Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Biochim Biophys Acta. Author manuscript; available in PMC 2008 May 4.
Published in final edited form as:
PMCID: PMC2366056

G Protein-Coupled Receptors in Major Psychiatric Disorders


Although the molecular mechanisms underlying psychiatric illnesses such as depression, bipolar disorder and schizophrenia remain incompletely understood, there is increasing clinical, pharmacologic, and genetic evidence that G protein-coupled receptors (GPCRs) play critical roles in these disorders and their treatments. This perspectives paper reviews and synthesizes the available data. Dysfunction of multiple neurotransmitter and neuropeptide GPCRs in frontal cortex and limbic-related regions, such as the hippocampus, hypothalamus and brainstem, likely underlies the complex clinical picture that includes cognitive, perceptual, affective and motoric symptoms. The future development of novel agents targeting GPCR signaling cascades remains an exciting prospect for patients refractory to existing therapeutics.

Keywords: G protein-coupled receptors (GPCRs), depression, bipolar disorder, schizophrenia, serotonin, dopamine, glutamate

1. Introduction

Although major psychiatric diseases such as mood disorders and schizophrenia are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex pathophysiology remains to be fully elucidated. Attempts to comprehend the biochemical underpinnings of major psychiatric disorders began in earnest as clinically effective mood-altering drugs began to appear in the late 1950s and early 1960s. Studies were, by and large, designed to detect relative excess or deficiency of individual neurotransmitters associated with pathological states; not surprisingly, progress in unraveling the neurobiology of these complex disorders was slow using such strategies in isolation. Psychiatry, like much of the rest of medicine, has entered a new and exciting age demarcated by current rapid advances and the future promises of genetics, molecular and cellular biology, and improving imaging technologies. Recent years have witnessed a more wide-ranging understanding of the neural circuits and the various mechanisms of synaptic transmission, a further elucidation of the molecular mechanisms of receptor and postreceptor signaling, a finer understanding of the process by which genes code for specific functional proteins, and the identification of causative genes in many neurological disorders that in toto reduce the complexity in gene to behavior pathways [1]. In other areas of medicine, the recent molecular medicine revolution has already had an immediate impact; unfortunately, clinical translation of these findings to psychiatric disorders has not been as rapid. In addition to the sheer complexity of the CNS, unraveling the etiology/pathophysiology of complex psychiatric disorders is hampered by numerous additional obstacles, including lack of a defined pathology, no direct tissue accessibility, and the daunting fact that the complexity of behavior is not simply the sum of its parts [1]. Nevertheless, major advances in our understanding of the role of G protein-coupled receptors (GPCRs) in the pathophysiology and treatment of major psychiatric disorders have indeed been made. In this perspectives article, we review and synthesize the available data, and discuss their implications for the strategic development of improved therapeutics. Due to space considerations, we have narrowed the scope of this review to the major psychiatric disorders, and the major families of GPCRs implicated, and have cited reviews in place of primary papers as often as possible.

2. Clinical Overview

It is beyond the scope of this article to discuss the role of GPCRs in all psychiatric disorders; here we limit ourselves to a discussion the most severe disorders – Schizophrenia and Mood Disorders. Since the readership of the journal may be less familiar with the clinical facets of these disorders, we first provide a brief clinical overview, prior to embarking on a discussion of GPCRs.

Mood disorders, such as major depression (MD) and bipolar disorder (BPD, previously referred to as manic-depressive illness), and schizophrenia are common, severe, and chronic illnesses. The Global Burden of Disease Study has identified major mood disorders among the leading causes of disability worldwide [2], and the World Health Organization estimates that mental illness accounts for 40 percent of disability funding in the U.S. [3].

2.1 Mood Disorders

MD has a lifetime incidence of about 15% [4], and affects twice as many women as men. There is a significant genetic component to the disorder; studies report an approximately three-fold increased risk of MD in first-degree relatives of probands with the disorder compared to the general population [4,5]. The course of MD is characterized by episodes of depressed mood, suicidal ideation, anhedonia, impaired sleep, changes in psychomotor activity, and impaired memory and concentration. Suicide is the cause of death in up to 15% of individuals with this disorder [6]. There are several classes of antidepressant medications used to treat MD, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and others that affect reuptake of monoamines such as norepinephrine, dopamine and serotonin.

BPD has an approximate lifetime incidence of 1% [8] and is characterized by two seemingly opposite mood states: mania and depression. It is equally prevalent in men and women [6]. The manic stages of BPD are characterized by a hyperaroused state (either euphoric or dysphoric), increases in motor activity, racing thoughts, impaired judgment, and an apparent decreased need for sleep [6,8]. The depressive phases of the illness present with similar symptomatology as those seen in MD. As with MD, suicide is the cause of death in up to 15% of individuals with BPD [6]. BPD is typically treated with the class of medications known as mood stabilizers (reviewed in [8]). Although other types of medications, including atypical antipsychotics, are also used to treat BPD, most studies have focused on mood stabilizers such as lithium, valproic acid and carbamazepine as the standard of treatment for this disorder.

3.2 Schizophrenia

Schizophrenia has a lifetime prevalence of approximately 1% [3] and affects men and women equally. Family prevalence, twin, and adoption studies have all demonstrated that there is a genetic component to this disorder; individuals with a first degree relative with schizophrenia are ten times more likely to be affected than an individual in the general population. Schizophrenia is a psychotic disorder characterized by delusions, hallucinations and/or thought disorganization (“positive symptoms”) and flattened affect, poverty of thought and/or avolition (“negative symptoms”). The cognitive impairments in schizophrenia (sometimes quite profound) are increasingly being recognized as playing a major role in the long-term disability observed in this devastating illness. Not surprisingly, much of the new medication strategies have focused on improving the cognitive deficits (vide infra). The suicide rate among schizophrenic individuals is twice that of the general population [3]. Like mood disorders, schizophrenia is associated with a significant increase in medical comorbidities [3], a difficulty compounded by the increasingly recognized fact that newer antipsychotic medications can cause medical complications such as obesity and diabetes. The economic cost of managing a patient with schizophrenia is estimated to be six times that of a patient with a myocardial infarction [3]. Schizophrenia is generally treated with antipsychotic medications. The use of first generation, or typical, antipsychotics, has largely given way to the use of newer, second generation, or atypical, antipsychotics which have equivalent efficacy, but different and arguably more favorable side effect profiles.

3. GPCRs and Mood Disorders

Although most families of medications currently used to treat affective illnesses have been in use since the 1950s, our understanding of their mechanisms, and the etiology of the underlying diseases, is still incomplete. The “pharmacological bridge” approach to biomedical research refers to the development of etiologic theories of disease based on the known mechanism of effective pharmacologic treatments. In mood disorders, this approach first led to the monoamine theory. As discussed below, monoamines are still considered to be among the most important neurotransmitters in the pathophysiology of mood disorders. However, other neurotransmitter systems, most notably the glutamatergic, cholinergic and GABAergic systems, have also been implicated.

3.1 G protein-coupled noradrenergic receptors and mood disorders

The noradrenergic system was one of the first neurotransmitter systems to be suspected to play a role in affective disorders. Many initial studies indirectly addressed the question of noradrenergic receptor abnormalities in these disorders by investigating expression in peripheral cells. Further evidence has come from postmortem studies, pharmacologic challenge experiments, studies to elucidate the mechanism of action of effective medications, and genetic studies.

3.1.1 Peripheral blood cell studies

Due to the accessibility of platelets and lymphocytes, both alpha2 and beta2 adrenergic receptors have been extensively studied in mood disorders. It must be acknowledged at the outset that there may be several problems with the assumption that changes in adrenergic receptors on peripheral cells reflect similar alterations in the CNS. To begin with, receptors on blood cells are, by definition, noninnervated, exist in a markedly different environment, and may therefore poorly reflect central, innervated, adrenergic receptors. Another major problem when interpreting studies of dynamic receptor regulation in blood cells is that white blood cell counts and the relative proportions of subsets of lymphocytes may vary. Recruitment of cells with different characteristics into the circulation may frequently explain altered receptor function. Nevertheless, in some cases, similar findings have been found in postmortem brain studies and in certain CNS challenge studies as has been observed in peripheral cell studies.

Alpha2-adrenergic receptors

Studies of alpha2-adrenergic receptor (alpha2-AR) levels in platelets of depressed patients have yielded mixed results. A series of studies using yohimbine-alkaloid radioligands showed no differences in receptor numbers, while other studies using partial or full agonists have reported an increased maximal binding capacity in depressed patients relative to controls (reviewed in [7]). The findings of these latter studies have been called into question, however, because the ligands have been discovered to bind to nonadrenergic imidazoline sites [9-11], which are present on platelets [12]. Thus the alpha2 receptor hypersensitivity theory of depression, based on these initial findings, remains in question.

Few studies have addressed this question in bipolar disorder. One such study found a trend toward increased density of alpha2-ARs on platelets of patients with bipolar disorder [13].

Beta2-adrenergic receptors

Although studies investigating the levels of beta2-adrenergic receptors (beta2-ARs) in peripheral cells have yielded inconsistent results (reviewed in [7]), multiple studies have reported decreased beta-AR-stimulated adenylate cyclase (AC) activity in leukocytes of depressed patients [14-19]. This is hypothesized to be due to a disruption of the receptor/Gs/AC complex [20]. For both the alpha2 and beta2 findings in peripheral cells, it remains to be determined which abnormalities relate specifically to the pathogenesis of mood disorders, and which are related to nonspecific effects of stress, or homeostatic mechanisms [21].

3.1.2 Postmortem studies

Alpha-adrenergic receptors

Limited data suggests alpha2-AR levels are altered in the postmortem brains of depressed suicide victims (reviewed in [22]). These preliminary findings are limited by methodological considerations regarding the use of postmortem brains (e.g., postmortem delay, cause of death, drug history) and by the fact that some of the ligands used also bind imidazoline sites, as discussed above.

Beta-adrenergic receptors

Several studies have reported an increase in beta-AR density in the brains of suicide victims [23], including specifically in cortex [24], while at least one other study found no difference in cortex [25].

3.1.3 Pharmacologic challenge experiments

Alpha2-adrenergic receptors

Numerous studies have investigated the role of alpha2-ARs in mood disorders using pharmacologic challenge strategies. Multiple studies have compared the downstream effects of alpha2-AR agonists (such as clonidine) or antagonists (such as yohimbine) on plasma MHPG, blood pressure, sedation and cortisol in depressed patients compared to normal controls. While the findings have not been entirely consistent, most do not show significant differences (reviewed in [21]). However, multiple studies have consistently demonstrated a significant decrease in growth hormone (GH) response to the alpha2-AR agonist clonidine [26-32], supporting the hypothesis of postsynaptic alpha2-AR subsensitivity in depressed patients.

Far fewer studies have addressed the question of alpha2-AR sensitivity in bipolar disorder. Several such studies have demonstrated a blunted GH response in manic and/or bipolar depressed states (reviewed in [21]). Similar findings have been reported in panic disorder, general anxiety, and obsessive-compulsive disorder, suggesting that it may be a nonspecific response to stress and/or elevated norepinephrine [33-36].

3.1.4 Effects of antidepressants and mood stabilizers

Alpha-adrenergic receptors

Antidepressants have been shown to decrease alpha2-ARs and increase alpha1-ARs in animal studies (reviewed in [22]). Long-term lithium administration has been shown to attenuate alpha2-AR-mediated behavioral effects [37].

