Inhibition of skeletal muscle nicotinic receptors by the atypical antipsychotic clozapine

We have previously observed that certain atypical antipsychotic drugs reduce the amplitude and duration of miniature end-plate currents (EPCs) at the frog neuromuscular junction (Effects of atypical antipsychotics on vertebrate neuromuscular transmission, Nguyen, Q.-T., Yang, J., Miledi, R. Neuropharmacology 42, 2002, 670-676), therefore suggesting that these drugs act on nicotinic acetylcholine receptors. In this study we examined the effects of the atypical antipsychotic clozapine on nicotinic receptors of frog neuromuscular end-plates or in Xenopus oocytes expressing the alpha(1)beta(1)gamma delta mouse skeletal muscle nicotinic receptor. At neuromuscular junctions, postsynaptic currents were reduced by micromolar concentrations of clozapine. This compound also acted presynaptically by increasing the quantal content of EPCs of muscles without noticeably affecting paired-pulse facilitation. In oocytes, clozapine inhibited alpha(1)beta(1)gamma delta receptors with an IC(50) of 10 microM and a Hill coefficient of 1. Blockage of alpha(1)beta(1)gamma delta receptors by clozapine bears several hallmarks of open-channel blockers, including faster response decays, strong voltage dependence of the block, large rebound currents upon wash, and reduction of peak responses even at saturating concentrations of acetylcholine. However, clozapine increased the EC(50) for acetylcholine and its blocking effect was enhanced by preincubation. These results suggest that clozapine antagonizes muscle nicotinic receptors by blocking open channels, and possibly also by another mechanism which still remains to be investigated.     

Functional upregulation of system xc- by fibroblast growth factor-2

The cystine/glutamate antiporter (system xc-) is a Na(+)-independent amino acid transport system. Disruption of this system may lead to multiple effects in the CNS including decreased cellular glutathione. Since multiple neurological diseases involve glutathione depletion, and disruption of growth factor signaling has also been implicated in these diseases, it is possible that some growth factors effects are mediated by regulation of system xc-. We tested the growth factors fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG), neurotrophin-4 (NT-4), and brain derived neurotrophic factor (BDNF) on system xc- mediated 14C-cystine uptake in mixed neuronal and glial cortical cultures. Only FGF-2 significantly increased cystine uptake. The effect was observed in astrocyte-enriched cultures, but not in cultures of neurons or microglia. The increase was blocked by the system xc- inhibitor (s)-4-carboxyphenylglycine, required at least 12 h FGF-2 treatment, and was prevented by the protein synthesis inhibitor cycloheximide. Kinetic analysis indicated FGF-2 treatment increased the V(max) for cystine uptake while the K(m) remained the same. Quantitative PCR showed an increase in mRNA for xCT, the functional subunit of system xc-, beginning at 3 h of FGF-2 treatment, with a dramatic increase after 12 h. Blocking FGFR1 with PD 166866 blocked the FGF-2 effect. Treatment with a PI3-kinase inhibitor (LY-294002) or a MEK/ERK inhibitor (U0126) for 1 h prior to and during the FGF-2 treatment, each partially blocked the increased cystine uptake. The upregulation of system xc- by FGF-2 may be responsible for some of the known physiological actions of FGF-2. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats

Rationale The atypical antipsychotic drug (APD) clozapine elicits a robust discriminative cue that is generally selective for other atypical APDS in two-choice drug discrimination (DD) procedures.Objectives The present study determined whether a three-choice DD procedure with the atypical APD clozapine (CLZ) versus the typical APD chlorpromazine (CPZ) versus vehicle (VEH) could provide greater selectivity between atypical and typical APDs.Methods Sprague-Dawley rats were trained to discriminate 5.0 mg/kg CLZ from 1.0 mg/kg CPZ from VEH in a three-lever DD task with an FR30 food reinforcement schedule.Results Generalization testing with CLZ produced CPZ-appropriate responding at lower doses (ED₅₀=0.103 mg/kg) and CLZ-appropriate responding at higher doses (ED₅₀=1.69 mg/kg). Generalization testing with the atypical APD olanzapine produced similar results. In contrast, the atypical APD risperidone and the typical APDs CPZ and haloperidol produced only CPZ-appropriate responding. The muscarinic antagonist scopolamine produced CPZ-appropriate responding at lower doses and CLZ-appropriate responding at higher doses in a manner similar to CLZ and olanzapine. The co-administration of haloperidol (0.00625 mg/kg) with scopolamine shifted the dose–response curve for CLZ-appropriate responding to the left. The 5-HT_2A/2C antagonist ritanserin and the H₁ histamine antagonist pyrilamine did not substitute for either CLZ or CPZ. The ₁ adrenergic antagonist prazosin did not substitute for CLZ, but produced full substitution for CPZ.Conclusions The three-choice DD procedure clearly distinguished the atypical APDs CLZ and olanzapine from the typical APDs CPZ and haloperidol; however, the stimulus properties of the atypical APD risperidone were similar to CPZ, but not to CLZ. These findings further suggest that CLZ, as well as CPZ, elicits a compound cue.     

Stress and cocaine interact to modulate basic fibroblast growth factor (FGF-2) expression in rat brain

Rationale Our laboratory has previously demonstrated that the expression of basic fibroblast growth factor (FGF-2), a protein involved in survival and maintenance of several cell phenotypes as well as in synaptic plasticity, is modulated by stress (Molteni et al., Brain Res Rev 37:249–258, 2001; Fumagalli et al., Neurobiol Dis 20:731–737, 2005) and cocaine (Fumagalli et al., J Neurochem 96:996–1004, 2006). Objectives Since it is widely recognized that stress influences drug seeking, we decided to investigate whether stress, acute or repeated, could influence the changes in FGF-2 gene expression brought about by cocaine. Results Our data demonstrate that stress and cocaine interact to produce significant changes on FGF-2 expression in rat prefrontal cortex and striatum. In prefrontal cortex, our experiments demonstrated that a single exposure to stress potentiated cocaine-induced FGF-2 elevation, whereas prolonged stress prevented the modulation of the trophic factor in response to cocaine. In striatum, the magnitude of cocaine-induced FGF-2 response is enhanced by repeated stress, whereas no interaction was observed when acute stress and single exposure to cocaine were combined. Conclusions Our findings demonstrate that stress interacts with cocaine to alter the pattern of FGF-2 expression in a way that depends on whether stress is acute or chronic and in a regionally selective fashion. These results identify a potential molecular target through which stress alters cellular sensitivity to cocaine and might prove useful in understanding the mechanisms underlying brain vulnerability to stress.     

Discriminative stimulus properties of the atypical antipsychotic drug clozapine in rats trained to discriminate 1.25 mg/kg clozapine vs. 5.0 mg/kg clozapine vs. vehicle

Clozapine, the prototype for atypical antipsychotic drugs, is used in the drug discrimination paradigm as a model for screening atypical from typical antipsychotic drugs. Previous drug discrimination studies in rats have shown that a 1.25 mg/kg clozapine training dose provides full stimulus generalization (i.e.) >or=80% condition-appropriate responding) to most atypical antipsychotic drugs, although a 5.0 mg/kg clozapine training dose appears necessary to provide stimulus generalization to other atypical antipsychotic drugs. The present study sought to characterize the pharmacological mechanisms that mediate these clozapine training doses. In rats trained to discriminate 1.25 vs. 5.0 mg/kg clozapine vs. vehicle in a three-choice drug discrimination task, various receptor-selective compounds were tested for stimulus generalization. The antidepressant mianserin was also tested. Full stimulus generalization from the 1.25 mg/kg clozapine training dose occurred only to mianserin (98.8%). Partial substitution (i.e. >or=60% and <80% condition-appropriate responding) to the 5.0 mg/kg clozapine training dose occurred for the muscarinic receptor antagonist scopolamine. The combined total percentage of responding on the 1.25 and 5.0 mg/kg clozapine levers, however, was well above the full substitution criteria at the 0.25, 0.5, and 1.0 mg/kg scopolamine doses. The M1 agonist N-desmethylclozapine, the nicotinic antagonist mecamylamine, the D1 antagonist SCH 23390, the D4 antagonist LU 38-012, the 5-HT1A agonist (+)-8-OH-DPAT, the 5-HT1A antagonist WAY 100 635, the 5-HT2A/2B/2C antagonist ritanserin, the 5-HT6 antagonist RO4368554, the alpha1 antagonist prazosin, the alpha2 antagonist yohimbine, and the histamine H1 antagonist pyrilamine all failed to substitute for either the 1.25 or the 5.0 mg/kg clozapine training doses. These results are consistent with previous evidence that antidepressant drugs have a tendency to substitute for clozapine and that muscarinic receptor antagonism may mediate the discriminative stimulus properties of 5.0 mg/kg clozapine. The lack of stimulus generalization from either clozapine training dose to other receptor-selective compounds, however, fails to explain how this model screens atypical from typical antipsychotic drugs and suggests that the discriminative stimulus properties of clozapine consist of a compound cue.     

