Atypical Antipsychotic Drug Clozapine Research Articles

Intracellular Modulation of NMDA Receptor Function by Antipsychotic Drugs

The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.

Effects of neurotensin receptor antagonists on the firing rate of rat ventral pallidum neurons.

Using anaesthetized adult rats, we compared the effects of i.v. injections of neurotensin receptor antagonists (SR48692 and SR142948), haloperidol and clozapine on neuronal firing rate in the two ventral pallidal areas. SR48692 (0.5, 1 and 2 mg/kg, i.v.) induced a dose-dependent inhibition of firing rate in two thirds of neurons in the ventromedial part without any effect in the ventrolateral part. These effects are in keeping with the preferential neurotensin immunoreactivity distribution reported in the ventral pallidum. The classical antipsychotic drug haloperidol (0.5 mg/kg, i.v.) induced an inhibition of neuronal firing rate in both ventral pallidal areas whereas the atypical antipsychotic drug clozapine (20 mg/kg, i.v.), like the neurotensin receptor antagonist SR48692, inhibited cell firing only in the ventromedial part.

Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs

Clinical studies utilizing imaging techniques demonstrate that classical antipsychotic drugs, such as haloperidol, in clinically effective doses display around 75% dopamine (DA)-D 2 receptor occupancy in the brain. In contrast, the atypical antipsychotic drug clozapine is even more effective at only about 45% D 2-receptor occupancy. Yet at this D 2-receptor occupancy classical antipsychotics are not effective, raising the question of which other receptors may be involved in mediating the atypical antipsychotic profile of clozapine and other atypical antipsychotics. The present paper describes experimental work aimed at elucidating this critical question, utilizing the phencyclidine (PCP) model of schizophrenia in combination with studies of typical and atypical antipsychotics as well as various specific receptor blocking agents. Both electrophysiological methods, i.e. single cell recording from DA neurons in the ventral tegmental area (VTA), and biochemical analysis of biogenic amines such as DA following microdialysis in difference DA terminal areas in the brain, were used. In addition, behavioural measurements using the conditioned avoidance response (CAR) paradigm and assessments of locomotor activity were utilized. Experiments with functional inactivation of the medial frontal cortex (mPFC) in the rat as well as with MK-801 and other antagonists at central NMDA-receptors revealed that following systemic administration of schizophrenomimetic NMDA-receptor antagonists a profound dysregulation of the mesocorticolimbic DA system occurs, severely impairing the dynamic physiological response range of the neurons. Specifically, DA neurons which largely project to the mPFC showed a profound loss of burst firing, whereas VTA-DA neurons, which mainly project subcortically, showed an increased monotonous high-frequency firing with increased DA output from nerve terminals and concomitant behavioural activation. Significantly, drugs with a prominent 5-HT 2A-receptor blocking action could effectively restore the burst firing mode, i.e. phasic responsivity, in mesocortically projecting DA neurons, and also potentiate the CAR suppressant effect of the selective D 2/D 3-receptor antagonist raclopride without increasing catalepsy scores. The selective α 1-adrenoreceptor antagonist prazosin effectively suppressed both the stereotyped, high-frequency firing of subcortically projecting DA neurons following systemic MK-801 and the concomitant behavioural, i.e. locomotor, activation. In addition, the MK-801 evoked DA release in the nucleus accumbens was suppressed. A similar effect was seen also with AMPA-receptor antagonists when applied locally into the VTA and, in addition, systemic administration of chemically different AMPA-receptor antagonists caused a CAR-suppressant effect similar to both classical and atypical antipsychotic drugs. These results and other data showing a clearcut difference between typical and atypical antipsychotic drugs on DA output in the shell and core, respectively, of the nucleus accumbens, suggest that both the 5-HT 2A- and the α 1-adrenoreceptor blocking effects of a number of atypical antipsychotic drugs in all probability contribute to their antipsychotic effect. Moreover, our results indicate that AMPA-receptor antagonists may possess an atypical antipsychotic profile.

A schizophrenic mouse?