Beta-adrenergic receptors

Most studies have shown a consistent pattern of beta-AR downregulation in response to long-term treatment with antidepressants of all classes or electroconvulsive therapy (ECT) [22, 38-42]. Long-term administration of desipramine, an antidepressant, results in uncoupling of beta-AR and Gs in cortex [43,44]. Both receptor downregulation and receptor-G protein uncoupling result in decreasing downstream cAMP signaling [43-45]. Desipramine also inhibits the breakdown of the beta-AR high affinity complex [46], which interferes with the downstream activation of adenylate cyclase [47].

Most studies addressing the effects of mood stabilizers have focused on lithium. Studies investigating the effects of lithium on adrenergic receptor binding in rat brain have been inconclusive (reviewed in [21]), but have consistently shown an inhibition in beta-AR-stimulated cAMP [48]. Lithium does not block antidepressant-induced beta-AR downregulation [49].

Fewer studies have investigated the effect of other mood stabilizers in this system. One in vitro study found that valproic acid caused decreased beta-AR density, as well as cAMP production and G-alpha-s levels [50], while other studies investigating beta-AR density in response to valproic acid have produced mixed findings. Carbamazepine has been shown to induce upregulation of beta-ARs, and, consistent with other mood stabilizers, carbamazepine decreases beta-AR-induced AC activity (reviewed in [21]).

3.1.5 Receptor polymorphisms

Studies examining alpha2-AR polymorphisms have not found an association with suicide or depression [51,52]. One study examining a beta1-AR polymorphism, G1165C, found a nonsignificant trend toward an association with an improved response to antidepressant treatment in depressed patients [53]. Most recently, a study investigated the effects of iv infusion of yohimbine on subjects carrying an-frame deletion of the alpha2C-adrenoreceptor subtype (alpha2CDel322-325) [54]. At rest, homozygotes for the alpha2CDel322-325 polymorphism had higher total body noradrenaline spillover than did heterozygotes; moreover, yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes than in the other groups. Since the pattern of catecholaminergic responses is similar to what has been observed in mood disorders [7], the role of this receptor polymorphism in these disorders is under investigation.

3.2 G protein-coupled serotonergic receptors and mood disorders

The efficacy of medications with serotonergic effects in the treatment of depression has been the primary impetus for proposing a role for serotonin in mood disorders. In addition to pharmacologic data, there is considerable evidence for serotonergic abnormalities in patients with depression, although the data for bipolar disorder is less clear. Some of the most compelling recent data that support a role for serotonin in mood disorders comes from the identification of receptor polymorphisms associated with disease susceptibility and/or treatment response.

3.2.1 Pharmacologic challenge, postmortem and imaging studies

Depressed patients have been shown to exhibit a blunted response of the serotonin system, as measured by fenfluramine-induced prolactin release [55], although other studies have not replicated this finding. This blunting was more pronounced in the subset of patients who made high lethality suicide attempts [56] and those with anger attacks [57].

5HT1A receptors

Several studies have shown blunted responses to 5HT1A receptor agonists and decreased 5HT1A receptor binding postmortem in depressed patients [58-59], although some studies have found an increase in the number of 5HT1 receptors in prefrontal cortex of suicide victims [60], or increased 5HT1A binding in depressed patients [61]. PET studies have demonstrated region-specific changes in 5HT1A receptor binding in depressed subjects compared to healthy controls [62,63]. It is speculated that the mechanism of decreased 5HT1A receptor binding is via increased cortisol secretion, which inhibits 5HT1A mRNA expression (reviewed in [21]).

5HT1B receptors

In a recent report, Svenningsson and colleagues [64] demonstrate that 5HT1B receptors are modulated by p11, which is decreased in an animal model of depression and in brain tissue from depressed patients, and is increased in rodent brains by antidepressants or ECT. The authors show that overexpression of p11 in mice increases 5HT1B receptor function and mimics certain behaviors seen in response to antidepressant treatment, while p11 knockout mice demonstrate a depression-like phenotype and have reduced responsiveness to 5HT1B receptor agonists. The intriguing findings from this study suggest a dynamic relationship between 5HT1B receptors and p11 that may be involved in the pathophysiology of depression.

5HT2 receptors

Postmortem studies have found an increase in the number of 5HT2A and 5HT2C receptors in the brains of patients with depression and in suicide victims (for example, see [65,66]), although other studies have found contradictory results (reviewed in [67,68]). Imaging studies [67, 69], and studies investigating 5HT2A receptors on platelets [21] have similarly yielded mixed results.

3.2.2 Effects of antidepressants and mood stabilizers

5HT1A receptors

The postulated role of 5HT1A receptors in mood disorders is supported by evidence that chronic antidepressant treatment results in desensitization of somatodendritic 5HT1A autoreceptors in the dorsal raphe and subsequent enhancement serotonergic transmission in hippocampus [70, 71]. Abnormalities in 5HT1A receptor binding in bipolar patients are normalized by chronic lithium administration [21]. Chronic antidepressant treatment has also been shown to increase 5HT1A receptor-G protein uncoupling [72].

5HT2 receptors

Antidepressants have been shown to downregulate 5HT2A receptor binding in cortex [73]. The evidence for the role of 5HT2A receptors in the mechanism of action of mood stabilizers is much less clear. Studies investigating 5HT2A receptor binding following chronic lithium administration have produced mixed results. Most suggest that lithium induces a decrease in 5HT2 receptor binding, with the strongest evidence in the hippocampus (reviewed in [21]), although studies in platelets have demonstrated a lithium-induced increase in 5HT2A receptor binding capacity in bipolar patients [74].

3.2.3 Receptor polymorphisms

5HT1A and 5HT1B receptors

Data from several studies support a role for the 5HT1A receptor in depression and treatment outcome. Lemonde and colleagues [75,76] report an association of the C-1019G 5HT1A promoter polymorphism with major depression and suicide, and with response to flibanserin, a 5HT1A agonist antidepressant. Other studies have similarly reported an association between antidepressant response and both this polymorphism [61,77] and Gly272Asp [78]. Arias and colleagues [79] found that a combined genetic effect of the HTR1A gene, which encodes the 5HT1A receptor, and the SLC6A4 gene, which encodes the serotonin transporter, influenced clinical outcome of depressed patients treated with the antidepressant citalopram. The G861C locus of the 5HTR1B gene has been shown to be associated major depression, but not bipolar disorder [80], although another study did not find such an association [81].

5HT2A receptors

A promoter polymorphism in the 5HTR2A gene, A-1438G, has been shown to be associated with major depression [82]. Many studies have attempted to identify an association between 5HT2A receptor polymorphisms and bipolar disorder, but these studies have yielded few demonstrated associations. The most widely studied polymorphism, T102C, has repeatedly not been found to have an association with bipolar disorder [83-85]. However, several studies have shown positive associations between other 5HT2A receptor polymorphisms (C516T, C1354T and A-1438G) and bipolar disorder [86-88].

Choi and colleagues [89] found an association between the A-1438G polymorphism of the 5HT2A receptor and treatment response to the antidepressant citalopram, although another group reported finding no such association using the antidepressant fluvoxamine [90]. Some of the most compelling evidence for a role for the 5HT2A receptor in the treatment of mood disorders comes from the Sequenced Treatment Alternatives for Depression (STAR*D) study. A significant association was found between treatment outcome and a marker in HTR2A, which encodes the 5HT2A receptor [91]. This study searched for genetic predictors of treatment outcome in 1,953 patients with major depression, and detected a significant and reproducible association between treatment outcome and an intronic marker in the 5HT2A receptor gene. Moreover, the A allele (associated with poorer response) was over six times more frequent in white than in black participants, and treatment was less effective among black participants [91]. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action; furthermore, the polymorphisms in this receptor may also contribute to racial differences in outcomes of antidepressant treatment.

5HT2C receptors

Lerer and colleagues [92] demonstrated an association between a 5HT2C receptor polymorphism and both major depression and bipolar disorder in a population derived from nine different European countries. Gutierrez and colleagues have investigated this same 5HT2C receptor polymorphism in bipolar disorder and have demonstrated a weak association in female bipolar patients that was not seen in a mixed gender sample [93,94]. Another group similarly found a trend toward an association between a 5HT2C polymorphism and female, but not mixed gender, bipolar patients [95].

3.3 G protein-coupled dopaminergic receptors and mood disorders

Although dopamine has been at the center of schizophrenia research for decades, it has been relatively under-examined with respect to its role in mood disorders. Nevertheless, there are several lines of evidence pointing to dopamine's role in these illnesses. The midbrain dopamine system regulates motor activity, motivation and reward pathways, and the mesolimbic dopamine system plays a critical role in goal-directed behavior. All of these functions are significantly disrupted in depression and mania. Multiple pharmacologic agents that act on dopamine receptors have effects on mood symptoms, further supporting the role of G protein-coupled dopamine receptors in mood disorders.

3.3.1 Imaging and pharmacologic studies

SPECT studies have demonstrated increased D2/D3 receptor availability in the striata of depressed patients with bipolar disorder (reviewed in [21]). Two such studies correlated increased receptor binding with psychomotor retardation [96,97].

Antipsychotics that block dopamine receptors are effective against acute mania. Multiple dopamine receptor agonists, including bromocriptine and pramipexole, have significant antidepressant properties, both in bipolar and unipolar depressed states [98]. Pramipexole has been found to be effective alone [99] and as an adjunct to selective serotonin reuptake inhibitor (SSRI) antidepressants [100] or mood stabilizers [101].

Dopamine receptor binding studies comparing lithium to placebo have been inconclusive. However, lithium has been shown to inhibit haloperidol-stimulated dopamine receptor upregulation and agonist-induced supersensitivity [21].

3.3.2 Receptor polymorphisms

D1 receptor

Although several studies have failed to find mutations in the D1 receptor gene in bipolar disorder [102, 103], the results of two studies suggest an association between the D1 receptor A48G polymorphism and bipolar disorder [104,105].

D2 receptor

Numerous studies have attempted to identify an association between D2 receptor polymorphism and bipolar disorder and have failed to find such an association. Two studies, however, have reported positive findings. In a large European multicenter study, Massat and colleagues [106] found a significant association between the D2 receptor and bipolar disorder. In a smaller study of Han Chinese patients with bipolar disorder, Li and colleagues [107] found an association with a D2 receptor polymorphism which was not replicated when studied in a Caucasian population, suggesting a possible race-specific risk factor.

D3 receptor

One small study has found an association between a D3 receptor polymorphism and unipolar depression [108]. Multiple studies have failed to show clear evidence for the involvement of the D3 receptor locus in bipolar disorder.

D4 receptor

Several studies have investigated a possible role for the D4 receptor in depression. Lopez Leon and colleagues [109] performed a meta-analysis of these studies and found a significant association between the D4 receptor gene 48 base pair repeat polymorphism and unipolar depression but not bipolar disorder.

3.4 G protein-coupled cholinergic receptors and mood disorder

There has been a long-standing interest in the potential involvement of the cholinergic system in bipolar disorder, based primarily on studies indicating the prominent mood and behavioral effects of cholinergic agonists and antagonists. (reviewed in [21]). Most studies documenting cholinergic receptor sensitivity in mood disorders have been quite indirect. For example, REM occurs during discreet periods of sleep, but its onset can be induced earlier in normal volunteers by cholinergic agents. Several research groups have reported a faster induction of REM sleep with arecoline (a cholinergic agonist) in medication-free mood disorder patients (primarily bipolar disorder) (reviewed in [21]).