Selective antidopaminergic effects of S(+)N-n-propylnoraporphines in limbic versus extrapyramidal sites in rat brain: comparisons with typical and atypical antipsychotic agents

Dopamine (DA), injected unilaterally into rat forebrain after pretreatment with a monoamine oxidase inhibitor, equipotently induced locomotor arousal when placed in the nucleus accumbens septi (a limbic site) and contralateral deviation of the head when placed in the corpus striatum (an extrapyramidal target); testing was done with an ED₅₀ dose of DA (16 µg). Systemic injections (IP) of the representative typical neuroleptic haloperidol showed high potency and minorstriatal selectivity against the behavioral effects of intracerebral DA [accumbens ID₅₀=0.090, striatum=0.027 mg/kg (0.24 and 0.072 µmol/kg); ID₅₀ ratio=3.3, favoring striatum]. The atypical antipsychotic agent clozapine was less potent against DA in both brain regions but, paradoxically, showed ever greater striatal selectivity [ID₅₀=12 and 1.4 mg/kg (37 and 4.2 µmol/kg); ratio=8.8, favoring striatum], while its analog, the piperazinyl-dibenzothiazepine ICI-204,636 showed intermediate potency and the lowest striatal selectivity of these three neuroleptic agents [ID₅₀=1.8 and 0.88 mg/kg (4.1 and 2.0 µmol/kg); ratio=2.1]. In striking contrast, the S(+) isomers of N-n-propylnorapomorphine, its orally active 10,11-methylenedioxy prodrug derivative, and its 11-monohydroxy analog all induced potent antagonism oflimbic DA but had little effect on extrapyramidal injections of DA except at high systemic doses [ID₅₀, accumbens=0.18–0.52, striatal=10–15 mg/kg (0.50–1.6 and 29–42 µmol/kg); regional ID₅₀ ratios=18–69, favoring accumbens]. The S(+)aporphines showed limbic potency similar to that of haloperidol and 25–73 times greater than that of clozapine. The S(+)11-OH-aporphine was 2.7–3.1 times more potent (on a molar dose basis) than the other aporphines against DA in accumbens, and 0.5, 8 and 73 times as potent as haloperidol, ICI-204,636 and clozapine. The significantly dissimilar slopes of dose-effect functions for the two groups of agents suggest that different actions may mediate the limbic effects of the aporphines and the neuroleptics tested. ICI-204-636 appears to be pharmacologically similar to clozapine, but 2.1 times more potents versus limbic-DA. The S(+)N-n-propylnoraporphines are potent and regionally highly selectivelimbic DA antagonists and S(+)-11-hydroxy-N-n-propylnoraporphine is orally active. These and other aporphine analogs are proposed for development as potential atypical antipsychotic agents with a low risk of extrapyramidal neurological side effects, and the present methods are proposed for predicting relative limbic versus extrapyramidal antidopaminergic activity.     

