Chronic Administration Of Antipsychotic Drugs Research Articles

Effects of chronic haloperidol treatment on the expression of fear memory and fear memory extinction in the cued fear-conditioned rats.

Impairments in emotional memory are frequently observed in several mental disorders, highlighting their significance as potential therapeutic targets. Recent research on the cued fear conditioning model has elucidated the neural circuits involved in fear memory processing. However, contradictory findings have been reported concerning the role of dopamine and the impact of dopamine D2 receptor (D2R) antagonists. There is notably limited knowledge regarding the clinical utility of chronic D2R antagonist treatments. This study aimed to uncover how such treatments affect fear memory processing. We utilized a cued fear conditioning rat model and conducted chronic haloperidol treatment for 14 days. Subsequently, to investigate the effect of chronic haloperidol treatment on fear-conditioned memory expression and extinction, we observed freezing behavior under exposure to a conditioned stimulus for 14 days. Chronic haloperidol treatment suppressed freezing time on the fear memory expression. In contrast, a single haloperidol administration enhanced the freezing time on fear memory expression and delayed extinction. The results of this study suggest that chronic administration of antipsychotic drugs affects fear memory processing differently from single-dose administration. This indicates that the effects of chronic D2R antagonist treatment are distinct from the nonspecific effects of the drugs. This study provides fundamental insights that may contribute to our understanding of therapeutic mechanisms for fear memory disorders related to D2R in the future.

Effects of antipsychotic drugs on neurites relevant to schizophrenia treatment.

Although antipsychotic drugs are mainly used for treating schizophrenia, they are widely used for treating various psychiatric diseases in adults, the elderly, adolescents and even children. Today, about 1.2% of the worldwide population suffers from psychosis and related disorders, which translates to about 7.5 million subjects potentially targeted by antipsychotic drugs. Neurites project from the cell body of neurons and connect neurons to each other to form neural networks. Deficits in neurite outgrowth and integrity are implicated in psychiatric diseases including schizophrenia. Neurite deficits contribute to altered brain development, neural networking and connectivity as well as symptoms including psychosis and altered cognitive function. This review revealed that (1) antipsychotic drugs could have profound effects on neurites, synaptic spines and synapse, by which they may influence and regulate neural networking and plasticity; (2) antipsychotic drugs target not only neurotransmitter receptors but also intracellular signaling molecules regulating the signaling pathways responsible for neurite outgrowth and maintenance; (3) high doses and chronic administration of antipsychotic drugs may cause some loss of neurites, synaptic spines, or synapsis in the cortical structures. In addition, confounding effects causing neurite deficits may include elevated inflammatory cytokines and antipsychotic drug-induced metabolic side effects in patients on chronic antipsychotic therapy. Unraveling how antipsychotic drugs affect neurites and neural connectivity is essential for improving therapeutic outcomes and preventing aversive effects for patients on antipsychotic drug treatment.

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers.

Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n = 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018. © 2017 Wiley Periodicals, Inc.

Parkinsonian axial signs in schizophrenia

IntroductionWe have recently demonstrated evidence of nigro-striatal denervation, disease progression and response to levodopa in a subgroup of patients with schizophrenia who developed parkinsonism. ObjectiveIn the present study, we investigated whether axial parkinsonian signs might be an early manifestation of parkinsonism in schizophrenia not necessarily related to chronic administration of antipsychotic drugs (AP) drugs. MethodsFrom a baseline cohort of 299 schizophrenic patients who did not satisfy the diagnostic criteria for parkinsonism (presence of at least two of the following appendicular signs: bradykinesia, tremor, rigidity), we identified a group of patients who manifested two out of three axial parkinsonian signs (abnormality of trunk posture, hypomimia and short-step gait). Accordingly, we obtained two sub-groups of patients with schizophrenia, with (Schiz-Axial, N = 26), and without parkinsonian axial signs (Schiz-NO-Axial, N = 273). Clinical and demographical variables were compared between groups. The motor section of the Unified Parkinson's disease rating scale (UPDRS) was employed to measure motor disability. ResultsSchiz-Axial patients were significantly older (p = 0.007) and had longer disease duration (p = 0.04) compared to Schiz-NO-Axial. The two groups did not differ for variables related to AP treatment. Total UPDRS motor score (p < 0.0001) as well as limb (p < 0.0001) and axial (p < 0.0001) UPDRS sub-scores were increased in Schiz-Axial patients compared to Schiz-NO-Axial. ConclusionsOur findings provide evidence that axial parkinsonian signs might be an early manifestation of parkinsonism in schizophrenia associated to older age and longer disease duration.