Most recently, Cannon and associates [110] used positron emission tomography and [18F]FP-TZTP (fluorodopa F 18 [3-(3-[3-fluoroproply]thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine), a selective M2 receptor radioligand, to assess the binding potential of muscarinic2 receptors in vivo. They found significantly lower M2 binding in anterior cingulate in BPD compared with both MD and control groups.

Many antidepressants, including tricyclics and serotonin reuptake inhibitors, have anticholinergic properties, although the relevance to their antidepressant action is not clear. Studies have produced conflicting reports regarding the effect of lithium on muscarinic receptor binding. Lithium has been shown to block muscarinic receptor supersensitivity without affecting the number of receptor binding sites, suggesting it acts at a post-receptor site [111].

One study has shown an increased frequency of homozygosity at the A1890T polymorphism in the cholinergic muscarinic receptor 2 (CHRM2) gene among women, but not men, with major depression [112].

3.5 G protein-coupled GABAergic receptors and mood disorders

There is some evidence that G protein-coupled GABA-B receptors play a role in mood disorders. Baclofen, a GABA-B receptor agonist, has been shown in a small number of patients to induce a reversible depression that remits following discontinuation of the agent [113]. Chronic administration of mood stabilizers such as lithium, valproic acid and carbamazepine increases GABA-B receptors in hippocampus [114,115], although the relevance of this finding to their pharmacologic effect is not known.

3.6 G protein-coupled glutamatergic receptors and mood disorders

It is surprising that the glutamatergic system has only recently undergone extensive investigation with regard to its possible involvement in the pathophysiology of mood disorders, since it is the major excitatory neurotransmitter in the CNS, known to play a role in regulating the threshold for excitation of most other neurotransmitter systems. There is now mounting evidence for a role of the glutamatergic system in the pathophysiology and treatment of mood disorders [116-118]. However, to date, most of the available evidence implicates ionotropic receptors -- both NMDA [118] and AMPA [119] -- in the treatment of mood disorders. In view of our focus on GPCRs, these will not be discussed here; interested readers are referred to recent reviews dealing with a broader discussion of the role of the glutamatergic system in mood disorders [116-118].

3.7 G protein-coupled neuropeptide receptors and mood disorders

Neuropeptides are short-chain amino acids that act as neurotransmitters in numerous brain circuits; indeed, the contribution of altered endocrine function to pathological mood states was among the earliest themes in biological psychiatry. The actions of a single neurohormone peptide on a wide range of brain receptors characteristically span a much longer time period than the actions of monoamines. The influence of neurohormones on neurons may have been elaborated for teleological reasons. The possibility that one substance effectively commands and organizes multiple coordinated physiological and behavioral responses is consistent with the importance of certain peptides in the long-term phasic changes typical of mood disorders [21]. The voluminous data implicating abnormalities of various neurohormones and neuropeptides is reviewed extensively elsewhere ([21] and other textbooks); here, we limit ourselves to those neuropeptide GPCRs that are being extensively investigated in the treatment of mood disorders.

3.7.1 Corticotropin-releasing factor (CRF) Receptors

CRF has become one of the most extensively studied of all the neuropeptides in relation to its potential role in mood disorders, due to demonstrations of abnormalities in patients and in animal models (reviewed in [21,120,121]). Preclinical studies using animal behavior models have indicated that CRF receptor antagonists, specifically of the CRF receptor-1 subtype, have anxiolytic and antidepressant activity [122]. These results led to the testing of a CRF receptor-1 antagonist, R121919, in an open trial in 24 patients with depression [123]. Initial results were encouraging, and further clinical studies are anticipated. However, at least two genetic linkage and association studies have failed to support the linkage of CRF polymorphisms to bipolar illness [124,125].

3.7.2 Neurokinin1 (NK1) receptors

Preclinical behavioral studies involving pharmacological or genetic inactivation of the neurokinin1 receptor [126] suggested a promising target for antidepressant and/or anxiolytic drug discovery. Importantly, genetic or pharmacologic blockade of NK1 receptors were also observed to induce some of the same long-term neural effects as standard antidepressants on cell signaling molecules such as BDNF and hippocampal neurogenesis [127]. However, despite the promising preclinical data, a recent pooled analysis of five 8-week randomized, double-blind placebo-controlled multicenter studies of the substance P antagonist aprepitant in major depression found lack of efficacy [128].

3.7.3 Neuropeptide Y (NPY)

NPY, the most abundant peptide in mammalian brain, is a 36-amino acid polypeptide, rich in tyrosine residues, with a molecular weight of 4272 Daltons. There are 6 recognized NPY receptor subtypes (Y1-Y5) present in the brain and other tissues. In the brain, major sites of NPY production are the cerebral cortex, locus coeruleus, hippocampus, brainstem, and hypothalamus, where the highest concentrations are present. In fact, NPY is the most potent physiological stimulant of feeding behavior yet described [129]. A recent report found decreased CSF concentrations of NPY in patients with treatment resistant unipolar major depression [130]. The upregulation of amygdala NPY mRNA levels after chronic stress suggests potential involvement in the adaptive responses to stress exposure [131].

4. GPCRs and Schizophrenia

4.1 G protein-coupled dopaminergic receptors and schizophrenia

The dopamine hypothesis of schizophrenia remains the primary explanatory hypothesis for the florid psychotic symptoms of the disease (notably hallucinations and delusions), although it is clear that the true pathophysiology is much more complex. The hypothesis that schizophrenia is caused by hyperactivity of limbic dopaminergic transmission arose from the fact that all effective antipsychotic agents block dopamine D2 receptors, and amphetamine, which facilitates dopamine release, induces schizophrenia-like psychotic symptoms. The majority of data supporting the dopamine theory continues to come from studies of antipsychotic medications (see below).

4.1.1 Postmortem and imaging studies

Many studies have looked for evidence of dopamine receptor dysregulation in schizophrenic patients, with mixed results. In contrast with some early findings, recent studies have generally been consistent in showing no abnormalities in D2 receptor density in schizophrenia (reviewed in [132,133]). With regard to other dopamine receptor subtypes, one intriguing study demonstrated decreased D1 receptor density in prefrontal cortex by PET and correlated this finding with the severity of negative symptoms and impairment in prefrontal cognitive performance [134]. One report demonstrated an increase in D3 receptor in the nucleus accumbens [135], while another showed decreased D3 receptor levels in parietal and motor cortex [136]. Studies have shown decreased D3 and D4 mRNA in orbitofrontal cortex [137] and increased D4 receptor levels in putamen in schizophrenia [138].

4.1.2 Effects of antipsychotic medications

The hyperactive dopamine theory was initially developed in light of the high D2 affinity of typical antipsychotics and the tight correlation between receptor affinity and clinical response [139]. PET and SPECT studies confirm the relationship between D2 receptor occupancy and therapeutic effect: typical antipsychotic efficacy appears to be optimized at 65-70% D2 receptor occupancy, and greater than 80% occupancy significantly increases the risk of extrapyramidal symptoms (EPS), a known side effect [140].

Several lines of evidence suggest that D2 receptor binding is insufficient to fully account for the pathophysiology of schizophrenia. First, not all patients with schizophrenia improve on typical antipsychotics, despite 70% or greater receptor occupancy [140]. Second, typical antipsychotics effectively treat only about 70% of positive symptoms [133] and are relatively ineffective with respect to negative and cognitive symptoms. Third, the timecourse of receptor blockade, which occurs in a matter of hours, does not correlate with the timecourse of clinical effect, which occurs over days or weeks [133,140]. It is hypothesized that downstream or longer-term changes mediate the clinical effect; for example, long-term administration of typical antipsychotics have been shown to upregulate D2 receptors [140]. Finally, atypical antipsychotics have overall lower D2 receptor binding affinity than typical antipsychotics but are not less effective. The atypical antipsychotics clozapine and quetiapine, for example, exert therapeutic effects at less than 70% occupancy [140].

Together these data suggest that although some level of D2 blockade is necessary for antipsychotic effects, it is not sufficient. Atypical antipsychotics act on other dopaminergic receptors subtypes as well as non-dopaminergic receptors. Compared to typical antipsychotics, atypicals have a much stronger binding affinity for D4 receptors as well as multiple other GPCRs, including D1, D3, 5HT1A, 5HT2A, 5HT2C, and muscarinic receptors. Typical antipsychotics have been shown to induce increased expression of D1 receptors [141].

Clinically, typical antipsychotics are effective only against positive symptoms, presumably via D2 receptor antagonism, while atypical antipsychotics are additionally effective with regard to negative and cognitive symptoms. D2 antagonists can block stimulant-induced psychosis in healthy individuals [142]. Dopamine agonists have been shown to improve negative symptoms and prefrontal cognitive performance [143], and these symptoms, when induced by amphetamine treatment, are not blocked by D2 antagonists [144]. Taken together these data lend support to a newer and more complex hypothesis of schizophrenia in which hypoactive D1 receptors in the mesocortical pathway correlate with negative symptoms and hyperactive D2 receptors are associated with positive symptoms [145].

4.1.3 Receptor polymorphisms

D2 receptors

Given the above findings, numerous researchers have investigated the role of D2 receptor polymorphisms in schizophrenia. Although controversial, multiple reports, both primary studies and meta-analyses, have demonstrated a positive association between the D2 receptor Ser311Cys polymorphism and schizophrenia [146-149]. Other studies, however, have found no association [150, 151]. One study did find an association between Ser311Cys and symptom severity, although not diagnosis [152]. A second polymorphism from the D2 receptor promoter region, -141C Ins/Del, has also been shown by several groups to be associated with schizophrenia [153-156]. Other reports have implicated other D2 receptor polymorphisms such as C957T [157], His313 [158], and the Taq1A locus [159]. Several studies have shown an association of -141C Ins/Del with timing or degree of response to antipsychotic medications, with a more favorable response associated with the -141C Ins allele [160-162], although other studies have not supported these findings [163, 164]. Multiple studies have similarly shown an association between treatment response and the Taq1A locus [162, 163, 165-166], the Ser311Cys polymorphism [167] and the His452Tyr polymorphism [168].

Other dopamine receptor subtypes

The D3 receptor polymorphism, Ser9Gly, is the most widely studied for the D3 receptor, but results correlating it with susceptibility to schizophrenia have been inconclusive [169-173]. Multiple studies have demonstrated an association between this polymorphism and response to antipsychotics [174-177]. There is some discrepancy among these studies regarding which subset of symptoms primarily correlates with this polymorphism, and one published study failed to find any correlation [173]. A pattern of association is seen between the Ser9 allele and response to typical antipsychotics, and between the Gly9 allele and response to atypical antipsychotics (reviewed in [162]).

Other D3 receptor variants that have shown association with schizophrenia include G-205A [169,171], G-7685C [169], and G-712C [171]. Mixed results have been reported regarding the BalI [178-184] and MscI [185, 186] restriction sites in exon 1.

In the D4 receptor, a 48 base pair repeat in exon 3 has been the subject of much research; however studies have failed to show a significant association with schizophrenia [187-190]. Although one study reports an association between this polymorphism and response to the atypical antipsychotic clozapine [191], two other studies showed no such correlation [192, 193].

4.2 G protein-coupled serotonergic receptors and schizophrenia

Although evidence for changes in serotonin receptors in schizophrenia has been controversial, pharmacologic data, such as the serotonergic effects of pro-psychotic drugs of abuse and of atypical antipsychotic medications, suggest a role for serotonin in this disease.