N-methyl-d-aspartate receptor (NMDAR) deficiency has been suggested as a possible cause of schizophrenia. In part, this is because intoxication with three different non-competitive antagonists of NMDARs [phencyclidine (PCP), MK-801 and ketamine] mimics the disorder.Mohn et al.1xMice with reduced NMDA receptor expression display behaviors related to schizophrenia. Mohn, A.R. et al. Cell. 1999; 98: 427–436Abstract | Full Text | Full Text PDF | PubMed | Scopus (715)See all References1 have studied the effect of NMDAR deficiency on murine behaviour. NMDAR complexes consist of one NMDAR subunit 1 (NR1) and one of four NR2 subunits. Mice that lack the NR1 protein die perinatally, so Mohn et al. generated, by insertional mutagenesis, a strain of mice in which NR1 is expressed at only 5–10% of wild-type levels. Although this was found to be sufficient for survival, the mice displayed hyperlocomotion, increased stereotypic behaviour and social withdrawal, which are believed to mirror behaviours seen in schizophrenia. Treatment with the atypical antipsychotic drug clozapine, which treats schizophrenic symptoms without causing severe side effects, reduced the locomotion and stereotypy in the NMDAR-deficient mice to wild-type levels and decreased the levels of social withdrawal; the behaviour of wild-type mice was not affected by the treatment. In addition, PCP and MK-801 had no effect on the NMDAR-deficient mice, suggesting that the behavioural effects of these compounds are mediated through suppression of NMDARs.This work has provided insight into a possible mechanism for some aspects of schizophrenia. In addition, it will allow the study of the effect of long-term NMDAR deficiency, which is important because schizophrenia is thought to be a progressive mental illness.

Region-specific induction of deltaFosB by repeated administration of typical versus atypical antipsychotic drugs.

Whereas acute administration of many types of stimuli induces c-Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region-specific accumulation of novel Fos-like proteins of 35-37 kD. These proteins, termed chronic FRAs (Fos-related antigens), have recently been shown to be isoforms of DeltaFosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsychotic drugs (APDs) on induction of Fos-like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these DeltaFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces DeltaFosB in caudate-putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of DeltaFosB in any of the three brain regions, and even tended to reduce DeltaFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of DeltaFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of DeltaFosB in CP and NAc is most dependent on antagonism of D2-D3 dopamine receptors, with antagonism of D1-like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of DeltaFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration of APDs results in the induction of long-lasting Fos-like transcription factors that could mediate some of the persistent and region-specific changes in brain function associated with chronic drug exposure. Synapse 33:118-128, 1999.

Region‐specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs

Whereas acute administration of many types of stimuli induces c-Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region-specific accumulation of novel Fos-like proteins of 35–37 kD. These proteins, termed chronic FRAs (Fos-related antigens), have recently been shown to be isoforms of ΔFosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsychotic drugs (APDs) on induction of Fos-like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these ΔFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces ΔFosB in caudate–putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of ΔFosB in any of the three brain regions, and even tended to reduce ΔFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of ΔFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of ΔFosB in CP and NAc is most dependent on antagonism of D2–D3 dopamine receptors, with antagonism of D1-like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of ΔFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration of APDs results in the induction of long-lasting Fos-like transcription factors that could mediate some of the persistent and region-specific changes in brain function associated with chronic drug exposure. Synapse 33:118–128, 1999. © 1999 Wiley-Liss, Inc.

Steady-state Pharmacokinetics of Clozapine in Refractory Schizophrenic Saudi Arabian Patients

The steady-state pharmacokinetics of the atypical antipsychotic drug clozapine in schizophrenic Saudi Arabian patients was studied and correlated with the clinical outcome. Twenty-six schizophrenic patients were given clozapine over a period of 2–41 months. The daily dose ranged from 100 to 700 mg, and the frequency of administration varied from 1 to 2 times daily. A blood sample was collected from each patient at the midpoint of the dosing interval and was repeated on different days in six randomly selected patients to establish the steady-state condition. The concentration of clozapine in plasma (Css) was measured by HPLC with UV detection at 250 nm using C18 bonded SepPak cartridges for sample preparation. The apparent oral clearance (CLp.o.) was calculated from the equation: CLp.o. = dose/tCss where t is the time between two consecutive doses. The effectiveness of the treatment was evaluated by the standard Positive and Negative Syndrome Scale (PANSS). The mean ± s.d. steady-state concentration (Css) was 491 ± 299 ng mL−1 There were no significant differences in Css or any of the pharmacokinetic parameters studied between the 11 patients who responded positively to the treatment and the 15 patients who responded negatively. These results do not support the hypothesis that there is a positive correlation between higher plasma concentrations and positive response from clozapine in Saudi Arabian patients.

Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation.

Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression. We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex. Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive. An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation.

The metabolism of atypical antipsychotic drugs: an update.

