Receptors In Schizophrenia Research Articles

The Effect of Antipsychotics on the High-Affinity State of D2 and D3 Receptors

Most antipsychotics are thought to have an effect on D(2) and D(3) receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([(11)C]-(+)-PHNO), the first agonist radioligand with higher affinity for D(3) than D(2) receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D(2) receptor and on D(3) vs D(2) receptor subtypes. To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D(2) and D(3) receptors by comparing the [(11)C]-(+)-PHNO and [(11)C]raclopride binding in the D(3) receptor-rich (globus pallidus and ventral striatum) and D(2) receptor-rich (caudate and putamen) regions. Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D(3) receptor-preferring agonist) vs placebo on the increased [(11)C]-(+)-PHNO signal observed in the globus pallidus of patients. Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Twenty-three patients with schizophrenia and 23 healthy controls. Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The antipsychotic-treated patients showed high occupancies with both [(11)C]-(+)-PHNO and [(11)C]raclopride in the dorsal striatum, with [(11)C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [(11)C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [(11)C]raclopride. This unblocked [(11)C]-(+)-PHNO signal was displaced by a single dose of pramipexole. Antipsychotics block both the high- and low-affinity states of the D(2) receptors across the brain, but antipsychotic treatment does not block the [(11)C]-(+)-PHNO signal in the D(3) receptor-rich regions, despite the ongoing D(2) receptor blockade. This [(11)C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D(3) receptor-preferring agonist. The radiotracer [(11)C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia.

Increased antibodies for the α7 subunit of the nicotinic receptor in schizophrenia

One of the etiological theories of schizophrenia is dysregulation of the immune system. Autoantibodies specific for the alpha7 subunit of the nicotinic receptor could potentially contribute to the pathophysiology of the disease. In this study, positive antibodies specific for the receptor were found to exist in 23% of the patients diagnosed with schizophrenia (n=21). On the average, levels for the antibody were elevated in the schizophrenia patient population than in controls. The data also suggests that there is a significant correlation between antibody titer and age, lending support to the neurodegenerative nature of the disease.

Evaluation of NMDA receptor models of schizophrenia: Divergences in the behavioral effects of sub-chronic PCP and MK-801

The hypothesis of hypo-functionality of NMDA receptors in schizophrenia originates from the observation that administration of the NMDA antagonist phencyclidine (PCP) induces psychotic states that closely resemble schizophrenic symptoms and that persist after drug discontinuation. A large number of animal studies have used PCP and the NMDA antagonist dizocilpine (MK-801) almost interchangeably to model schizophrenia. However, PCP interacts with pharmacological targets other than NMDA receptors that are not affected by MK-801. In addition, although acute administration of either compound produces similar effects in animals, there is little information whether withdrawal from chronic MK-801 causes behavioral deficits that mimic schizophrenia symptoms as in the case of PCP. To clarify this issue, we compared the following behaviors in rats subjected to withdrawal from sub-chronic administration (2 × 7 days) of either PCP (5 mg/kg, i.p.) or MK-801 (0.5 mg/kg, i.p.): (1) working memory in a variable-delayed alternation task in a T-maze, (2) social interaction, and (3) motor activity in response to a (a) novel environment, (b) mild stressor, and (c) d-amphetamine challenge. Withdrawal from sub-chronic PCP caused a delay-dependent impairment of working memory, reduced social interaction and enhanced d-amphetamine-induced motor activity. These results were not replicated in animals sub-chronically treated with MK-801, which displayed only a slight decrease in social interaction. These data suggest that pharmacological antagonism at NMDA receptors is not sufficient to explain the full spectrum of PCP psychotomimetic properties.

Evaluation of the Brain 5-HT2A Receptor Binding Index in Dogs with Anxiety Disorders, Measured with 123I-5I-R91150 and SPECT

