic Drugs
Atypical antipsychotic drugs (APDs) are those antipsy-
chotic drugs that produce their antipsychotic effect in
humans while causing minimal to modest extrapyrami-
dal side effects (EPS) and reduced catalepsy in rodents
[22]. Clozapine, the prototypical APD, was discovered in
1959. Other atypical APDs were found more or less seren-
dipitously (fluperlapine, melperone, tiaspirone, etc) on the
basis of their low EPS at doses that produced an antipsy-
chotic-like action in animal models or in humans [23••].
It was found that the shared pharmacology of these agents,
which distinguished them from the first-generation typi-
cal APDs, which produce significant EPS and catalepsy,
was weak D2 receptor blockade compared with 5-HT2A
receptor blockade [23••,24]. Therefore, these agents have
been called serotonin/dopamine antagonists, although
they have other pharmacologic features, but not neces-
sarily all of the compounds. This theory contributed to
the development of risperidone, olanzapine, quetiapine,
ziprasidone, perospirone and asenapine. Aripiprazole and
bifuprenox are two partial DA agonists which owe their
efficacy, in part, to 5-HT2A receptor antagonism or the
closely related 5-HT1A receptor agonism, as is discussed
below. Partial DA receptor agonism has the functional
effect of weak D2 receptor antagonism.
Subsequently, other important clinical differences
between typical APDs and clozapine, but not necessarily
other and atypical APDs, were found. Clozapine (but not
other atypical APDs) was found to be effective to treat
delusions and hallucinations in 60% to 70% of the 30%
of patients with schizophrenia who have persistent psy-
chotic symptoms despite treatment with typical APDs at
adequate dosages and durations [25,26]. Atypical APDs
also are able to modestly improve negative symptoms
more effectively than typical APDs. Clozapine also has
been found to be more effective in reducing the risk of
suicide in schizophrenia [27]. Most importantly, they
also improve some domains of cognition in patients with
schizophrenia, particularly storage memory and seman-
tic memory (verbal fluency) while having minimal effect
on working memory and executive function [28,29].
The advantages of greater efficacy for these domains of
schizophrenia coupled with advantages for EPS, both
 Serotonergic Mechanisms in Schizophrenia Meltzer et al. 15
acute and chronic (eg, tardive dyskinesia), has led to this
group of compounds becoming the most widely pre-
scribed antipsychotic drugs in developed countries. The
important role 5-HT plays in the action of these drugs
further supports the role of 5-HT in specific components
of schizophrenia.
Serotonin Receptors Involved in
Antipsychotic Drug Action
The hypothesis that a relatively high affinity for the 5-
HT2A receptor compared to their affinities for the D2
receptor was the basis for the difference between atypical
and typical antipsychotic agents contributed to the devel-
opment of the newer antipsychotic agents listed above, all
of which support the previously mentioned hypothesis of
high affinity for 5-HT2A and low affinity for D2 recep-
tors [23••,24]. However, other 5-HT receptors may be
important in the action of clozapine and other recently
introduced antipsychotic agents, or of potential value
for developing more effective or better-tolerated antipsy-
chotic agents. These include: 5-HT1A, 5-HT2C, 5-HT3,
5-HT6, and 5-HT7 receptors [24,30••]. Although some of
the atypical APDs developed on the basis of the 5-HT2A/
D2 hypothesis also have affinities for 5-HT2C, 5-HT3,
5-HT6 or 5-HT7 receptors that are in the same range as
that for the 5-HT2A receptor, this is not characteristic of
all of these agents; therefore, it is not likely that affini-
ties for these receptors are primary factors contributing to
the low EPS profile of the entire class of agents [31–33].
However, this does not rule out that actions at various
5-HT receptors contribute to low EPS of specific drugs,
or other actions (eg, cognitive improvement or improve-
ment in negative symptoms). For example, 5-HT1A
receptor agonism has also been suggested to contribute
to an atypical antipsychotic drug profile [34], and some
of the atypical antipsychotic are 5-HT1A partial agonists
and 5-HT2A/5-HT2C antagonists such as clozapine, que-
tiapine, ziprasidone, and S16924 [35].