This paper reviews the current literature describing the metabolism of both multi-receptor clozapine analogue atypical antipsychotic drugs (clozapine, olanzapine, and quetiapine) and serotonin-dopamine antagonist atypical antipsychotic drugs (risperidone, sertindole and ziprasidone), to highlight the significance of those data in the context of clinical practice. The former group of atypical antipsychotic drugs shares a similar tricyclic structural nucleus and are metabolized through three major categorical metabolic pathways--N+-oxidation, N-glucuronidation, and phases 1 and 2 biotransformation with final glucuronidation before renal excretion. Differing in clozapine and olanzapine, quetiapine has incomplete data describing its metabolism. The latter group of atypical antipsychotic drugs has diversified chemical structures and absence of data on N+-oxidation and N-glucuronidation in the literature. But their metabolic routes in phase 1 biotransformation are versatile although current data are far from completion. No apparent significant drug interactions in clinical practice are reported, although QT prolongation is implicated in all those three drugs. None of all six atypical antipsychotic drugs are identified as significant inhibitors or inducers to any co-administered medication. The author suggests the need for more research to address some pertinent clinical issues in the metabolism of those drugs.

Haloperidol, raclopride, and eticlopride induce microcatalepsy during operant performance in rats, but clozapine and SCH 23390 do not.

The purpose of this work was (1) to assess the ability of selected antipsychotic and comparison drugs to induce arrest of movement phenomena during operant responding and (2) to evaluate the capacity of muscarinic anitcholinergics to block such effects. The effects of haloperidol (0.02-0.12 mg/kg, i.p., 45 min), raclopride (0.05-0.80 mg/kg, i.p., 30 min) eticlopride (0.02-0.16 mg/kg, i.p., 45 min), clozapine (1.0-8.0 mg/kg, i.p., 60 min) and SCH 23390 (0.01-0.16 mg/kg, i.p., 30 min) were administered to rats for 4 weeks in a between-groups dosing design. Operant responses in 15 min and the maximum duration of the rat's muzzle entry into the reinforcement dipper well (the measure of arrest of movement that reflected microcatalepsy) were the quantitative measures of behavior. The D2 antagonists dose-relatedly decreased operant responding and increased maximum muzzle duration, effects that were significantly reversed by the anticholinergic scopolamine (0.1 mg/kg) or atropine (6.0 mg/kg). Although the atypical antipsychotic drug clozapine and the selective D1 antagonist SCH 23390 both significantly reduced operant responding, these drugs did not produce microcatalepsy. The results suggested that microcatalepsy expressed in the context of ongoing operant behavior may model low-dose extrapyramidal side effects.

Childhood-Onset Schizophrenia Associated With Parkinsonism in a Patient With a Microdeletion of Chromosome 22

The deletion of a gene or genes on chromosome 22q11 is responsible for the velocardiofacial syndrome (VCFS), which is associated with cardiac anomalies, short stature, palate abnormalities, learning disabilities, and developmental delay. Herein we describe a 30-year-old man with VCFS in whom a chronic psychotic disorder originated during childhood. A 10% rate of psychotic disorders has been reported in association with this genetic syndrome. In our patient, the clinical manifestation was complicated by extrapyramidal symptoms that predated the onset of psychotic symptoms. To our knowledge, extrapyramidal symptoms have not previously been reported in a patient with VCFS. The diagnosis of VCFS was confirmed with the fluorescence in situ hybridization probe for VCFS. The role of the atypical antipsychotic drug clozapine is discussed with respect to treating this patient who has severe psychotic symptoms coexisting with extrapyramidal symptoms and seizures. In light of the observation that patients with VCFS have an unexpectedly high rate of psychotic disorders, issues concerning the genetics of schizophrenia are intriguing.

Acute and chronic administration of clozapine produces greater proconvulsant actions than haloperidol on focal hippocampal seizures in freely moving rats.

In this study, we assessed the effects of the acute (a single injection) and repeated (once daily injections for 21 days) administration of the atypical antipsychotic drug clozapine (1.5, 5, or 15 mg/kg i.p.) and the typical antipsychotic drug haloperidol (0.15, 0.5, and 1.5 mg/kg, i.p.) on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold (PNT) and the primary afterdischarge duration (ADD), respectively. A single injection of either 5 or 15 mg/kg of clozapine significantly decreased the PNT and significantly increased the primary ADD, indicating a proconvulsant action. The repeated administration of clozapine (1.5, 5, or 15 mg/kg, i.p.) produced dose-dependent, proconvulsant effects by significantly decreasing the PNT and by significantly increasing the primary ADD. In contrast to clozapine, the acute administration of haloperidol did not significantly alter the PNT or the primary ADD. The repeated administration of haloperidol (0.5 and 1.5 mg/kg, i.p.), unlike clozapine, significantly decreased the primary ADD, but did not alter the PNT. Overall, clozapine produces a greater proconvulsant action than haloperidol in an animal model of hippocampal seizures.