4.2.1 Postmortem and imaging studies

Some postmortem studies show a decrease in 5HT2A receptors in schizophrenia, although others do not (reviewed in [194]). One PET study showed no difference between untreated schizophrenic patients and controls with respect to 5HT2A receptor expression in cortex [194], while another demonstrated an increase in both 5HT1 and 5HT2A receptors [195].

4.2.2 Pharmacologic studies

The strongest evidence for a role for serotonin in schizophrenia comes from pharmacologic studies. D-lysergic acid diethylamide (LSD) can cause psychotic symptoms in healthy individuals, and its structural similarity to serotonin prompted further investigation of this neurotransmitter system in psychosis [196]. It is now known that LSD exhibits effects on the serotonin system in the raphe nucleus via 5HT1A receptors, and most likely induces hallucinations via agonist action at the 5HT2A receptor (reviewed in [196, 197]).

The discovery of atypical antipsychotics, which block the 5HT2A receptor in addition to dopamine receptors and others, prompted the development of the serotonindopamine antagonism theory. This theory states that the higher the ratio of 5HT2A receptor affinity to D2 receptor affinity, the more “atypical” the antipsychotic, i.e., the more effective and the less likely to produce EPS (reviewed in [140]). The atypicals clozapine, risperidone, olanzapine and ziprasidone demonstrate greater than 80% occupancy of cortical 5HT2A receptors at therapeutic doses [140]. It is hypothesized that 5HT2A receptor antagonism partially reverses D2 receptor blockade, resulting in less EPS [140, 198]. The 5HT2A effects of these medications are not sufficient to mediate their antipsychotics effects, however, as 5HT2A receptor antagonist monotherapy with M-100907 is ineffective [199].

In addition to receptor blockade, atypical antipsychotics have also been found to induce subcellular redistribution of the 5HT2A receptor. Willins and colleagues [200] demonstrated that atypical antipsychotics with high affinity for the 5HT2A receptor (clozapine, olanzapine and risperidone) induce internalization of the 5HT2A receptor in fibroblasts in vitro. Consistent with this finding, they also report loss of 5HT2A receptor immunoreactivity on pyramidal neurons in response to clozapine and olanzapine [200].

Action at the 5HT1A receptor is thought to synergize with actions at the dopamine receptor and 5HT2A receptor in the treatment of schizophrenia. Some studies have demonstrated that 5HT1A agonists augment the effect of dopamine antagonists [201], and it is hypothesized that the partial 5HT1A agonism of clozapine [202] and aripiprazole [203] contribute to their therapeutic effects on negative and cognitive symptoms.

4.2.3 Receptor polymorphisms

5HT1A receptor

Multiple studies have investigated an association between the T102C polymorphism of the 5HT1A receptor and susceptibility for schizophrenia, with both primary studies and meta-analyses producing mixed results [204-217]. An association of genotype distribution and allele frequency of the 5-HTR1A C-1019G locus with schizophrenia has been reported [218].

5HT2A and 5HT2C receptors

Results from studies investigating an association between 5HT2A receptor polymorphisms and response to antipsychotic treatment have been variable and generally not significant. Some studies have shown an association between the T102C polymorphism and atypical antipsychotic response [219-221], while at least one other has not [222]. The results of two studies have shown a nonsignificant association between G-1438A polymorphism variants and response to the atypical antipsychotics olanzapine or clozapine [223, 224]. Studies investigating the his452tyr polymorphism have yielded mixed results, and in those that found an association, it was not significant or not replicated with the same significance in subsequent reports [222, 224-226].

Two 5HT2C polymorphisms have been shown to be associated with response of schizophrenic patients to antipsychotic treatment: the C-759T polymorphism in the promoter region [227] and Cys23Ser [228].

4.3 G protein-coupled noradrenergic receptors and schizophrenia

While a primary abnormality in the noradrenergic system has not been demonstrated in schizophrenia, norepinephrine plays a key role in regulating prefrontal cognitive function, which is impaired in patients with this disorder. In addition, several pharmacologic agents have effects on adrenergic receptors, suggesting a potential, indirect role for this system in the treatment of the disease.

4.3.1 Pharmacologic challenge studies

Recent studies have investigated the potential role of stress-induced noradrenergic dysfunction of prefrontal cortical function. The prefrontal cortex allows us to appropriately guide our behaviors, thoughts, and emotions by using representational knowledge [229]. Lesions of the prefrontal cortex produce symptoms of impulsivity, distractibility, and poor judgment; more extensive disruptions of prefrontal cortical function may also contribute to thought disorder and hallucinations -- among the hallmarks of schizophrenia. It is thus noteworthy that studies have shown that alpha1 adrenergic antagonists (or agents affecting its signaling cascades, such as protein kinase C) attenuate stress induced PFC-mediated cognitive deficits [229], and the alpha2-AR agonist clonidine improves prefrontal cognitive functioning in patients with schizophrenia [230]. Guanfacine, another alpha2A-AR agonist, was demonstrated to be safe and efficacious in treating cognitive impairment in schizophrenic patients when given as an adjunctive treatment with risperidone in a placebo-controlled, double-blind trial [231]. These findings raise the possibility that some of the beneficial cognitive effects of atypical antipsychotics like clozapine may be mediated by their effects on alpha1 adrenergic receptors, and is worthy of further study.

4.3.2 Effects of antipsychotic medications

Most atypical antipsychotics, as well as many typical antipsychotics including haloperidol, have high binding affinity for alpha1-AR (reviewed in [140]), although the clinical significance of this action is unclear. Some atypical antipsychotics, including clozapine and risperidone, act as potent antagonists at alpha2-ARs. It is hypothesized that this action contributes to their antipsychotic effect by enhancing dopaminergic transmission in the frontal cortex relative to subcortical pathways via the blockade of inhibitory alpha2-ARs on dopaminergic neuron terminals [232, 233].

4.3.3 Receptor polymorphisms

Clark and colleagues [234] identified two single nucleotide polymorphisms (SNPs) in the promoter region of the alpha1A-adrenergic receptor gene that are associated with schizophrenia.

4.4 G protein-coupled cholinergic receptors and schizophrenia

4.4.1 Postmortem and pharmacologic studies

M1 receptor expression has been shown to be decreased in the cortex of postmortem brains of schizophrenic patients [235]. Muscarinic agonists are effective in animal models of negative symptoms and cognitive dysfunction (reviewed in [236, 237]), and the atypical antipsychotics clozapine and olanzapine act as partial agonists at cholinergic M1, M2 and M4 receptors [140], although the clinical significance of these actions is not known.

4.4.2 Receptor polymorphisms

Liao and colleagues [238] demonstrated an association between the C267A polymorphism of the M1 cholinergic receptor and performance of schizophrenic patients on the Wisconsin Card Sorting Test, a measure of prefrontal cognitive function. This polymorphism was not associated with susceptibility to the disease or treatment response [238].

4.5 G protein-coupled glutamatergic receptors and schizophrenia

There is now compelling evidence for the involvement of the glutamatergic system in schizophrenia [239-241]. However, as is the case with mood disorders, the preponderance of the available data pertains to the role of ionotropic glutamatergic receptors, and is not discussed here. The interested reader is referred to several outstanding recent reviews on the topic [239-241].

4.5.1 Pharmacologic studies

Growing interest in the glutamate system in schizophrenia is based primarily on pharmacologic studies. Studies have shown that Group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists potentiate the schizophrenia-like behavioral effects induced by phencyclidine (PCP) and amphetamines (reviewed in [242]). Group I agonists inhibit amphetamine-induced sensorimotor gating deficits [242] and PCP-stimulated dopamine release in prefrontal cortex in rats [243]. Group II receptor (mGluR2/3) agonists block PCP-induced behavioral activation and working memory impairment [244, 245]. mGluR1 and mGluR5 knockout mice show disruptions in sensorimotor gating, which is disrupted in schizophrenia (reviewed in [242]).

4.5.2 Receptor polymorphisms

Several studies have examined the metabotropic glutamate receptors for associations with schizophrenia. Fujii and colleagues [246] found a single nuclear polymorphism (SNP) in GRM3, the gene for mGluR3, to have a positive association with schizophrenia. A second study failed to replicate these results but identified another SNP in GRM3 associated with the disease [247]. One study by Takaki and colleagues [248] identified haplotypes of GRM8, the gene for mGluR8, associated with schizophrenia, suggesting a susceptibility locus in this gene.

5. Summary and Conclusions

Major depression, bipolar disorder, and schizophrenia are severe, chronic diseases that cause significant morbidity and mortality, as well as extraordinary economic costs to patients, their families, and society. Our limited but increasing understanding of the etiology of these diseases comes from the convergence of pharmacologic, postmortem, imaging and genetic research. There is a clear need to elucidate the molecular and cellular underpinnings of these disorders in order to develop improved therapeutics. As we have reviewed here, there is a considerable body of evidence both conceptually and experimentally that support abnormalities in the regulation of GPCRs as integral to the underlying neurobiology of schizophrenia and mood disorders. The pathophysiology of these illnesses must account for profound changes in cognition, mood, and motoric function, as well as a constellation of neurovegetative features derived from dysfunction in limbic-related regions, such as the hippocampus, hypothalamus and brainstem. The highly integrated monoamine and prominent neuropeptide pathways are known to originate and project heavily within these regions of the brain, and it is thus not surprising that abnormalities have been noted in their function across clinical studies. In fact, the contribution of these pathways to the pathophysiology of these illnesses must be reasonably robust, given the variability that might be expected in assessing such dynamic systems under the constraints in experimental design imposed upon such research.

Through functional brain imaging studies, circuits have been identified that mediate the behavioral, cognitive, and somatic manifestations of schizophrenia and mood disorders. Key areas of these circuits include the orbital and medial prefrontal cortex, anterior cingulate, amygdala and related limbic structures, medial thalamus, and related regions of the basal ganglia. Imbalance within these circuits, rather than an increase or decrease in any single neurotransmitter in a given region of the circuit, seems to predispose to and mediate the expression of the major psychiatric illnesses. Treatments that more directly restore balance to these circuits may prove more effective particularly in refractory cases.

It is also becoming increasingly clear that for many patients with refractory illnesses, new drugs simply mimicking the ‘traditional’ drugs that directly or indirectly alter neurotransmitter levels may be of limited benefit. This is clear because such strategies implicitly assume that the target receptor(s)—and downstream signal mediators—are functionally intact, and that altered synaptic activity will thus be transduced to modify the postsynaptic ‘throughput’ of the system. However, the possible existence of abnormalities in GPCRs (and potentially their signal transduction pathways) suggests that for patients refractory to conventional medications, improved therapeutics may only be obtained by the direct targeting of post-receptor sites. Recent discoveries concerning a variety of mechanisms involved in the formation and inactivation of second messengers offer the promise for the development of novel pharmacological agents designed to target signal transduction pathways (discussed in [249]).

Although clearly more complex than the development of receptor-specific drugs, it may be possible to design novel agents to selectively affect second messenger systems, because they are quite heterogeneous at the molecular and cellular level, are linked to receptors in a variety of ways, and are expressed in different stoichiometries in different cell types. Additionally, since signal transduction pathways display certain unique characteristics depending on their activity state, they offer built-in targets for relative specificity of action, depending on the ‘set-point’ of the substrate. These developments hold much promise for the advancement of novel therapeutics for the long-term treatment of these major psychiatric disorders. The challenge for the next era in neuropsychopharmacology is to transform the knowledge gained from advances in neurobiology, cellular physiology and molecular pharmacology into clinical use.


We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Heath, NARSAD, and the Stanley Medical Research Institute.