The serotonergic system has been implicated in emotional and cognitive functions since early work. In particular, an important role has been attributed to the 5-HT2A receptor in schizophrenia, depression, eating disorders, and anxiety. The aim of the study was to evaluate the involvement of the brain 5-HT2A receptor in dogs with severe anxiety disorder, using 123I-5I-R91150 and SPECT. SPECT was performed with the 5-HT2A receptor-specific radioligand 123I-5I-R91150 to determine the 5-HT2A receptor binding index (BI) in the brains of dogs. Sixteen dogs with pathologic anxiety problems were compared with 22 normal-behaving reference dogs. Lower 5-HT2A receptor BI was found in the left (P=0.001) and right (P=0.002) frontal cortices in the group of dogs with anxiety disorders than in the reference group. Right (P=0.022) and left (P=0.048) temporocortical BIs were also significantly lower in the dogs with anxiety disorders. Finally, the BI was significantly lower in the right occipital cortex (P=0.038) of dogs with anxiety disorders than in the reference dogs. After correction for multiple comparisons (P<0.0056), only the bilateral frontocortical lower BI remained significant. The findings in this study indicate that the 5-HT2A receptor is involved in the pathophysiology of anxiety disorders in dogs. The affected brain regions are in concordance with the brain regions involved in human anxiety disorders. The acquired data confirm the potential of using the dog as a natural model for investigation of the different mechanisms of anxiety disorders. In this regard, the use of dogs may contribute to the development of novel treatment approaches and new drugs for veterinary and human use.

Successful Smoking Cessation and Improvement of Negative Symptoms With Varenicline in a Stable Schizophrenia Patient

Back to table of contents Previous article Next article LETTERFull AccessSuccessful Smoking Cessation and Improvement of Negative Symptoms With Varenicline in a Stable Schizophrenia PatientIon Anghelescu M.D.,Ion Anghelescu M.D.Search for more papers by this author,Published Online:1 Jan 2009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: The selective nicotinic partial agonist varenicline is approved for smoking cessation 1 in more than 30 countries. Freedman 2 has reported a case of a patient with a schizophrenic exacerbation after initiation of varenicline for smoking cessation. Here we present a case of successful smoking cessation and substantial improvement of negative symptoms in a clinically stable patient with schizophrenia. Case ReportMr. A is a 27-year-old former student with the diagnosis of schizophrenia, paranoid subtype for 4 years. His last admission as an inpatient took place 2 years ago and was due to delusions, visual and tactile hallucinations, and ideas of reference. He had no insight into his disorder and ideas of grandiosity (“the creator and guardian of the light”). By then he had also been a cannabis user (on average 0.5 g per day). No somatic disorders had been reported. He was then put on depot medication which he received every 14 days (risperidone, 37.5 mg). He smoked cigarettes for 5 years, increasing to 30 cigarettes a day over the last 6 months. His Positive and Negative Syndrome Scale (PANSS) negative symptoms score fluctuated between 42 and 45 over this period of time, with a PANSS positive symptoms score of only 8 points. Quitting smoking strategies like group counseling and nicotine replacement therapy via patch were altogether unsuccessful. Therefore, a trial with varenicline added to risperidone was started. The drug was titrated to 2 mg per day over a period of 1 week. It was tolerated well, and he experienced no nausea. After 2 weeks, complete abstinence was achieved (that was confirmed via CO measurement in the expiration air) and maintained for 6 months. Moreover, his PANSS negative score decreased from the second week on varenicline to 22 points. Risperidone and 9-hydroxy-risperidone concentrations remained unchanged.Discussion We report for the first time a successful trial of smoking cessation in a patient with very mild positive but marked negative symptoms which substantially improved during the treatment with varenicline without exacerbation of psychotic symptoms. We interpret this clinical observation by the indirect dopamine releasing properties of varenicline. 3 Schizophrenia patients seem to have altered nicotinic acetylcholine receptors and stimulation by nicotine has a positive effect on cognition and other symptoms of schizophrenia, which is thought a transient effect. 4 Nicotine as a full agonist on nicotinic acetylcholine receptors has a very high affinity for these receptors and a tolerance inducing effect that has not been described for varenicline yet. Since the patient still received risperidone he was probably sufficiently protected from the development of new positive symptoms. Systematic controlled studies of schizophrenia patients with different predominant symptoms treated with varenicline seem warranted to evaluate its possible risks and advantages in this population.Department of Psychiatry and Psychotherapy, Charité, University Medicine Berlin, Germany, Campus Benjamin Franklin, GermanyReferences1 . Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2007; CD00103Google Scholar2 . Freedman R: Exacerbation of schizophrenia by varenicline. Am J Psychiatry 2007; 164:1269Google Scholar3 . Rollema H, Coe JW, Chambers LK, et al: Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation. Trends Pharmacol Sci 2007; 28:316–325Google Scholar4 . Adams CE, Stevens KE: Evidence for a role of nicotinic acetylcholine receptors in schizophrenia. Front Biosci 2007; 12:4755–4772Google Scholar FiguresReferencesCited byDetailsCited ByFrontiers in Psychiatry, Vol. 9Varenicline disrupts prepulse inhibition only in high-inhibitory ratsProgress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 53EPA Guidance on Tobacco Dependence and Strategies for Smoking Cessation in People with Mental Illness30 January 2014 | European Psychiatry, Vol. 29, No. 2Acta Neuropsychiatrica, Vol. 23, No. 5Expert Opinion on Pharmacotherapy, Vol. 12, No. 11Journal of the Korean Society for Research on Nicotine and Tobacco, Vol. 1, No. 2 Volume 21Issue 1 Winter, 2009Pages 102-103 Metrics PDF download History Published online 1 January 2009 Published in print 1 January 2009