Role of D1 and D2 dopamine receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine in rats

The purpose of the present study was to assess the role of dopamine D₁ and D₂ receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine (CLZ). Two groups of rats were trained to discriminate either a moderate dose of clozapine (5.0 mg/kg) from vehicle or a high dose of clozapine (10.0 mg/kg) from vehicle in a two‐lever drug discrimination paradigm. Generalization testing with clozapine yielded an ED₅₀ of 0.9 mg/kg (95% confidence limits = 0.5–2.0 mg/kg) for the 5.0 CLZ group and 2.0 mg/kg (95% confidence limits = 1.4–2.8 mg/kg) for the 10.0 CLZ group. Substitution testing with the D₁ antagonist SCH 23390 and the D₂ dopamine antagonist haloperidol failed to produce clozapine‐appropriate responding for either of the clozapine training doses. The antipsychotic drug thioridazine (which binds to a number of neurotransmitters in addition to dopamine) produced partial substitution (64.5% drug lever responding) in the 5.0 CLZ group at the 5.0 mg/kg dose. These results suggest that antagonism of D₁ and D₂ dopamine receptors alone is not sufficient to produce clozapine‐appropriate responding, even with the higher training dose of 10.0 mg/kg. Drug Dev. Res. 46:139–147, 1999. © 1999 Wiley‐Liss, Inc.     

The atypical antipsychotic drug clozapine enhances chronic PCP-induced regulation of prefrontal cortex 5-HT2A receptors

The ability of antipsychotic drugs to affect 5-HT(2A) receptor function has been widely suggested to contribute to their therapeutic properties. We have compared the ability of the antipsychotic drugs clozapine and haloperidol, alone and in combination with chronic phencyclidine (PCP), to modulate 5-HT(2A) receptor binding and mRNA. Acute (i.p. 45 min) and chronic (21-day) clozapine (osmotic minipump (OMP); 20 mg/kg/day) produced widespread decreases in 5-HT(2A) receptor binding (-60%-80%), measured using [(3)H]ketanserin autoradiography. Conversely, 5-HT(2A) mRNA levels, determined using in-situ hybridisation, were modestly increased by chronic clozapine treatment (+10%-30%). Chronic PCP treatment, at a dose (2.58 mg/kg i.p. intermittently for 28 days) that reproduces many of the neurochemical deficits of schizophrenia, decreased 5-HT(2A) receptor binding in the prefrontal cortex (PFC; -16%), consistent with the changes in post-mortem brain tissue from schizophrenic patients. Combined chronic PCP (i.p.) and clozapine (OMP) treatment down-regulated 5-HT(2A) receptor binding in many areas, similar to the effects of clozapine treatment alone and clozapine further enhanced the effects of PCP in the prefrontal cortex. In contrast 5-HT(2A) mRNA was not altered. Haloperidol treatment alone (1 mg/kg/day; OMP) and in combination with PCP (i.p.), generally produced no changes in 5-HT(2A) receptor protein or mRNA. Hence chronic PCP treatment, as employed here, mimics the decreased 5-HT(2A) receptor binding observed in the PFC of schizophrenic patients. Clozapine's enhancement of the natural response of PCP to down-regulate PFC 5-HT(2A) receptors may contribute to it's improved therapeutic profile against negative symptoms and cognitive deficits.     

Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine,the prototype atypical antipsychotic

Rationale. Clozapine has been shown to increase extracellular dopamine (DA) and noradrenaline (NA) in the medial prefrontal cortex (mPFC). A recent study of ours suggested that extracellular DA in the PFC originates not only from dopaminergic but also from noradrenergic terminals, its release being controlled by α₂-adrenoceptors. Objectives. Since clozapine binds to α₂-adrenoceptors, the possibility that it might co-release DA and NA was studied. Methods. By means of microdialysis coupled to HPLC with electrochemical detection, the effect of clozapine on extracellular DA and NA in the mPFC, densely innervated by DA and NA, was compared to that in the occipital cortex, equally innervated by NA but receiving few DA projections. Results. Extracellular NA was found to be the same in the two cortices, consistent with homogeneous NA innervation. On the other hand, extracellular DA in the occipital cortex was only 29% lower than in the mPFC, in spite of the scarce dopaminergic innervation in the occipital cortex. Clozapine (10 mg/kg IP) increased extracellular DA and NA not only in the mPFC (by about 320% and 290%, respectively) but also in the occipital cortex (by 560% and 230%, respectively). Administration of the α₂-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D₂-agonist quinpirole (0.1 mg/kg IP) was ineffective. Conclusions. The results suggest that clozapine, by inhibiting α₂-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC. Electronic Publication     

Improvement of prefrontal brain function in endogenous psychoses under atypical antipsychotic treatment.