Novel Antipsychotics and the
5-HT2A Receptor
It is well established that some typical and atypical APDs
can decrease the density of 5-HT2A receptors in rat brain
[36•]. The antipsychotic effect of clozapine has been
attributed, in part, to its ability to block excessive 5-HT2A
receptor stimulation without excessive blockade of D2
receptors [23••]. This conclusion is consistent with the
high occupancy of 5-HT2A receptors produced by clozap-
ine at clinically effective doses and its low occupancy of
D2 receptors (in the 30% to 50% range as measured with
the [3H]raclopride), the latter being signicantly below
the 80% to 100% occupancy usually produced by typical
neuroleptic drugs [37]. The occupancy of 5-HT2A and D2
receptors has been studied with other novel APDs such as
risperidone, olanzapine, sertindole, and quetiapine with
results similar to those of clozapine; all are more potent
5-HT2A and D2 antagonists at appropriate doses, but less
so than clozapine.
As a test of the contribution of 5-HT2A receptor
antagonism to antipsychotic drug action, clinical trials
of ritanserin, a potent 5-HT2A /2C antagonist, as add-on
therapy to typical neuroleptic drug treatment have been
done. Little or no beneficial effect was found (see [38]).
The bell-shaped dose response curve of risperidone,
with higher doses being less effective than lower doses
[39], suggests that excessive D2 receptor antagonism
may diminish some of the beneficial effects of 5-HT2A
receptor blockade. The highly selective 5-HT2A agonist
M100907 (Sanofi-Aventis, Paris, France), has been found
in a controlled study to have some efficacy for treating
positive and negative symptoms in hospitalized schizo-
phrenic patients (Potkin, 2005). However, because it
was less effective than haloperidol, no further testing
in schizophrenia has been scheduled at present. The 5-
HT2A/2C selective agent SR 46349B has been reported to
be as effective as haloperidol to improve total psychopa-
thology and negative symptoms in a trial in acutely ill,
recently hospitalized patients [40].
There is additional basic research that also is consis-
tent with the relevance of 5-HT2A receptor blockade for
antipsychotic drug action. Therefore, M100907 or other
selective 5-HT2A receptor antagonists, alone or in combi-
nation with selective antagonists of other receptors, have
been found to be effective in various animal models of
psychosis. These include: 1) blockade of amphetamine-
induced locomotor activity and the slowing of ventral
tegmental area (A10) dopaminergic neurons [41]; 2)
blockade of phencyclidine (PCP)- and dizocilpin (MK-
801)-induced locomotor activity [42,43]; and blockade of
the conditioned avoidance response [44].
Increased dopaminergic activity in the nucleus accum-
bens, other mesolimbic and possibly cortical regions, may
contribute to positive symptoms, including formal thought
disorder. The 5-HT2a/2c agonist DOI (1-(2,5-dimethoxy-
4-iodophenyl)-2-aminopropane), which had no effect
on basal DA release, potentiated amphetamine-induced
DA release and attenuated the ability of apomorphine,
a direct acting D1/2/3 agonist, to decrease DA release in
the striatum [45]. There is now considerable evidence
from behavioral and neurochemical studies involving N-
methyl-D-aspartate antagonists such as phencyclidine and
MK-801 that 5-HT2A receptors modulate activated DA
function, but not basal mesolimbic DA function [46,47].
Therefore, stimulated DA release, such as with stress, may
be increased in the forebrain terminal regions secondary
to enhanced stimulation of 5-HT2A receptors. Agents
that block the effect of excessive, but not basal, 5-HT2A
receptor stimulation may be the most useful clinically.
M100907 has been found to diminish the increase in DA
efflux in the nucleus accumbens produced by haloperidol
16 Schizophrenia
[48] or S-sulpiride [49]. Taken together, these data suggest
that 5-HT2A may have antipsychotic action when dopa-
minergic activity increased slightly or moderately. More
studies are needed to define the ability of 5-HT2a recep-
tor antagonists to potentiate the action of low doses of
D2 receptor blockers in animal models and in the clinic.