Role of serotonin-1A receptors in the action of antipsychotic drugs: comparison of prepulse inhibition studies in mice and rats and relevance for human pharmacology

This study aimed to explore strain and species differences in the involvement of 5-HT1A receptors in the action of antipsychotic drugs, using prepulse inhibition (PPI), a model of sensory processing which is deficient in schizophrenia patients. We used automated startle boxes to compare the effect of the 5-HT1A receptor agonist, (+/-)-8-hydroxy-dipropyl-amino-tetralin (8-OH-DPAT), on PPI in three mouse strains. Balb/c mice were then pretreated with antipsychotics, treated with 8-OH-DPAT or saline, and tested for PPI. 8-OH-DPAT treatment dose dependently increased PPI in Balb/c mice, but had less effect in 129Sv and C57Bl/6 mice. In Balb/c mice, the effect of 8-OH-DPAT was blocked by the typical antipsychotic and dopamine D2 receptor antagonist, haloperidol and the third generation antipsychotic, aripiprazole, which has activity at both 5-HT1A and dopamine D2 receptors. The atypical antipsychotics, clozapine, olanzapine and risperidone, had lesser effects. Similar to our earlier studies in rats, the present PPI results suggest that 5-HT1A receptors are involved in the action of some antipsychotic drugs in mice. Despite strain and species differences in the magnitude and direction of the effect of 8-OH-DPAT, downstream dopamine D2 receptor activation seems to be an important mediator. These comparative results allow a theoretical framework of receptor interactions, which may guide further studies on the involvement of 5-HT1A receptors in schizophrenia.

Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia

We have shown a decrease in cortical serotonin2A receptors using tissue sections, but not with washed membranes, from the same cohort of subjects. These discrepant findings led us to determine if we could obtain similar results using samples from the same tissue block. Our studies used single-point saturation analyses to estimate the total number of [3H]ketanserin binding sites in tissue sections, crude homogenate, membrane-enriched and cytosol-enriched tissue samples from Brodmann's area 9. There were significant decreases in the levels of [3H]ketanserin binding using tissue sections (mean±SD: 38±16 vs. 56±16 fmol/mg ETE; p=0.008) and crude tissue homogenates (131±53 vs. 168±38 fmol/mg protein; p<0.05) from subjects with schizophrenia compared to that in controls. By contrast, there was no significant difference in radioligand binding to the membrane-enriched (155±95 vs. 145±48 fmol/mg protein; p=0.72) or cytosol-enriched (8.6±14 vs. 7.5±10 mol/mg protein; p=0.85) tissue fraction. Significantly, adding 10− 5 M risperidone or chlorpromazine, as surrogates for residual antipsychotic drugs in the CNS, to crude homogenate from control subjects did not alter [3H]ketanserin binding. Our data therefore is consistent with the hypothesis that apparent decreases in serotonin2A receptors in schizophrenia are due to altered levels of a regulatory factor(s) that modulates the binding of ligands to the serotonin2A receptor and that separating the membrane and cytosol removes this regulatory control.