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Gould TD, Manji HK. The molecular medicine revolution and psychiatry: bridging the gap between basic neuroscience research and clinical psychiatry. J Clin Psychiatry. 2004;65:598–604. [PubMed]
2. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997;349:1436–42. [PubMed]
3. Patel JK, Pinals DA, Breier A. Schizophrenia and other psychoses. In: Tasman A, Kay JA, Lieberman J, editors. Psychiatry. 2nd ed. John Wiley and Sons, Ltd; England: 2003. pp. 1131–1206.
4. Fava M, Kendler KS. Major Depressive Disorder. Neuron. 2000;28:335–41. [PubMed]
5. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry. 2000;157:1552–62. [PubMed]
6. Goodwin FK, Jamison KR. Manic-depressive illness. Oxford University Press; New York: 1990. KR.
7. Manji HK, Rudorfer MV, Potter WZ. Affective disorders and adrenergic function. In: Cameron OG, editor. Adrenergic Dysfunction and Psychobiology. American Psychiatric Press; Washington, DC: 1994.
8. Belmaker RH. Bipolar Disorder. New Engl J Med. 2004;351:476–486. [PubMed]
9. Meeley MP, Ernsberger PR, Granata AR, Reis DJ. An endogenous clonidine-displacing substance from bovine brain: receptor binding and hypotensive actions in the ventrolateral medulla. Life Sci. 1986;38:1119–26. [PubMed]
10. Bricca G, Dontenwill M, Molines A, Feldman J, Belcourt A, Bousquet P. Evidence for the existence of a homogeneous population of imidazoline receptors in the human brainstem. Eur J Pharmacol. 1988;150:401–2. [PubMed]
11. Boyajian CL, Leslie FM. Pharmacological evidence for alpha-2 adrenoceptor heterogeneity: differential binding properties of [3H]rauwolscine and [3H]idazoxan in rat brain. J Pharmacol Exp Ther. 1987;241:1092–8. [PubMed]
12. Michel MC, Regan JW, Gerhardt MA, Neubig RR, Insel PA, Motulsky HJ. Nonadrenergic [3H]idazoxan binding sites are physically distinct from alpha 2-adrenergic receptors. Mol Pharmacol. 1990;37:65–8. [PubMed]
13. Karege F, Bovier P, Widmer J, Gaillard JM, Tissot R. Platelet membrane alpha 2-adrenergic receptors in depression. Psychiatry Res. 1992;43:243–52. [PubMed]
14. Chen G, Hasanat K, Bebchuk JM, Moore GJ, Glitz D, Manji HK. Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosom Med. 1999;61:599–617. [PubMed]
15. Pandey GN, Dysken MW, Garver DL, Davis JM. Beta-adrenergic receptor function in affective illness. Am J Psychiatry. 1979;136:675–8. [PubMed]
16. Extein I, Tallman J, Smith CC, Goodwin FK. Changes in lymphocyte [beta]-adrenergic receptors in depression and mania. Psychiatry Res. 1979;1:191–7. [PubMed]
17. Mann JJ, Brown RP, Halper JP, Sweeney JA, Kocsis JH, Stokes PE, Bilezikian JP. Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. N Engl J Med. 1985;313:715–20. [PubMed]
18. Healy D, Carney PA, Leonard BE. Monoamine-related markers of depression: changes following treatment. J Psychiatry Res. 1983;17:251–60. [PubMed]
19. Ebstein RP, Lerer B, Shapira B, Shemesh Z, Moscovich DG, Kindler S. Cyclic AMP second-messenger signal amplification in depression. Br J Psychiatry. 1988;152:665–9. [PubMed]
20. Wright AF, Crichton DN, Loudon JP, Morten JE, Steel CM. Beta-adrenoceptor binding defects in cell lines from families with manic-depressive disorder. Ann Hum Genet. 1984;48:201–14. [PubMed]
21. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar and Recurrent Unipolar Disorders. second edition. Oxford University Press; New York: KR. in press.
22. Mann JJ, Currier D, Quiroz J, Manji HK. Neurobiology of severe mood and anxiety disorders. In: Siegel GJ, Albers RW, Brady S, Price D, editors. Basic neurochemistry: molecular, cellular and medical aspects. 7th ed. Elsevier; San Diego, Calif.: 2005.
23. Arango V, Ernsberger P, Marzuk PM, Chen JS, Tierney H, Stanley M, Reis DJ, Mann JJ. Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic receptor binding sites in the brain of suicide victims. Arch Gen Psychiatry. 1990;47:1038–47. [PubMed]
24. Biegon A, Israeli M. Regionally selective increases in beta-adrenergic receptor density in the brains of suicide victims. Brain Res. 1988;442:199–203. [PubMed]
25. Stockmeier CA, Meltzer HY. Beta-adrenergic receptor binding in frontal cortex of suicide victims. Biol Psychiatry. 1991;29:183–91. [PubMed]
26. Matussek N, Ackenheil M, Hippius H, Muller F, Schroder HT, Schultes H, Wasilewski B. Effect of clonidine on growth hormone release in psychiatric patients and controls. Psychiatry Res. 1980;2:25–36. [PubMed]
27. Checkley SA, Slade AP, Shur E. Growth hormone and other responses to clonidine in patients with endogenous depression. Br J Psychiatry. 1981;138:51–5. [PubMed]
28. Checkley SA, Glass IB, Thompson C, Com T, Robinson P. The GH response to clonidine in endogenous as compared with reactive depression. Psychol Med. 1984;14:773–7. [PubMed]
29. Charney DS, Heninger GR, Sternberg DE, Hafstad KM, Giddings S, Landis DH. Adrenergic receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects. Arch Gen Psychiatry. 1982;39:290–4. [PubMed]
30. Siever LJ, Trestman RL, Coccaro EF, Bernstein D, Gabriel SM, Owen K, Moran M, Lawrence T, Rosenthal J, Horvath TB. The growth hormone response to clonidine in acute and remitted depressed male patients. Neuropsychopharmacology. 1992;6:165–177. [PubMed]
31. Lechin F, van der Dijs B, Jakubowicz D, Camero RE, Villa S, Arocha L, Lechin AE. Effects of clonidine on blood pressure, noradrenaline, cortisol, growth hormone, and prolactin plasma levels in high and low intestinal tone depressed patients. Neuroendocrinology. 1985;41:156–62. [PubMed]
32. Ansseau M, Von Frenckell R, Cerfontaine JL, Papart P, Franck G, Timsit-Berthier M, Geenen V, Legros JJ. Blunted response of growth hormone to clonidine and apomorphine in endogenous depression. Br J Psychiatry. 1988;153:65–71. [PubMed]
33. Uhde TW, Vittone BJ, Siever LJ, Kaye WH, Post RM. Blunted growth hormone response to clonidine in panic disorder patients. Biol Psychiatry. 1986;21:1081–5. [PubMed]
34. Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry. 1986;43:1042–54. [PubMed]
35. Nutt DJ. Altered central alpha 2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry. 1989;46:165–9. [PubMed]
36. Siever LJ, Insel TR, Jimerson DC, Lake CR, Uhde TW, Aloi J, Murphy DL. Growth hormone response to clonidine in obsessive-compulsive patients. Br J Psychiatry. 1983;142:184–7. [PubMed]
37. Smith DF. Lithium attenuates clonidine-induced hypoactivity: further studies in inbred mouse strains. Psychopharmacology (Berl) 1988;94:428–30. [PubMed]
38. Sulser F. Functional aspects of the norepinephrine receptor coupled adenylate cyclase system in the limbic forebrain and its modification by drugs which precipitate or alleviate depression: molecular approaches to an understanding of affective disorders. Pharmakopsychiatr Neuropsychopharmakol. 1978;11:43–52. [PubMed]
39. Banerjee SP, Kung LS, Riggi SJ, Chanda SK. Development of beta-adrenergic receptor subsensitivity by antidepressants. Nature. 1977;268:455–6. [PubMed]
40. Bergstrom DA, Kellar KJ. Effect of electroconvulsive shock on monoaminergic receptor binding sites in rat brain. Nature. 1979;278:464–6. [PubMed]
41. Honegger UE, Disler B, Wiesman UN. Chronic exposure of human cells in culture to the tricyclic antidepressant desipramine reduces the number of beta-adrenoceptors. Biochem Pharmacol. 1986;35:1899–902. [PubMed]
42. Fishman PH, Finberg JP. Effect of the tricyclic antidepressant desipramine on beta-adrenergic receptors in cultured rat glioma C6 cells. J Neurochem. 1987;49:282–9. [PubMed]
43. Okada F, Tokumitsu Y, Ui M. Desensitization of beta-adrenergic receptor-coupled adenylate cyclase in cerebral cortex after in vivo treatment of rats with desipramine. J Neurochem. 1986;47:454–9. [PubMed]
44. Tiong AH, Richardson JS. Beta-adrenoceptor and post-receptor components show different rates of desensitization to desipramine. Eur J Pharmacol. 1990;188:411–5. [PubMed]
45. Vetulani J, Sulser F. Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature. 1975;257:495–6. [PubMed]
46. Tsuchiya F, Ikeda H, Hatta Y, Saito T. Effects of desipramine administration of receptor adenylate cyclase coupling in rat cerebral cortex. Jpn J Psychiatr Neurol. 1988;42:858–60.
47. Yamaoka K, Nanba T, Nomura S. Direct influence of antidepressants on GTP binding protein of adenylate cyclase in cell membranes of the cerebral cortex of rats. J Neural Transm. 1988;71:165–75. [PubMed]
48. Mork A, Klysner R, Geisler A. Effects of treatment with a lithium-imipramine combination on components of adenylate cyclase in the cerebral cortex of the rat. Neuropharmacology. 1990;29:261–7. [PubMed]
49. Rosenblatt JE, Pert CB, Tallman JF, Pert A, Bunney WE., Jr. The effect of imipramine and lithium on alpha- and beta-receptor binding in rat brain. Brain Res. 1979;160:186–91. [PubMed]
50. Chen G, Manji HK, Wright CB, Hawver DB, Potter WZ. Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells. Neuropsychopharmacology. 1996;15:271–80. [PubMed]
51. Martin-Guerrero I, Callado LF, Saitua K, Rivero G, Garcia-Orad A, Meana JJ. The N251K functional polymorphism in the alpha(2A)-adrenoceptor gene is not associated with depression: a study in suicide completers. Psychopharmacology (Berl) 2006;183:82–6. [PubMed]
52. Ohara K, Nagai M, Tani K, Tsukamoto T, Suzuki Y, Ohara K. Polymorphism in the promoter region of the alpha 2A adrenergic receptor gene and mood disorders. Neuroreport. 1998;9:1291–4. [PubMed]
53. Zill P, Baghai TC, Engel R, Zwanzger P, Schule C, Minov C, Behrens S, Bottlender R, Jager M, Rupprecht R, Moller HJ, Ackenheil M, Bondy B. Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response. Am J Med Genet B Neuropsychiatr Genet. 2003;120:85–9. [PubMed]
54. Neumeister A, Charney DS, Belfer I, Geraci M, Holmes C, et al. Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans. Pharmacogenet Genomics. 2005;15:143–9. [PubMed]
55. Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB, Mohs RC, Davis KL. Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. Archives of General Psychiatry. 1989;46:587–599. [PubMed]
56. Malone KM, Corbitt EM, Li S, Mann JJ. Prolactin response to fenfluramine and suicide attempt lethality in major depression. British Journal of Psychiatry. 1996;168:324–329. [PubMed]
57. Fava M, Vuolo RD, Wright EC, Nierenberg AA, Alpert JE, Rosenbaum JF. Fenfluramine challenge in unipolar depression with and without anger attacks. Psychiatry Research. 2000;94:9–18. [PubMed]
58. Lopez JF, Chalmers DT, Little KY, Watson SJ. A.E. Bennett Research Award. Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry. 1998;43:547–73. [PubMed]
59. Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci. 1998;18:7394–401. [PubMed]
60. Matsubara S, Arora RC, Meltzer HY. Serotonergic measures in suicide brain: 5HT1A binding sites in frontal cortex of suicide victims. J Neural Transm Gen Sect. 1991;85:181–94. [PubMed]