Typical and atypical antipsychotics are thought to exert their effects on different neurotransmitter pathways with specific action of atypical compounds on the prefrontal cortex, but studies directly investigating the effect of those drugs on neurophysiological measures of prefrontal brain function are sparse. We therefore investigated the influence of different antipsychotics on an electrophysiological marker of prefrontal brain function (NoGo anteriorization, NGA) and neuropsychological test scores. For this purpose, 38 patients with endogenous psychoses were investigated at the beginning of a stationary psychiatric treatment and at a 6-week-follow-up. Patients were treated with typical or atypical antipsychotics, or a combination of both. They underwent psychopathological diagnostic and neuropsychological testing, as well as electrophysiological investigations during a Continuous Performance Test. The results indicate that typical and atypical antipsychotics differentially affected the development of the NGA over the course of the treatment, typical antipsychotics tending to result in decreased values at follow-up, and atypical antipsychotics stabilizing, or increasing this parameter. Performance in tests of frontal lobe function generally declined under typical antipsychotics and improved with atypical compounds, changes in Stroop interference correlated with changes in the NGA. We conclude that typical and atypical antipsychotics differ regarding their effect on prefrontal brain function in schizophrenia, atypical neuroleptics often showing a more favorable impact than conventional antipsychotics on respective parameters.     

Homobivalent ligands of the atypical antipsychotic clozapine: design, synthesis, and pharmacological evaluation

To date all typical and atypical antipsychotics target the dopamine D(2) receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D(2) receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D(2) receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.     

Biochemical evidence that the atypical antipsychotic drugs clozapine and risperidone block 5-HT(2C) receptors in vivo

Clozapine and risperidone are two atypical antipsychotic drugs which bind, among other receptors, to 5-HT(2C) receptor subtypes. They inhibit the basal inositol phosphate production in mammalian cells expressing rat or human 5-HT(2C) receptors. This biochemical effect is indicative of inverse agonist activity at these receptors. There is evidence that 5-HT(2C) receptors are involved in the control of the activity of central dopaminergic system. Therefore, the effects of clozapine (5 mg/kg ip), risperidone (0.08 mg/kg ip) and of the typical antipsychotic haloperidol (0.1 mg/kg ip) were studied on the extracellular concentration of dopamine (DA) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. When injected alone, clozapine, risperidone and haloperidol caused only small variations in DA efflux. However, clozapine and risperidone completely prevented the inhibitory action of RO 60-0175 (1 mg/kg ip), a 5-HT(2C) receptor agonist, on DA release. On the other hand, haloperidol did not affect RO 60-0175-induced decrease in DA release. Taken together, these data indicate that clozapine and risperidone, unlike haloperidol, are capable of blocking 5-HT(2C) receptors in the nucleus accumbens. It is concluded that the experimental model presented in this study might represent a simple and useful in vivo biochemical method to test the effect of putative atypical antipsychotic drugs on 5-HT(2C) receptors.     

The modulation by chlormethiazole of the GABAA-receptor complex in rat brain.