Cholinergic Agonists as Novel Treatments for Schizophrenia: The Promise of Rational Drug Development for Psychiatry

Cholinergic Agonists as Novel Treatments for Schizophrenia: The Promise of Rational Drug Development for Psychiatry

Ketamine induces hyperactivity in rats and hypersensitivity to nicotine in rat striatal slices

The symptoms of schizophrenia can be modeled in rats through blockade of ionotropic glutamate receptors, which induces changes in central dopamine circuits. These circuits also contain nicotinic acetylcholine receptors that are activated by nicotine. A role for nicotine in the etiology of schizophrenia is supported by clinical observations of high tobacco use rates in individuals experiencing the psychopathology. The present study investigated the effect of the ionotropic glutamate receptor antagonist ketamine on the function of striatal nicotinic acetylcholine receptors to understand better the potential role of these receptors in schizophrenia. Ketamine (0.1–300 µM) was ineffective to evoke [ 3H] overflow from rat striatal slices preloaded with [ 3H]dopamine. Application of psychotomimetic ketamine concentrations (1–10 µM) to striatal slices augmented nicotine-evoked [ 3H] overflow. Finally, rats received ketamine (30–50 mg/kg) injections for 30 days, to model the development of the disorder, and hyperactivity was observed, although repeated ketamine treatment did not significantly alter nicotine-evoked [ 3H]dopamine overflow. These data indicate that the function of nicotinic acetylcholine receptors that mediate dopamine release are altered by ketamine, and support a role for nicotinic acetylcholine receptors in schizophrenia pathology.

Schizophrenia: more evidence for less glutamate

Evaluation of: Hahn CJ, Hoau-Yan W, Dan-Sung C et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12, 824–828 (2006) [1].Schizophrenia may be associated with deficits in glutamate transmission at the N-methyl-d-aspartate (NMDA) receptor complex. Recent work has shown that neuregulin 1 (NRG1) acts via ErbB4 receptors to inhibit NMDA receptor currents. This is important given that NRG1 is a convincing susceptibility gene in schizophrenia. Hahn and colleagues add to our knowledge of NRG1 modulation of NMDA receptors and show intriguing differences between control and schizophrenic brains. NMDA receptors in the schizophrenic prefrontal cortex showed smaller responses to exogenously applied NMDA/glycine. Furthermore, NMDA receptors in tissue from schizophrenic patients appeared to be more sensitive to the inhibitory effects of a fixed dose of NRG1. In agreement, the ErbB4–PSD-95–NMDA complex was more tightly coupled in schizophrenic brains and NRG1-mediated stimulation of ErbB4 was markedly enhanced. These findings underscore the importance of NMDA receptors in schizophrenia and support therapeutic strategies aimed at boosting glutamate transmission.

Evidence for a role of nicotinic acetylcholine receptors in schizophrenia

Schizophrenia is a debilitating, complex and costly illness affecting roughly 1% of the world's inhabitants. The excessive degree of cigarette smoking exhibited by schizophrenic patients suggests that they might be self-medicating to ameliorate certain aspects of the characteristic positive, negative and cognitive symptoms associated with the disease. Morphological examinations found alterations in nicotinic receptors in postmortem tissue from schizophrenic individuals compared to controls, especially in the a7 and a4b2 subtypes. These data were consistent with molecular biology studies which demonstrated associations between polymorphisms in gene coding for these receptors and schizophrenia. In studies of nicotinic receptor stimulation in schizophrenia patients, improvement in sensory inhibition and cognitive deficits were observed following treatment, though the effects were transient. These results have spurred the development of new pharmaceuticals specifically designed to modulate nicotinic receptor function. The initial results from clinical trials of these new drugs appear promising, potentially opening new avenues of treatment for this devastating disease.

Targeting the dopamine D2 receptor in schizophrenia

After a 12-year search for the antipsychotic receptor, the binding site was discovered and labelled by [3H]haloperidol in 1975. Of the various neurotransmitters, dopamine was the most potent in inhibiting the binding of [3H]haloperidol, indicating that the antipsychotic receptor was a dopamine receptor, now named the dopamine D2 receptor, a major targeting site in schizophrenia. All antipsychotic drugs, including traditional and newer antipsychotics, either bind to D2 in direct relation to their clinical potencies or hinder normal dopamine neurotransmission, as in the case of partial dopamine agonists. In fact, the antipsychotic concentrations found in the plasma water of treated patients closely match the predicted therapeutic absolute concentrations, adjusted for the 60 – 75% D2 occupancy needed for clinical efficacy. Antipsychotics that elicit low or no Parkinsonism or prolactinaemia are loosely attached to D2 and rapidly dissociate from D2, whereas those eliciting Parkinsonism stay tightly attached to D2 for many hours. Because animal models of psychosis (amfetamine sensitisation, brain lesions) all show a marked elevation in the number of high-affinity states of D2, the antipsychotics are thought to specifically target these D2High states in psychosis in general and schizophrenia in particular.