61. Parsey RV, Olvet DM, Oquendo MA, Huang YY, Ogden RT, Mann JJ. Higher 5-HT(1A) Receptor Binding Potential During a Major Depressive Episode Predicts Poor Treatment Response: Preliminary Data from a Naturalistic Study. Neuropsychopharmacology. 2006 advanced online publication. [PubMed]
62. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biological Psychiatry. 1999;46:1375–1387. [PubMed]
63. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry. 2000;57:174–80. [PubMed]
64. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois J-M, Nomikos GG, Greengard P. Alterations in 5HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80. [PubMed]
65. Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Pandey SC, Pesold C, Roberts RC, Conley RR, Tammings CA. Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims. Am J Psychiatry. 2002;159:419–29. [PubMed]
66. Pandey GN, Dwivedi Y, Ren X, Rizavi HS, Faludi G, Sarosi A, Palkovits M. Regional distribution and relative abundance of serotonin(2c) receptors in human brain: effect of suicide. Neurochem Res. 2006;31:167–76. [PubMed]
67. Mann JJ, Stanley M, McBride PA, McEwen BS. Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims. Arch Gen Psychiatry. 1986;43:954–9. [PubMed]
68. Stockmeier CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res. 2003;37:357–373. [PubMed]
69. Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ. Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biological Psychiatry. 2004;55:217–224. [PubMed]
70. Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology. 1991;5:219–29. [PubMed]
71. Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994;15:220–226. [PubMed]
72. Shen C, Li H, Meller E. Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated [35S]GTP gamma S binding in rat brain regions. Neuropharmacology. 2002;42:1031–8. [PubMed]Pejchal T, Foley MA, Kosofsky BE, Waeber C. Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography. Br J Pharmacol. 2002;135:1115–22. [PubMed]
73. Yatham LN, Liddle PF, Dennie J, Shiah IS, Adam MJ, Lane CJ, Lam RW, Ruth TJ. Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18-labeled setoperone. Archives of General Psychiatry. 1999;56:705–711. [PubMed]
74. Pandey GN, Pandey SC, Ren X, Dwivedi Y, Janicak PG. Serotonin receptors in platelets of bipolar and schizoaffective patients: effect of lithium treatment. Psychopharmacology (Berl) 2003;170:115–23. [PubMed]
75. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci. 2003;23:8788–99. [PubMed]
76. Lemonde S, Du L, Bakish D, Hrdina P, Albert PR. Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Int J Neuropsychopharmacol. 2004;7:501–6. [PubMed]
77. Hong CJ, Chen TJ, Yu YW, Tsai SJ. Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J. 2006;6:27–33. [PubMed]
78. Suzuki Y, Sawamura K, Someya T. The effects of a 5-hydroxytryptamine 1A receptor gene polymorphism on the clinical response to fluvoxamine in depressed patients. Pharmacogenomics J. 2004;4:283–6. [PubMed]
79. Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L. Evidence for a combined genetic effect of the 5-HT(1A) receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram. J Psychopharmacol. 2005;19:166–72. [PubMed]
80. Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM, Khait V, Mann JJ. Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism. Neuropsychopharmacology. 2003;28:163–9. [PubMed]
81. Fehr C, Grintschuk N, Szegedi A, Anghelescu I, Klawe C, Singer P, Hiemke C, Dahmen N. The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy. Psychiatry Res. 2000;97:1–10. [PubMed]
80. Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS. Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene. Neuropsychobiology. 2004;49:38–41. [PubMed]
83. Ni X, Trakalo JM, Mundo E, Lee L, Parikh S, Kennedy JL. Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder. Neuromolecular Med. 2002;2:251–9. [PubMed]
84. Massat I, Souery D, Lipp O, Blairy S, Papadimitriou G, Dikeos D, Ackenheil M, Fuchshuber S, et al. A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder. Am J Med Genet. 2000;96:136–40. [PubMed]
85. Arranz MJ, Erdmann J, Kirov G, Rietschel M, Sodhi M, et al. 5-HT2A receptor and bipolar affective disorder: association studies in affected patients. Neurosci Lett. 1997;224:95–8. [PubMed]
86. Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS. Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene. Neuropsychobiology. 2004;49:38–41. [PubMed]
87. Ranade SS, Mansour H, Wood J, Chowdari KV, Brar LK, Kupfer DJ, Nimgaonkar VL. Linkage and association between serotonin 2A receptor gene polymorphisms and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2003;121:28–34. [PubMed]
88. Chee IS, Lee SW, Kim JL, Wang SK, Shin YO, Shin SC, Lee YH, Hwang HM, Lim MR. 5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder. Psychiatr Genet. 2001;11:111–4. [PubMed]
89. Choi MJ, Kang RH, Ham BJ, Jeong HY, Lee MS. Serotonin receptor 2A gene polymorphism (-1438A/G) and short-term treatment response to citalopram. Neuropsychobiology. 2005;52:155–62. [PubMed]
90. Sato K, Yoshida K, Takahashi H, et al. Association between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine response in Japanese patients with major depressive disorder. Neuropsychobiology. 2002;46:136–40. [PubMed]
91. McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolau GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78:804–14. [PubMed]
92. Lerer B, Macciardi F, Segman RH, et al. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol Psychiatry. 2001;6:579–85. [PubMed]
93. Gutierrez B, Arias B, Papiol S, Rosa A, Fananas L. Association study between novel promoter variants at the 5-HT2C receptor gene and human patients with bipolar affective disorder. Neurosci Lett. 2001;309:135–7. [PubMed]
94. Gutierrez B, Fananas L, Arranz MJ, Valles V, Guillamat R, van Os J, Collier D. Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder. Neurosci Lett. 1996;212:65–7. [PubMed]
95. Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P, Van Broeckhoven C. Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder. Am J Med Genet. 1997;74:504–6. [PubMed]
96. Ebert D, Feistel H, Loew T, Pirner A. Dopamine and depression--striatal dopamine D2 receptor SPECT before and after antidepressant therapy. Psychopharmacology (Berl) 1996;126:91–4. [PubMed]
97. Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP. Clinical and psychometric correlates of dopamine D2 binding in depression. Psychol Med. 1997;27:1247–56. [PubMed]
98. Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, Sachs GS, Rosenbaum JF, Fava M. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry. 2000;12:137–40. [PubMed]
99. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161:564–6. [PubMed]
100. DeBattista C, Solvason HB, Breen JA, Schatzberg AF. Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression. J Clin Psychopharmacol. 2000;20:274–5. [PubMed]
101. Zarate CA, Jr., Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004;56:54–60. [PubMed]
102. Cichon S, Nothen MM, Rietschel M, Korner J, Propping P. Single-strand conformation analysis (SSCA) of the dopamine D1 receptor gene (DRD1) reveals no significant mutation in patients with schizophrenia and manic depression. Biol Psychiatry. 1994;36:850–3. [PubMed]
103. Shah M, Coon H, Holik J, Hoff M, Helmer V, Panos P, Byerley W. Mutation scan of the D1 dopamine receptor gene in 22 cases of bipolar I disorder. Am J Med Genet. 1995;60:150–3. [PubMed]
104. Dmitrzak-Weglarz M, Rybakowski JK, Slopien A, Czerski PM, Leszczynska-Rodziewicz A, Kapelski P, Kaczmarkiewicz-Fass M, Hauser J. Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population. Neuropsychobiology. 2006;53:46–50. [PubMed]
105. Severino G, Congiu D, Serreli C, De Lisa R, Chillotti C, Del Zompo M, Piccardi MP. A48G polymorphism in the D1 receptor genes associated with bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2005;134:37–8. [PubMed]
106. Massat I, Souery D, Del-Favero J, et al. Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders. Am J Med Genet. 2002;114:177–85. [PubMed]
107. Li T, Liu X, Sham PC, et al. Association analysis between dopamine receptor genes and bipolar affective disorder. Psychiatry Res. 1999;86:193–201. [PubMed]
108. Dikeos DG, Papadimitriou GN, Avramopoulos D, et al. Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder. Psychiatr Genet. 1999;9:189–95. [PubMed]
109. Lopez Leon S, Croes EA, Sayed-Tabatabaei FA, et al. The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis. Biol Psychiatry. 2005;57:999–1003. [PubMed]
110. Cannon DM, Carson RE, Nugent AC, Echelman WC, Kiesewetter DO, et al. Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder. Arch Gen Psychiatry. 2006;63:741–7. [PubMed]
111. Ellis J, Lenox RH. Chronic lithium treatment prevents atropine-induced supersensitivity of the muscarinic phosphoinositide response in rat hippocampus. Biol Psychiatry. 1990;28:609–19. [PubMed]
112. Comings DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP. Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women. Am J Med Genet. 2002;114:527–9. [PubMed]
113. Post RM, Ketter TA, Joffe RT, Kramlinger KL. Lack of beneficial effects of l-baclofen in affective disorder. Int Clin Psychopharmacol. 1991;6:197–207. [PubMed]
114. Motohashi N. GABA receptor alterations after chronic lithium administration. Comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry. 1992;16:571–9. [PubMed]
115. Motohashi N, Ikawa K, Kariya T. GABAB receptors are up-regulated by chronic treatment with lithium or carbamazepine. GABA hypothesis of affective disorders? Eur J Pharmacol. 1989;166:95–9. [PubMed]
116. Kendell SF, Krystal JH, Sanacora G. GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets. 2005;9:153–68. [PubMed]
117. Carlson PJ, Singh JB, Zarate CA, Drevets WC, Manji HK. Neural Circuitry and Neuroplasticity in Mood Disorders: Insights for Novel Therapeutic Targets. Neurotherapeutics. 2006;3:22–41. [PubMed]
118. Zarate CA, Singh J, Manji HK. Cellular Plasticity Cascades: targets for the development of novel therapeutics for Bipolar Disorder. Biological Psychiatry. 2006;59:1006–1020. [PubMed]
119. Du J, Gray NA, Falke CA, Chen W, Yuan P, Einat H, Szabo ST, Diamond J, Manji HK. Structurally Dissimilar Anti-manic Agents Modulate Synaptic Plasticity by Regulating AMPA Glutamate Receptor Subunit GluR1 Synaptic Expression. J. Neurosci. 2004;24:6578–6589. [PubMed]
120. Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002;7:254–275. [PubMed]
121. Nemeroff CB, Vale WW. The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry. 2005;66(Suppl 7):5–13. [PubMed]
122. Mansbach RS, Brooks EN, Chen YL. Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. Eur J Pharmacol. 1997;323:21–26. [PubMed]
123. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res. 2000;34:171–181. [PubMed]
124. Alda M, Turecki G, Groff P, Cavazzoni P, Duffy A, et al. Association and linkage studies of CRH and PENK genes in bipolar disorder: a collaborative IGSLI study. Am J Med Genet. 2000;96:178–81. [PubMed]