Basal ganglia anatomy and schizophrenia: the role of antipsychotic treatment.

Progressive enlargement of basal ganglia volume has been observed in schizophrenia individuals, potentially being sustained by chronic administration of antipsychotic drugs. Here we briefly summarise the state of the art of the role of antipsychotic in leading to increased basal ganglia in schizophrenia, particularly focusing on the caudate nucleus.

Regional differences in homovanillic acid concentrations after acute and chronic administration of antipsychotic drugs.

Regional differences in homovanillic acid concentrations after acute and chronic administration of antipsychotic drugs.

The effect of chronic antipsychotic drug administration on nitric oxide synthase activity and gene expression in rat penile tissues

Antipsychotic drug treatment may be associated with common and problematic sexual dysfunction, especially impotence, which can diminish quality of life and lead to treatment noncompliance. Nitric oxide synthase (NOS) is an important cellular modulator of erectile function. We have therefore investigated the effect of antipsychotic drug on activity and gene expression of NOS in rat penile tissues. The activity of constitutive NOS was significantly suppressed below control by a 21 days administration of 1 mg/kg haloperidol, which also significantly decreased expression of endothelial NOS (eNOS) and neural NOS mRNA. Risperidone at 0.5 mg/kg also reduced eNOS mRNA expression. Haloperidol or risperidone did not change gene expression and activity of inducible NOS (iNOS). Quetiapine significantly increased activity and mRNA expression of iNOS with 20 and 40 mg/kg doses. These preliminary results have important implications for enhancing our understanding of mechanisms by which antipsychotic drugs induce sexual dysfunction.

Behavioral adaptation in C. elegans produced by antipsychotic drugs requires serotonin and is associated with calcium signaling and calcineurin inhibition

Chronic administration of antipsychotic drugs produces adaptive responses at the cellular and molecular levels that may be responsible for both the main therapeutic effects and rebound psychosis, which is often observed upon discontinuation of these drugs. Here we show that some antipsychotic drugs produce significant functional changes in serotonergic neurons that directly impact feeding behavior in the model organism, Caenorhabditis elegans. In particular, antipsychotic drugs acutely suppress pharyngeal pumping, which is regulated by serotonin from the NSM neurons. By contrast, withdrawal from food and drug is accompanied by a striking recovery and overshoot in the rate of pharyngeal pumping. This rebound response is absent or diminished in mutant strains that lack tryptophan hydroxylase (TPH-1) or the serotonin receptors SER-7 and SER-1, and is blocked by serotonin antagonists, which implicates serotonergic mechanisms in this adaptive response. Consistent with this, continuous drug exposure stimulates an increase in serotonin and the number of varicosities along the NSM processes. Cyclosporin A and calcineurin mutant strains mimic the effects of the antipsychotic drugs and reveal a potential role for the calmodulin–calcineurin signaling pathway in the response of serotonergic neurons. Similar molecular and cellular changes may contribute to the long-term adaptive response to antipsychotic drugs in patients.

Chronic antipsychotic drug administration alters the expression of neuregulin 1β, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus

Neuregulin 1 (NRG1) has been identified as a susceptibility gene for schizophrenia, and dysregulation of NRG1 and its ErbB receptors is implicated in the pathophysiology of the disorder. The present study examined the protein expression levels of NRG1beta, ErbB2, ErbB3 and ErbB4 in the rat prefrontal cortex and hippocampus following a 4-wk administration of haloperidol (1 mg/kg i.p.), clozapine (10 mg/kg i.p.), or risperidone (1 mg/kg i.p.) by using immunohistochemistry and Western blot. The results showed that haloperidol promoted the expression of NRG1beta and ErbB4, whereas clozapine inhibited NRG1beta expression in the rat prefrontal cortex. Both haloperidol and clozapine significantly increased the protein levels of NRG1beta and ErbB receptors in the rat hippocampus. Repeated administration of risperidone only increased the expression of NRG1beta and ErbB4 in the hippocampus. Our findings demonstrate that antipsychotic drugs differentially regulate the expression of NRG1 and ErbB receptors in the rat brain, which may provide insight into the molecular basis of the pharmacological profile of antipsychotic drugs.

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino- d-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.

AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs

Disturbances in glutamate neurotransmission are thought to be one of the major contributing factors to the pathophysiology of schizophrenia. In the dorsolateral prefrontal cortex (DLPFC), glutamate neurotransmission is largely mediated by AMPA receptors. Data regarding alterations of subunit expression in the brains of patients with schizophrenia remain equivocal. This may be due to differences in technique sensitivity, endogenous control selection for normalization of data, or effect of antipsychotic drug treatment in different cohorts of schizophrenia. This study attempted to address these issues by examining the expression of AMPA receptor subunits and splice variants in the DLPFC of two schizophrenia cohorts using quantitative PCR (qPCR) with normalization to the geometric mean of multiple endogenous controls. In addition, a non-human primate model of chronic antipsychotic drug administration was used to determine the extent to which the transcript expression may be altered by antipsychotic drug treatment in the primate DLPFC. AMPA receptor subunits and flip and/or flop splice variants were not significantly different in the DLPFC of schizophrenia subjects versus controls in either of the two cohorts. However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA. Expression of AMPA receptor splice variants was not significantly altered by antipsychotic drug administration. This is the first study to show that AMPA receptor subunit mRNAs in the primate DLPFC are altered by antipsychotic drug administration. Antipsychotic drug-induced alterations may help explain differences in human post-mortem studies regarding AMPA receptor subunit expression and provide some insight into the mechanism of action of antipsychotic drugs.

Region Specific Regulation of NR1 in Rhesus Monkeys Following Chronic Antipsychotic Drug Administration

Altered NMDA receptor subunit protein levels have been reported in various regions of the schizophrenic brain; however, chronic antipsychotic administration in schizophrenic subjects may confound interpretation. The effects of chronic antipsychotic drug administration (haloperidol and clozapine) on protein levels of NR1, NR2A and NR2B proteins were evaluated in the nucleus accumbens (NAc), putamen (PUT), dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), and entorhinal cortex (EC) of rhesus monkeys using Western blot analysis. Haloperidol administration significantly decreased NR1 expression in the DLPFC. In contrast, NR2B expression was not affected by antipsychotic administration in any brain region examined. NR2A was not reliably detected in any of the brain regions. Results indicate that the NR1 subunit in the DLPFC may be a substrate for antipsychotic action and that glutamatergic hypofunction in the DLPFC commonly associated with cognitive dysfunction in schizophrenia may be associated with haloperidol administration.

Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus

The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60–70% with HAL or CPZ, and by only 25–30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70–90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.

Association analysis of a neural nitric oxide synthase gene polymorphism and antipsychotics-induced tardive dyskinesia in Chinese schizophrenic patients.

Recent findings from rodent studies with chronic administration of antipsychotic drugs have indicated the role of neural nitric oxide synthase (NOS1) on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a 3'-untranslated region C267T (3'-UTR C267T) polymorphism of the NOS1 gene and TD as well as TD severity was investigated in 251 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 128, non-TD: 123). After adjusting the effects of confounding factors, there was no significant association between NOS1 3'-UTR C276T genotypes and TD occurrence (p=0.758). With in the TD group, we could not discover a significant correlation between NOS1 3'-UTR C276T genotypes and the scores of abnormal involuntary movement scale (AIMS) (p=0.219 and 0.774). We concluded that the NOS1 3'-UTR C276T polymorphism might not play a major role in the susceptibility of TD development, or on the severity of TD.

Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain

We have recently shown that the expression of the nerve growth factor-inducible gene B (NGFI-B, or Nur77), a transcription factor belonging to the large ligand-activated nuclear receptor family, is modulated by antipsychotic drugs in the rat forebrain. In the present work, we have investigated the impact of antipsychotic drugs on a series of transcription factors also belonging to the nuclear receptor family. The receptors investigated include retinoid X receptor (RXR), thyroid hormone receptor (TR), retinoic acid receptor (RAR), RAR-related orphan receptor (RZR) and Rev- erb receptor isoforms in addition to the NGFI-B transcript. We have used in situ hybridization to monitor their mRNA levels after acute and chronic antipsychotic drug administration. RZRβ and NGFI-B mRNA levels are down-regulated after chronic haloperidol or clozapine treatment in the primary somatosensory cortex. The TRβ1 isoform mainly expressed in the cingulate cortex is modulated only after chronic clozapine treatment, whereas TRα isoform mRNAs are modulated by both antipsychotics in the cingulate cortex and nucleus accumbens shell; two brain areas associated with limbic functions. The RXRγ1 isoform, mostly expressed in the dorsolateral portion of the striatum is modestly affected by antipsychotics. Modulation of the expression of transcription factors belonging to the ligand-activated nuclear receptor family by antipsychotics represents an additional molecular event in the mechanism of action of these drugs. We suggest that modification of the pattern of transcription factor expression may play a role in long-term cellular responses to these drugs.