The role of group I metabotropic glutamate receptors in schizophrenia

It has been proposed that glutamatergic transmission, in particular NMDA receptor function, might be altered in schizophrenia. This hypothesis is mainly based on the observation that uncompetitive NMDA receptor antagonists, e.g. phencyclidine, evoke psychotic symptoms in healthy subjects, whereas agonists interacting at the glycine site of the NMDA receptor complex, e.g. glycine or D-serine, administered jointly with typical neuroleptics, can alleviate schizophrenic symptoms. The function of NMDA receptors may be modulated by group I mGluRs (mGluR1 and mGluR5), which have also been shown to be altered in schizophrenia. In rodents, mGluR5 antagonists, but not mGluR1 ones, potentiate the locomotor activity and the deficit of prepulse inhibition (PPI) induced by uncompetitive NMDA receptor antagonists. These antagonists (of either type) administered alone are not active in the above tests. Hence, antagonists of mGluR1 and mGluR5 may evoke different effects on the NMDA receptor antagonists-induced behavior and, possibly, on schizophrenic symptoms.

Expression of the α 1A-adrenergic receptor in schizophrenia

The α 1-adrenergic receptors may contribute to cognitive functions relevant to schizophrenia. Following the discovery of an association between polymorphisms in the regulatory region of the α 1A-adrenergic receptor and schizophrenia we investigated the expression of mRNA for this receptor between schizophrenics ( n = 19) and controls ( n = 19) using a TaqMan approach in post-mortem brains. No differences were found suggesting that mRNA levels are not altered in schizophrenia. Genotypic data for the subjects found that possession of the previously associated genotypes did not convey a difference in mRNA expression suggesting that these polymorphisms do not affect the level of transcription.

Search for Psychotropics Focuses on Receptors

Search for Psychotropics Focuses on Receptors

P.1.e.024 Progesterone modulates the serotonergic influence on autobiographic memory in healthy men

On the basis of postmortem data and the pharmacological action of atypical antipsychotics, serotonin-1A receptors are of interest in the study of the pathophysiology of schizophrenia. To investigate serotonin-1A receptors in schizophrenia and their relation to symptoms, we measured the availability of serotonin-1A receptors in patients with schizophrenia using positron emission tomography with [carbonyl-11C]WAY-100635.Serotonin-1A receptor binding of 11 patients with schizophrenia (8 drug-naive and 3 drug-free) was compared with that of 22 age-matched and gender-matched healthy control subjects. Symptoms were assessed using the Positive and Negative Syndrome Scale. Serotonin-1A receptor binding in selected regions of interest was quantified by binding potential obtained by the reference tissue method.The regional binding potential value was lower in the amygdala by about 19% in patients with schizophrenia than in normal controls. A significant negative correlation was observed between binding potential in the amygdala and the negative and depression/anxiety symptom scores on the five-symptom subscale of the Positive and Negative Syndrome Scale.Decreased serotonin-1A receptor binding in the amygdala may underlie the affective components included in the symptoms of negative and depression/anxiety in schizophrenia.

Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia

Increasing evidence suggests that the metabolism of glutathione, an endogenous redox regulator, is abnormal in schizophrenia. Patients show a deficit in glutathione levels in the cerebrospinal fluid and prefrontal cortex and a reduction in gene expression of the glutathione synthesizing enzymes. We investigated whether such glutathione deficit altered synaptic transmission and plasticity in slices of rat hippocampus, with particular emphasis on NMDA receptor function. An ∼40% decrease in brain glutathione levels was induced by s.c. administration of l-buthionine-( S, R)-sulfoximine, an inhibitor of glutathione synthesis. Such glutathione deficit did not affect the basal synaptic transmission, but produced several NMDA receptor-dependent and -independent effects. Glutathione deficit caused an increase in excitability of CA1 pyramidal cells. The paired-pulse facilitation was diminished in glutathione-depleted slices, in a manner that was independent of NMDA receptor activity. This suggests that lowering glutathione levels altered presynaptic mechanisms involved in neurotransmitter release. NMDA receptor-dependent long-term potentiation induced by high-frequency stimulation was impaired in glutathione-depleted slices. Pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials were significantly smaller in l-buthionine-( S, R)-sulfoximine-treated than in control slices. Hypofunction of NMDA receptors under glutathione deficit was explained at least in part by an excessive oxidation of the extracellular redox-sensitive sites of the NMDA receptors. These results indicate that a glutathione deficit, like that observed in schizophrenics, alters short- and long-term synaptic plasticity and affects NMDA receptor function. Thus, glutathione deficit could be one causal factor for the hypofunction of NMDA receptors in schizophrenia.