125. Stratakis CA, Sarlis NJ, Berretini WH, Badner JA, Chrousos GP, Gershon ES, Deters-Wadleigh SD. Lack of linkage between the corticotropin-releasing hormone (CRH) gene and bipolar affective disorder. Mol Psychiatry. 1997;2:483–5. [PubMed]
126. Santarelli L, Gobbi G, Blier P, Hen R. Behavioral and physiologic effects of genetic or pharmacologic inactivation of the substance P receptor (NK1) J Clin Psychiatry. 2002;63(Suppl 11):11–7. [PubMed]
127. Gobbi G, Blier P. Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs. Peptides. 2005;26:1383–93. [PubMed]
128. Keller MB, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, Hargreaves R, Hietala J, Lines C, Beebe K, Reines S. Lack of efficacy of the substance P (Neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psych. in press. [PubMed]
129. Carvajal C, Dumont Y, Quirion R. Neuropeptide y: role in emotion and alcohol dependence. CNS Neurol Disord Drug Targets. 2006 Apr;5(2):181–95. [PubMed]
130. Helig M. The NPY system in stress, anxiety and depression. Neuropeptides. 2004;38:213–24. [PubMed]
131. Thorsell A, Carlsson K, Ekman R, Heilig M. Behavioral and endocrine adaptation, and up-regulation of NPY expression in rat amygdala following repeated restraint stress. Neuroreport. 1999;10:3003–7. [PubMed]
132. Sedvall G, Farde L. Chemical brain anatomy in schizophrenia. Lancet. 1995;346:743–9. [PubMed]
133. Heckers S, Goff DC. Neural circuitry and signaling in schizophrenia. In: Kaplan GB, Hammer RP, editors. Brain Circuitry and Signaling in Psychiatry: Basic Science and Clinical Implications. American Psychiatric Publishing, Inc.; Washington, D.C.: 2002. pp. 67–97.
134. Okubo Y, Suhara T, Suzuki K, et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature. 1997;385:634–6. [PubMed]
135. Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch Gen Psychiatry. 1997;54:225–32. [PubMed]
136. Schmauss C, Haroutunian V, Davis KL, Davidson M. Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. Proc Natl Acad Sci U S A. 1993;90:8942–6. [PubMed]
137. Meador-Woodruff JH, Haroutunian V, Powchik P, Davidson M, Davis KL, Watson SJ. Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia. Arch Gen Psychiatry. 1997;54:1089–95. [PubMed]
138. Seeman P, Guan HC, Van Tol HH. Schizophrenia: elevation of dopamine D4-like sites, using [3H]nemonapride and [125I]epidepride. Eur J Pharmacol. 1995;286:R3–5. [PubMed]
139. Remington G, Kapur S. D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET. J Clin Psychiatry. 1999;60(Suppl 10):15–19. [PubMed]
140. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Molec Psychiatry. 2005;10:79–104. [PubMed]
141. Knable MB, Hyde TM, Murray AM, Herman MM, Kleinman JE. A postmortem study of frontal cortical dopamine D1 receptors in schizophrenics, psychiatric controls, and normal controls. Biol Psychiatry. 1996;40:1191–9. [PubMed]
142. Angrist B, Lee HK, Gershon S. The antagonism of amphetamine-induced symptomatology by a neuroleptic. Am J Psychiatry. 1974;131:817–9. [PubMed]
143. Angrist B, Peselow E, Rubenstein M, Corwin J, Rotrosen J. Partial improvement in negative schizophrenic symptoms after amphetamine. Psychopharmacology (Berl) 1982;78:128–30. [PubMed]
144. van Kammen DP, Boronow JJ. Dextro-amphetamine diminishes negative symptoms in schizophrenia. Int Clin Psychopharmacol. 1988;3:111–21. [PubMed]
145. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474–86. [PubMed]
146. Glatt SJ, Jonsson EG. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am J Med Genet B Neuropsychiatr Genet. 2006;141:149–54. [PMC free article] [PubMed]
147. Glatt SJ, Faraone SV, Tsuang MT. Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia. Mol Psychiatry. 2003;8:911–5. [PubMed]
148. Jonsson EG, Sillen A, Vares M, Ekholm B, Terenius L, Sedvall GC. Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2003;119:28–34. [PubMed]
149. Arinami T, Itokawa M, Enguchi H, et al. Association of dopamine D2 receptor molecular variant with schizophrenia. Lancet. 1994;343:703–4. [PubMed]
150. Hori H, Ohmori O, Shinkai T, Kojima H, Nakamura J. Association analysis between two functional dopamine D2 receptor gene polymorphisms and schizophrenia. Am J Med Genet. 2001;105:176–8. [PubMed]
151. Spurlock G, Williams J, McGuffin P, et al. European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms. Am J Med Genet. 1998;81:24–8. [PubMed]
152. Himei A, Koh J, Sakai J, Inada Y, Akabame K, Yoneda H. The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms. Psychiatry Clin Neurosci. 2002;56:97–102. [PubMed]
153. Arinami T, Gao M, Hamaguchi H, Toru M. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet. 1997;6:577–82. [PubMed]
154. Inada T, Arinami T, Yagi G. Association between a polymorphism in the promoter region of the dopamine D2 receptor gene and schizophrenia in Japanese subjects: replication and evaluation for antipsychotic-related features. Int J Neuropsychopharmacol. 1999;2:181–186. [PubMed]
155. Jonsson EG, Nothen MM, Neidt H, et al. Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia. Schizophr Res. 1999;40:31–6. [PubMed]
156. Ohara K, Nagai M, Tani K, Nakamura Y, Ino A, Ohara K. Functional polymorphism of -141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia. Psychiatry Res. 1998;81:117–23. [PubMed]
157. Lawford BR, Young RM, Swagell CD, et al. The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia. Schizophr Res. 2005;73:31–7. [PubMed]
158. Kukreti R, Tripathi S, Bhatnagar P, et al. Association of DRD2 gene variant with schizophrenia. Neurosci Lett. 2006;392:68–71. [PubMed]
159. Golimbet VE, Aksenova MG, Nosikov VV, Orlova VA, Kaleda VG. Analysis of the linkage of the Taq1A and Taq1B loci of the dopamine D2 receptor gene with schizophrenia in patients and their siblings. Neurosci Behav Physiol. 2003;33:223–5. [PubMed]
160. Lencz T, Robinson DG, Xu K, et al. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006;163:529–31. [PubMed]
161. Wu S, Xing Q, Gao R, Li X, Gu N, Feng G, He L. Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. Neurosci Lett. 2005;376:1–4. [PubMed]
162. Scharfetter J. Pharmacogenetics of dopamine receptors and response to antipsychotic drugs in schizophrenia--an update. Pharmacogenomics. 2004;5:691–8. [PubMed]
163. Hwang R, Shinkai T, De Luca V, et al. Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology (Berl) 2005;181:179–87. [PubMed]
164. Arranz MJ, Li T, Munro J, Liu X, Murray R, Collier DA, Kerwin RW. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics. 1998;8:481–4. [PubMed]
165. Schafer M, Rujescu D, Giegling I, Guntermann A, Erfurth A, Bondy B, Moller HJ. Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene. Am J Psychiatry. 2001;158:802–4. [PubMed]
166. Suzuki A, Mihara K, Kondo T, Tanaka O, Nagashima U, Otani K, Kaneko S. The relationship between dopamine D2 receptor polymorphism at the Taq1 A locus and therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. Pharmacogenetics. 2000;10:335–41. [PubMed]
167. Lane HY, Lee CC, Chang YC, Lu CT, Huang CH, Chang WH. Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function. Int J Neuropsychopharmacol. 2004;7:461–70. [PubMed]
168. Arranz MJ, Collier DA, Munro J, Sham P, Kirov G, Sodhi M, Roberts G, Price J, Kerwin RW. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett. 1996;217:177–8. [PubMed]
169. Staddon S, Arranz MJ, Mancama D, et al. Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population. Schizophr Res. 2005;73:49–54. [PubMed]
170. Joober R, Toulouse A, Benkelfat C, et al. DRD3 and DAT1 genes in schizophrenia: an association study. J Psychiatr Res. 2000;34:285–91. [PubMed]
171. Ishiguro H, Okuyama Y, Toru M, Arinami T. Mutation and association analysis of the 5' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia. Mol Psychiatry. 2000;5:433–8. [PubMed]
172. Sivagnanasundaram S, Morris AG, Gaitonde EJ, McKenna PJ, Mollon JD, Hunt DM. A cluster of single nucleotide polymorphisms in the 5'-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. Neurosci Lett. 2000;279:13–6. [PubMed]
173. Malhotra AK, Goldman D, Buchanan RW, Rooney W, Clifton A, Kosmidis MH, Breier A, Pickar D. The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry. 1998;3:72–5. [PubMed]
174. Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z. Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur Neuropsychopharmacol. 2005;15:143–51. [PubMed]
175. Lane HY, Hsu SK, Liu YC, Chang YC, Huang CH, Chang WH. Dopamine D3 receptor Ser9Gly polymorphism and risperidone response. J Clin Psychopharmacol. 2005;25:6–11. [PubMed]
176. Szekeres G, Keri S, Juhasz A, Rimanoczy A, Szendi I, Czimmer C, Janka Z. Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;124:1–5. [PubMed]
177. Scharfetter J, Chaudhry HR, HOrnik K, Fuchs K, Sieghard W, Kasper S, Aschauer HN. Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakastani patients. Eur Neuropsychopharmacol. 1999;10:17–20. [PubMed]
178. Kremer I, Rietschel M, Dobrusin M, et al. No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family-based study of a Palestinian Arab population. Am J Med Genet. 2000;96:778–80. [PubMed]
179. Tanaka T, Igarashi S, Onodera O, et al. Association study between schizophrenia and dopamine D3 receptor gene polymorphism. Am J Med Genet. 1996;67:366–8. [PubMed]
180. Griffon N, Crocq MA, Pilon C, et al. Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia. Am J Med Genet. 1996;67:63–70. [PubMed]
181. Inada T, Sugita T, Dobashi I, Inagaki A, Kitao Y, Matsuda G, Kato S, Takano T, Yagi G, Asai M. Dopamine D3 receptor gene polymorphism and the psychiatric symptoms seen in first-break schizophrenic patients. Psychiatr Genet. 1995;5:113–6. [PubMed]
182. Saha N, Tsoi WF, Low PS, Basair J, Tay JS. Lack of association of the dopamine D3 receptor gene polymorphism (BalI) in Chinese schizophrenic males. Psychiatr Genet. 1994;4:201–4. [PubMed]
183. Yang L, Li T, Wiese C, Lannfelt L, Sokoloff P, Xu CT, Zeng Z, Schwartz JC, Liu X, Moises HW. No association between schizophrenia and homozygosity at the D3 dopamine receptor gene. Am J Med Genet. 1993;48:83–6. [PubMed]
184. Crocq MA, Mant R, Asherson P, et al. Association between schizophrenia and homozygosity at the dopamine D3 receptor gene. J Med Genet. 1992;29:858–60. [PMC free article] [PubMed]
185. Gaitonde EJ, Morris A, Sivagnanasundaram S, McKenna PJ, Hunt DM, Mollon JD. Assessment of association of D3 dopamine receptor MscI polymorphism with schizophrenia: analysis of symptom ratings, family history, age at onset, and movement disorders. Am J Med Genet. 1996;67:455–8. [PubMed]
186. Kennedy JL, Billett EA, Macciardi FM, Verga M, Parsons TJ, Meltzer HY, Lieberman J, Buchanan JA. Association study of dopamine D3 receptor gene and schizophrenia. Am J Med Genet. 1995;60:558–62. [PubMed]
187. Ambrosio AM, Kennedy JL, Macciardi F, Barr C, Soares MJ, Oliveira CR, Pato CN. No evidence of association or linkage disequilibrium between polymorphisms in the 5' upstream and coding regions of the dopamine D4 receptor gene and schizophrenia in a Portuguese population. Am J Med Genet B Neuropsychiatr Genet. 2004;125:20–4. [PubMed]