Recently Jakab and Goldman-Rakic [50] have proposed
that the 5-HT2A receptors on cortical pyramidal neurons
may play a crucial role in psychosis by virtue of their
ability to modulate intracortical and cortical-subcortical
glutamatergic neurotransmission. This could contribute
to the ability of 5-HT2A antagonists to attenuate some of
the behavioral effects of PCP and ketamine.
Serotonin, Prefrontal Cortex, Hippocampus
and Cognitive Function
As cognitive impairment is a central feature of schizo-
phrenia, it is essential that one consider the possibility of
a serotonergic component to this deficit, which precedes
and outlasts the presence of positive symptoms. The
prefrontal cortex (PFC) and hippocampus play a crucial
role in cognition. Pyramidal neurons in these two brain
regions control the activity of many subcortical motor
and limbic areas which play a role in schizophrenia.
These two regions receive afferents from brainstem nuclei,
including the dorsal and medial raphe nuclei. The PFC
and hippocampus contain very large densities of 5-HT1A
and 5-HT2A receptors, which exert inhibitory and excit-
atory control of pyramidal neuronal activity. However,
under physiologic conditions, the inhibitory influence of
the 5-HT1A receptors is predominant, possibly because
the 5-HT1A receptors are mainly localized in the axon
hillock [51]. In addition, 5-HT can inhibit pyramidal
neurons indirectly through the activation of 5-HT2A and
5-HT3 receptors located on GABA-ergic (γ-aminobutyric
acid) interneurons and a subsequent increase in inhibi-
tory synaptic GABA inputs [51].
There is extensive evidence for a role of 5-HT receptors
in cognition [52,53]. 5-HT2A/2C antagonists have little
adverse effect and no apparent beneficial effects on learn-
ing and memory [54]. Interactions between the 5-HT and
cholinergic systems have been previously reported [55].
The 5-HT2C, 5-HT3, 5-HT1A, and 5-HT4 receptors also
have been reported to have significant effects on acetylcho-
line release in the rat PFC [56–58]. Sumiyoshi et al. [59]
have found that tandospirone, a 5-HT1A partial agonist,
can improve other domains of cognition in patients with
schizophrenia treated with typical neuroleptic drugs.
Brain-derived neurotrophic factor (BDNF) regulates
the survival, differentiation, synaptic strength, and neu-
ronal morphology of serotonergic neurons in the cerebral
cortex and hippocampus [60]. BDNF SNPs have been
associated with schizophrenia in some but not all studies
[61]. It has recently been shown that stimulation of 5-
HT2A receptors by DOI increases the expression of BDNF
[62]. This effect was blocked by MDL 100907, which,
alone, did not have any effect in these regions. Recent
studies have shown that activation of metabotropic glu-
tamate group II (mGlu2/3) receptors suppresses 5-HT2A
receptor-stimulated excitatory postsynaptic potentials/
currents (EPSP/Cs) in pyramidal neurons in medial pre-
frontal cortex. Conversely, blockade of mGlu2/3 receptors
enhances 5-HT-induced EPSP/Cs. The highly selective
mGlu2/3 agonist LY354740 suppressed and the mGlu2/3
antagonist LY341495 enhanced the effect of DOI on BDNF
mRNA expression in medial prefrontal cortex. BDNF
mRNA expression was not altered by administration of
the mGlu agonist or the antagonist alone. In addition,
there is evidence from auditory-evoked potential studies
in normal control subjects that low serum BDNF levels
reflect low central serotonergic activity [63].
The Role of the 5-HT2C Receptor in
Antipsychotic Drug Action: 5-HT2A and
5-HT2C Interactions
There has been some consideration given to the role of
5-HT2C receptors in the action of atypical antipsychot-
ics. The 5-HT2C receptor is found throughout the central
nervous system, including the ventral tegmentum and
the nucleus accumbens [64]. There is conclusive evidence
of a tonic inhibitory action of 5-HT2C receptors on the
burst firing of mesolimbic and mesocortical dopami-
nergic neurons. This includes microdialysis studies that
show that 5-HT 2C antagonists increase extracellular con-
centrations of DA in the nucleus accumbens and medial
prefrontal cortex [65–67].