Changes in hippocampal GABA A receptor subunit composition in bipolar 1 disorder

Postmortem CNS studies have suggested an uncoupling of the γ-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA A receptor in schizophrenia. The GABA A receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA A receptor would be a change in receptor subunit composition. To test this hypothesis we measured the density of GABA ([ 3H]muscimol) and benzodiazepine ([ 3H]flumazenil) binding sites on the GABA A receptor in hippocampi, obtained postmortem, from schizophrenic, bipolar I disorder and control subjects. In addition, we measured the amount of [ 3H]flumazenil binding that could be displaced with zolpidem and clonazepam. Levels of both [ 3H]muscimol and [ 3H]flumazenil binding were significantly decreased in part of the CA2 from subjects with schizophrenia; the decrease in [ 3H]flumazenil being due to decreases in both zolpidem-sensitive and -insensitive radioligand binding. There were complex regionally specific changes in [ 3H]muscimol binding in the hippocampus from subjects with bipolar I disorder but there were no significant changes in the overall levels of [ 3H]flumazenil binding. There were significant decreases in zolpidem-sensitive and increases in zolpidem-insensitive [ 3H]flumazenil binding in most regions of the sections of the hippocampal formation studied in bipolar I disorder. Unlike [ 3H]flumazenil, zolpidem does not bind to the α5 subunit of the GABA A receptor; therefore, we postulate that there is an increase in GABA A receptors containing α5 subunit in the hippocampus from subjects with bipolar I disorder.

5-HT 2A and muscarinic receptors in schizophrenia: a postmortem study

Although evidence suggests that 5-HT 2A and muscarinic M1/M4 receptors are implicated in the pathology of schizophrenia, the results are not conclusive. In the present study we tested the hypothesis that binding of 5-HT 2A and M1/M4 receptors is altered in the postmortem brain of schizophrenia subjects. Quantitative autoradiography was employed to measure [ 3H]ketanserin binding to 5-HT 2A receptors and [ 3H]pirenzepine binding to both M1 and M4 receptors in Brodmann's area 9 (BA9), caudate/putamen, and the hippocampal formation from six schizophrenic and six control subjects. A significant reduction in the density of 5HT 2A receptors in BA 9 of schizophrenic subjects was observed ( p = 0.036). No significant difference was observed in the density of 5HT 2A receptors in the hippocampus or caudate/putamen between the two groups. No significant changes in the density of M1/M4 receptors was observed in these three regions between the two groups. These findings support a possible involvement of the serotonergic system in the pathology of schizophrenia.

The expression of retinoic acid receptor alpha is increased in the granule cells of the dentate gyrus in schizophrenia

Mounting evidence suggests that schizophrenia is a neurodevelopmental disease resulting in dysfunctional connectivity between various brain regions. Retinoid pathway dysregulation has been proposed as a potentially important factor in the etiology of schizophrenia. Retinoid signaling plays a central role in many aspects of development, ranging from neurogenesis to activity-dependent plasticity, and regulates the expression of many candidate genes for schizophrenia. The retinoid pathway acts through two families of nuclear receptors highly expressed in the hippocampus, the retinoic acid (RAR) and retinoid X (RXR) receptors, both existing in three different subtypes (α, β and γ) and several isoforms. The present study examines the expression of the retinoid receptors in the dentate gyrus of schizophrenia and nonpsychiatric controls. The proportion of granule cells of the dentate gyrus expressing RARα is increased by twofold in schizophrenia, while the proportion of cells expressing RARγ1 and 2, as well as RXRβ and γ, is unchanged. These results demonstrate a dysregulation in the expression of at least one member of the RAR family of retinoid receptors in schizophrenia. Understanding the basis for this and how it affects downstream molecular pathways associated with hippocampal plasticity may provide insight into the dysfunctional connectivity of schizophrenia.