1. The interactions of chlormethiazole with gamma-aminobutyric acid (GABA) synthesis and release, and with ligand binding to sites associated with the GABAA-receptor complex and the GABAB-receptor have been studied in the rat. The GABAA-receptor was studied using [3H]-muscimol, [3H]-flunitrazepam was used to label the benzodiazepine modulatory site, and [35S]-butyl-bicyclophosphorothionate ([35S]-TBPS) to label the chloride channel. 2. Chlormethiazole had no effect on GABA synthesis in the cortex, hippocampus and striatum or on GABA release from cortical slices in vitro. Chlormethiazole did not displace [3H]-baclofen binding to the GABAB-receptor. 3. Chlormethiazole (IC50 = 140 microM) and pentobarbitone (IC50 = 95 microM) both inhibited [35S]-TBPS binding by increasing the rate of [35S]-TBPS dissociation. In addition, chlormethiazole caused an apparent decrease in the affinity of [35S]-TBPS binding. 4. Chlormethiazole enhanced the binding of [3H]-muscimol but had no effect on [3H]-flunitrazepam binding. In contrast, the sedative barbiturate pentobarbitone enhanced both [3H]-muscimol and [3H]-flunitrazepam binding. 5. It is concluded that the sedative and anticonvulsant effects of chlormethiazole are probably mediated through an action at the GABAA-receptor. However, chlormethiazole does not interact with the GABAA-receptor complex in an identical manner to the sedative barbiturate pentobarbitone.     

Stimulus properties of the "atypical" antipsychotic zotepine in rats: comparisons with clozapine and quetiapine

The stimulus properties of the "atypical" antipsychotic zotepine were assessed in three studies in rats. In Study 1, the ability of zotepine to generalise to clozapine was studied. Two groups of rats were trained to discriminate clozapine at 2 and 5 mg/kg. Clozapine induced full generalisation in both groups, with the generalisation curves shifted significantly to the left in the low dose group. In generalisation tests clozapine did not suppress responding. Zotepine induced dose-related generalisation in both groups, with full generalisation in the low dose group and 50% maximal generalisation in the high dose group at the highest dose that could be tested. In contrast to clozapine, zotepine induced substantial (50% or more) substitution for clozapine only at doses which suppressed responding. In Study 2 zotepine was investigated in rats trained to discriminate quetiapine (10 mg/kg). Quetiapine induced full generalisation and zotepine only induced 54% generalisation at the highest dose that could be tested. Generalisation was accompanied by response suppression induced by both quetiapine and zotepine. In Study 3 an attempt was made to train a zotepine discrimination (1 mg/kg increased to 2 mg/kg). Even after 150 training sessions it proved impossible to obtain reliable discriminative responding with zotepine. These data suggest that: (i) The actions of zotepine in discrimination assays are similar to, but not identical with, those of clozapine and quetiapine; (ii) The differences among the actions of clozapine, quetiapine and zotepine may be related to either the unique ability of zotepine to block noradrenaline (NA) uptake, or to its more marked affinity for D(2) receptors; (iii) The finding that zotepine only mimicked quetiapine up to a level of 54% was unexpected, since quetiapine and clozapine generalise reciprocally and zotepine generalised fully to (low dose) clozapine. This finding may also be related either to zotepine's ability to inhibit NA uptake or its relatively high D(2) affinity; (iv) Although zotepine clearly possesses discriminative properties, it is not possible to train it as a reliable stimulus, in contrast to clozapine and quetiapine. This may be due to its more marked D(2) receptor affinity. Collectively, these data demonstrate both similarities and differences between zotepine and other novel atypical antipsychotics in drug discrimination assays.     

Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic seroquel (quetiapine fumarate).

The interplay between dopamine and glutamate appears to be relevant in the etiopathology of schizophrenia. Although currently used antipsychotics do not interact with glutamatergic receptors, previous results have demonstrated that the expression profile of ionotropic glutamate receptors can be regulated by drugs such as haloperidol or clozapine. In the present investigation, the mRNA levels for NMDA and AMPA receptor subunits were measured after chronic treatment with the novel antipsychotic agent Seroquel (quetiapine fumarate, quetiapine) as compared to haloperidol and clozapine. Similarly to the prototype atypical clozapine, quetiapine reduced the mRNA expression for NR-1 and NR-2C, two NMDA forming subunits, in the nucleus accumbens. Furthermore, quetiapine, but not haloperidol or clozapine, increased the hippocampal expression for the AMPA subunits GluR-B and GluR-C. The differences between classical and atypical antipsychotics, as well as among the novel agents, might be relevant for specific aspects of their therapeutic activity and could provide valuable information for the role of glutamate in specific symptoms of schizophrenia.