The Role of the 5-HT1A Receptor in
Antipsychotic Drug Action: 5-HT1a and
5-HT2a Interactions
The 5-HT1A receptors are located presynaptically in the
raphe nuclei where they act as autoreceptors to inhibit
firing of 5-HT neurons. They also are located post-
synaptically in hippocampus and PFC. Stimulation of
postsynaptic 5-HT1A receptors leads to hyperpolariza-
tion of pyramidal neurons [51]. This is opposite to the
effect of stimulation of 5-HT2A receptors. Because of this
action, the 5-HT1A receptor is able to play a major role in
cognition [51,68]. We and others have shown that stimu-
lation of 5-HT1A receptors by atypical antipsychotic
drugs leads to increased DA release in the cortex, which
should have a beneficial effect on cognition, provided
the synaptic levels of DA are not excessive [69,70]. The
5-HT1A receptor is coupled to a guanine nucleotide-
binding protein that inhibits adenylate cyclase. The gene
is located on chromosome 5 (5q11.2-13). A common C-
1019G functional polymorphism in the promoter region
of the human 5-HT1A receptor has been associated
with schizophrenia. Specifically, the frequency of the C
 Serotonergic Mechanisms in Schizophrenia Meltzer et al. 17
allele and the C/C genotype was significantly reduced in
patients with schizophrenia [71]. 5-HT1A receptor den-
sity has been reported to be increased in frontal cortex
in schizophrenia [72,73]. There is evidence that 5-HT1A
receptor stimulation leads to decreased glutamate release
[74]. Several atypical APDs are partial agonists at the
5-HT1A receptor including clozapine, ziprasidone, que-
tiapine, and tiospirone. Their affinities for the 5-HT1A
receptor were similar to their affinities at the human
D2 receptor [35,70]. Rollema et al. [75] showed that the
ability of clozapine to increase DA release in the rat PFC
was attributable to its 5-HT1a agonist properties in that
it could be blocked by WAY-100635, a 5-HT1A antago-
nist. These findings suggest that the combination of D2
antagonism or D2 partial agonism and 5-HT1A agonism
should produce an atypical antipsychotic agent. S16924
is an example of such a compound and it has atypical
properties very similar to those of clozapine in various
animal models [70]. Bifuprenox is a partial DA agonist
with 5-HT1A agonist but not 5-HT2A antagonist proper-
ties. How these agents compare with antipsychotic drugs,
which also are 5-HT2A antagonists, will be of interest.
Conclusions
Serotonin was once thought to have a role only in the
development of visual hallucinations. However, it is now
clear that it is important for the major components of
the schizophrenia syndrome: auditory hallucinations,
delusions, cognitive impairment, and probably negative
symptoms. This broad effect of 5-HT most likely occurs
through its ability to regulate cortical and hippocam-
pal pyramidal neuronal function through 5-HT1A and
5-HT2A receptors, located on these neurons, but also
on afferents to these neurons. Modulation of DA and
glutamate release in the cortex, hippocampus, nucleus
accumbens, and striatum by 5-HT1A, 5-HT2A, and 5-
HT2C receptors is a central component of how 5-HT
affects cognition, positive symptoms, and extrapyra-
midal side effects in schizophrenia. There is conclusive
evidence for the role of 5-HT receptors in the action of
multireceptor-acting atypical antipsychotic drugs related
to clozapine. The shared pharmacology of these agents
is more potent 5-HT2A than D2 receptor blockade, with
partial DA receptor agonism replacing direct D2 antago-
nism in agents such as aripiprazole and bifuprenox.
Genetic studies identifying key SNPs of these three recep-
tors, which increase vulnerability for schizophrenia and
affect the efficacy and side effects of atypical antipsy-
chotic drugs, are being done.
Acknowledgment
Supported, in part, by grants from the William K Warren
Medical Research Foundation and the Ritter Foundation.
References and Recommended Reading
Papers of particular interest, published recently,
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