188. Glatt SJ, Faraone SV, Tsuang MT. Schizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis. Biol Psychiatry. 2003;54:629–35. [PubMed]
189. Hong CJ, Lee YL, Sim CB, Hwu HG. Dopamine D4 receptor variants in Chinese sporadic and familial schizophrenics. Am J Med Genet. 1997;74:412–5. [PubMed]
190. Petronis A, Macciardi F, Athanassiades A, et al. Association study between the dopamine D4 receptor gene and schizophrenia. Am J Med Genet. 1995;60:452–5. [PubMed]
191. Zhao AL, Zhao JP, Zhang YH, Xue ZM, Chen JD, Chen XG. Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine. Int J Neurosci. 2005;115:1539–47. [PubMed]
192. Kaiser R, Konneker M, Henneken M, Dettling M, Muller-Oerlinghausen B, Roots I, Brockmoller J. Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry. 2000;5:418–24. [PubMed]
193. Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK, Crocq MA, Gill M, Kerwin R. Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. Am J Med Genet. 1995;60:541–5. [PubMed]
194. Lewis R, Kapur S, Jones C, DaSilva J, Brown GM, Wilson AA, Houle S, Zipursky BB. Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. Am J Psychiatry. 1999;156:72–8. [PubMed]
195. Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE. Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology. 1993;8:315–36. [PubMed]
196. Krystal JH, Abi-Dargham A, Laruelle M, Moghaddam B. Pharmacologic models of psychoses. In: Charney DS, Nestler EJ, Bunney BS, editors. Neurobiology of Mental Illness. 1st ed. Oxford University Press; New York: 1999. pp. 214–235.
197. Aghajanian GK. Electrophysiological studies on the actions of hallucinogenic drugs at 5-HT2 receptors in rat brain. NIDA Res Monogr. 1994;146:183–202. [PubMed]
198. Stahl SM. Essential psychopharmacology: neuroscientific basis and practical applications. 2nd ed. Cambridge Univ Press; Cambridge: 2000.
199. Carlsson A. Focussing on dopaminergic stabilizers and 5-HT2A receptor antagonists. Curr Opin CPNS Invest Drugs. 2000;2:22–24.
200. Willins DL, Berry SA, Alsayegh L, Backstrom JR, Sanders-Bush E, Friedman L, Roth BL. Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo. Neuroscience. 1999;91:599–606. [PubMed]
201. Evenden JL. Effects of 8-hydroxy-2-(di-n-propylanimo)tetralin (8-OH-DPAT) after repeated administration of a conditioned avoidance response (CAR) in the rat. Psychopharmacology. 1997;131:134–144. [PubMed]
202. Millan MJ. Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors. J Pharmacol Exp Ther. 2000;295:853–861. [PubMed]
203. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol. 2002;441:137–140. [PubMed]
204. Vaquero Lorenzo C, Baca-Garcia E, Hernandez M, et al. Association between the T102C polymorphism of the serotonin-2A receptor gene and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1136–8. [PubMed]
205. Li D, Duan Y, He L. Association study of serotonin 2A receptor (5-HT2A) gene with schizophrenia and suicidal behavior using systematic meta-analysis. Biochem Biophys Res Commun. 2006;340:1006–15. [PubMed]
206. Baritaki S, Rizos E, Zafiropoulos A, Soufla G, Katsafouros K, Gourvas V, Spandidos DA. Association between schizophrenia and DRD3 or HTR2 receptor gene variants. Eur J Hum Genet. 2004;12:535–41. [PubMed]
207. Zhang XN, Jiang SD, He XH, Zhang LN. 102T/C SNP in the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia in two southern Han Chinese populations: lack of association. Am J Med Genet B Neuropsychiatr Genet. 2004;126:16–8. [PubMed]
208. Abdolmaleky HM, Faraone SV, Glatt SJ, Tsuang MT. Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr Res. 2004;67:53–62. [PubMed]
209. Herken H, Erdal ME, Erdal N, Aynacioglu S. T102C polymorphisms at the 5-HT2A receptor gene in Turkish schizophrenia patients: a possible association with prognosis. Neuropsychobiology. 2003;47:27–30. [PubMed]
210. Czerski PM, Leszczynska-Rodziewicz A, Dmitrzak-Weglarz M, Kapelski P, Godlewski S, Rybakowski J, Hauser J. Association analysis of serotonin 2A receptor gene T102c polymorphism and schizophrenia. World J Biol Psychiatry. 2003;4:69–73. [PubMed]
211. Haider MZ, Zahid MA. No evidence for an association between the 5-hydroxytryptamine 5-HT2a receptor gene and schizophrenia in Kuwaiti Arabs. Psychiatry Clin Neurosci. 2002;56:465–7. [PubMed]
212. Polesskaya OO, Sokolov BP. Differential expression of the “C” and “T” alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res. 2002;67:812–22. [PubMed]
213. Serretti A, Cusin C, Lorenzi C, Lattuada E, Lilli R, Smeraldi E. Serotonin-2A receptor gene is not associated with symptomatology of schizophrenia. Am J Med Genet. 2000;96:84–7. [PubMed]
214. He L, Li T, Melville C, et al. 102T/C polymorphism of serotonin receptor type 2A gene is not associated with schizophrenia in either Chinese or British populations. Am J Med Genet. 1999;88:95–8. [PubMed]
215. Shinkai T, Ohmori O, Kojima H, Terao T, Suzuki T, Abe K. Negative association between T102C polymorphism of the 5-HT2a receptor gene and schizophrenia in Japan. Hum Hered. 1998;48:212–5. [PubMed]
216. Spurlock G, Keils A, Holmans P, et al. A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry. 1998;3:42–9. [PubMed]
217. Williams J, Spurlock G, McGuffin P, et al. Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group. Lancet. 1996;347:1294–6. [PubMed]
218. Huang YY, Battistuzzi C, Oquendo MA, et al. Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. Int J Neuropsychopharmacol. 2004;7:441–51. [PubMed]
219. Lane HY, Chang YC, Chiu CC, Chen ML, Hsieh MH, Chang WH. Association of risperidone treatment response with a polymorphism in the 5-HT(2A) receptor gene. Am J Psychiatry. 2002;159:1593–5. [PubMed]
220. Joober R, Benkelfar C, Brisebois K, et al. T102C polymorphism in the 5HT2A gene and schizophrenia: relation to phenotype and drug response variability. J Psychiatry Neurosci. 1999;24:141–6. [PMC free article] [PubMed]
221. Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J, Sham P, Kerwin R. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet. 1995;346:281–2. [PubMed]
222. Malhotra AK, Goldman D, Ozaki N, Breier A, Buchanan R, Pickar D. Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am J Psychiatry. 1996;153:1092–4. [PubMed]
223. Ellingrod VL, Lund BC, Miller D, Fleming F, Perry P, Holman TL, Bever-Stille K. 5-HT2A receptor promoter polymorphism, -1438G/A and negative symptom response to olanzapine in schizophrenia. Psychopharmacol Bull. 2003;37:109–12. [PubMed]
224. Arranz MJ, Munro J, Owen MJ, Spurlock G, Sham PC, Zhao J, Kirov G, Collier DA, Kerwin RW. Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry. 1998;3:61–6. [PubMed]
225. Masellis M, Basile V, Meltzer HY, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology. 1998;19:123–32. [PubMed]
226. Arranz MJ, Collier DA, Munro J, Sham P, Kirov G, Sodhi M, Roberts G, Price J, Kerwin RW. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett. 1996;217:177–8. [PubMed]
227. Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z. Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur Neuropsychopharmacol. 2005;15:143–51. [PubMed]
228. Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, Roberts GW, Price J, Collier DA, Kerwin RW. Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport. 1995;7:169–72. [PubMed]
229. Birnbaum S, Yuan PX, Wang M, Vijayraghaven S, Bloom AK, Davis DJ, Gobeske KT, Sweatt JD, Manji HK, Arnsten A. Protein Kinase C Overactivity Impairs Prefrontal Cortical regulation of working memory. Science. 2004;306:882–884. [PubMed]
230. Fields RB, Van Kammen DP, Peters JL, Rosen J, Van Kammen WB, Nugent A, et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res. 1988;19:417–423. [PubMed]
231. Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L, et al. Guanifacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology. 2001;25:402–409. [PubMed]
232. Gobert A, Rivet JM, Audinot V, Newman-Tancredi A, Cistarelli L, Millan MJ. Simultaneous quantification of serotonin, dopamine, and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release. Neuroscience. 1998;84:413–429. [PubMed]
233. Millan MJ, Gobert A, Newman-Tancredi A, Lajeune F, Cussac D, Rivet JM, et al. S18327 (1-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperid-1-yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1)- and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile. J Pharmacol Exp Ther. 2000;292:38–53. [PubMed]
234. Clark DA, Arranz MJ, Mata I, Lopez-Ilundain J, Perez-Nievas F, KErwin RW. Polymorphisms in the promoter region of the alpha1A-adrenoceptor gene are associated with schizophrenia/schizoaffective disorder in a Spanish isolate population. Biol Psychiatry. 2005;58:435–9. [PubMed]
235. Manacama D, Arranz MJ, Landau S, Kerwin R. Reduced expression of the muscarinic 1 receptor cortical subtype in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2003;119:2–6. [PubMed]
236. Rowley M, Bristow LJ, Huston PH. Current and novel approaches to the drug treatment of schizophrenia. J Med Chem. 2001;44:477–501. [PubMed]
237. Bymaster FP, Felder C, Ahmed S, McKinzie D. Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Target CNS Neurol Disord. 2002;1:163–181. [PubMed]
238. Liao DL, Hong CJ, Chen HM, Chen YE, Lee SM, Chang CY, Chen H, Tsai SJ. Association of muscarinic m1 receptor genetic polymorphisms with psychiatric symptoms and cognitive function in schizophrenic patients. Neuropsychobiology. 2003;48:72–6. [PubMed]
239. Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 2003;169:215–33. [PubMed]
240. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68. [PubMed]
241. Coyle JT. Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis. Cell Mol Neurobiol. 2006 Jun;14 [Epub ahead of print] [PubMed]
242. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9:984–997. [PubMed]
243. Maeda J, Suhara T, Okauchi T, Semba J. Different roles of group I and group II metabotropic glutamate receptors on phencyclidine-induced dopamine release in the rat prefrontal cortex. Neurosci Lett. 2003;336:171–174. [PubMed]
244. Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, varney MA. Effects of kitamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience. 2003;117:697–706. [PubMed]
245. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metaboptropic glutamate receptor agonist in rats. Science. 1998;281:1349–1352. [PubMed]
246. Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y. Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr Genet. 2003;13:71–6. [PubMed]
247. Chen Q, He G, Chen Q, Wu S, Xu Y, Feng G, Li Y, Wang L, He L. A case-control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr Res. 2005;73:21–6. [PubMed]
248. Takaki H, Kikuta R, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y. Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;128:6–14. [PubMed]
249. Quiroz JA, Singh J, Gould TD, Denicoff KD, Zarate CA, Manji HK. Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology. Mol Psychiatry. 2004;9:756–76. [PubMed]