Increased density of glutamate/ N-methyl- d-aspartate receptors in superior temporal cortex in schizophrenia

Saturable radioligand binding of [ 3H]L-689,560 to the glycine site of the N-methyl- d-aspartate (NMDA) receptor was determined bilaterally in superior temporal cortex (BA22) and prefrontal cortex (BA10) taken post mortem from patients with schizophrenia and matched control subjects. A significant increase in NMDA receptor density above control values was found bilaterally in BA22 in schizophrenia, but not in BA10. The effect was greatest in those patients described as primarily type II, in whom the effect was significantly lateralized, with a greater elevation in the left hemisphere. A significant decrease in NMDA receptor density was found in rat frontal cortex following chronic antipsychotic drug administration, indicating that prior drug treatment was unlikely to have contributed to the differences in schizophrenia.

Glucose tolerance and serum insulin levels in an animal model of obesity induced by sub-acute or chronic administration of antipsychotic drugs

1. 1. To assess the role of insulin in the development of the obesity induced by antipsychotic drugs, a glucose tolerance test was conducted in female rats after 10 or 30 days of sulpiride administration. 2. 2. At day 10, the area under the glucose curve did not differ between sulpiride and vehicle-treated rats, however, the area under the insulin curve was significantly decreased by sulpiride. At day, 30 the insulin response was similar in both groups, but the area under the glucose curve was significantly lower in the sulpiride-treated rats. 3. 3. The results suggest that insulin resistance and hyperinsulinemia are not involved in the development and maintenance of the obesity induced by sulpiride. Contrarily, these findings may be related to an increased insulin sensitivity. 4. 4. The absence of hyperinsulinemia and insulin resistance indicates important differences between primary obesity in humans and rodents and this model of drug-induced excessive weight gain.

Antipsychotic drug regulation of AMPA receptor affinity states and GluR1, GluR2 splice variant expression.

We recently reported that chronic administration of antipsychotic drugs dramatically elevated [3H]AMPA binding, with minimal elevation of [3H]CNQX binding in rat brain. The aim of the current study was to examine the mechanism of this effect. Chronic haloperidol minimally increased the total number of binding sites (total Bmax) compared to saline-injected animals. Specifically, haloperidol dramatically increased the proportion of high-affinity-site AMPA receptors (approximately 30% increase) without inducing a significant change in the low-affinity constant. In situ hybridization for flip and flop isoforms of GluR1 and GluR2 (AMPA receptors) was not altered in a pattern or degree that compared to the changes seen in AMPA receptor binding. These findings suggest that the long-term action of antipsychotic drugs may be to regulate AMPA receptor responsiveness to agonist stimulation via posttranscriptional means, and is unlikely to be related to GluR1 or GluR2 splice variant expression. This effect may have relevance to both the therapeutic effects and side effects of antipsychotic drugs in humans.

P.2.063 The efficacy of zotepine in reducing negative symptoms

The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60–70% with HAL or CPZ, and by only 25–30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70–90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.

The effects of antipsychotic drugs on the mRNA levels of serotonin 5HT2A and 5HT2C receptors.

We have looked for both global and regional changes in rat brain mRNA levels encoding serotonin 5HT2A and 5HT2C receptors following acute and chronic administration of antipsychotic drugs. In whole brain clozapine (30 mg/kg/day) elicited a transient rise in 5HT2C mRNA levels after 4 days and chlorpromazine (15 mg/kg/day) elicited a decrease of 20% in 5HT2A mRNA levels after 32 days. Regionally, 32 days treatment with haloperidol (3 mg/kg/day), sulpiride (100 mg/kg/day) or clozapine (10 mg/kg/day) resulted in a drop of approximately 30-40% in 5HT2C mRNA levels in both cortex and cerebellum, and decreases (or non-significant trends) of 15-40% in 5HT2A mRNA levels in hippocampus, brainstem and mid brain. 4 days treatment with clozapine resulted in a 40% rise of 5HT2C mRNA in the mid brain and a 24% rise of 5HT2A mRNA in the nucleus accumbens which were not found after 32 days of treatment. These results demonstrate common chronic effects of typical and atypical drugs but unique short term effects of clozapine.