Within-session behavioral decrement of atypical antipsychotics: Role of novelty

In order to gain a better understanding of the characteristics of antipsychotic-induced within-session decrements in unconditioned behavioral responses of mice, and whether they are sensitive to novel environmental stimuli, we studied the acute effects of haloperidol and atypical antipsychotic drugs (sulpiride, thioridazine, clozapine, and remoxipride) in familiar and novel open-field conditions in mice. The results show that familiarized controls and antipsychotic-treated groups had a progressive reduction in ambulation and rearing during the 10-minute open-field session. By manipulating the configuration of the open-field situation, familiarized controls as well as mice treated with typical or atypical antipsychotic drugs were able to exhibit an enhanced response to the presentation of novel stimuli. It may be noted that both the maintenance and the initiation of ambulation were affected by antipsychotic treatment. Furthermore, when comparing novel versus familiar groups during the 10-minute session, the increase in ambulation induced by atypical antipsychotic treatment was maintained longer (6-8 minutes) than that induced by haloperidol (4 minutes). In summary, these findings show that an important feature in the reinstatement of both typical and atypical antipsychotic-induced behavioral decrement may be a change in the stimulus conditions.

Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine.

The effects of the psychotomimetic drug phencyclidine on the neurochemistry and function of the prefrontal cortex in vervet monkeys were investigated. Monkeys treated with phencyclidine twice a day for 14 days displayed performance deficits on a task that was sensitive to prefrontal cortex function; the deficits were ameliorated by the atypical antipsychotic drug clozapine. Repeated exposure to phencyclidine caused a reduction in both basal and evoked dopamine utilization in the dorsolateral prefrontal cortex, a brain region that has long been associated with cognitive function. Behavioral deficits and decreased dopamine utilization remained after phencyclidine treatment was stopped, an indication that these effects were not simply due to direct drug effects. The data suggest that repeated administration of phencyclidine in monkeys may be useful for studying psychiatric disorders associated with cognitive dysfunction and dopamine hypofunction in the prefrontal cortex, particularly schizophrenia.

Characterization of dopamine-induced depolarization of prefrontal cortical neurons.

Dopamine (DA) has been reported to depolarize neurons in the prefrontal cortex (PFC). To further characterize this effect of DA, we made whole cell recordings from PFC pyramidal cells in rat brain slices. As reported previously, DA depolarized most PFC cells tested. This effect of DA was concentration-dependent and persisted in the presence of synaptic blockade, indicating a direct effect of DA on the recorded cell. During DA-induced depolarization, PFC neurons consistently showed an increase in excitability, suggesting that the depolarization is not directly related to DA-induced inhibition of PFC neurons previously observed in vivo. Surprisingly, the effect of DA was not mimicked or blocked by several commonly used DA agonists and DA antagonists. The alpha and beta antagonists phentolamine and alprenolol and the atypical antipsychotic drug clozapine also showed no significant effect on DA-induced depolarization. These results suggest that DA-induced depolarization may be mediated by a nonspecific mechanism. However, it remains possible that there exists a new type of DA receptors in the PFC not sensitive to classical DA agonists and antagonists, particularly given the fact that DA applied in the same manner depolarized only PFC neurons but not those in the striatum or the substantia nigra.

Effect of chronic antipsychotic drug treatment on preprosomatostatin and preprotachykinin A mRNA levels in the medial prefrontal cortex, the nucleus accumbens and the caudate putamen of the rat.

In situ hybridization histochemistry was used to study the expression of preprosomatostatin (PPSOM) and preprotachykinin A (PPT-A) mRNA in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAC) and the caudate putamen (CP) of the rat after chronic (21 days) treatment with the classical antipsychotic drug haloperidol (1 mg/kg i.p.), the atypical antipsychotic drugs clozapine (15 mg/kg i.p.) and amperozide (5 mg/kg i.p.), and the selective dopamine (DA)-D2/D3 receptor antagonist raclopride (2 mg/kg i.p.). Whereas amperozide markedly elevated the numerical density of PPSOM mRNA expressing neurons in the mPFC (52%), the other drugs did not significantly affect PPSOM mRNA levels in any of the brain regions studied. Amperozide also altered PPT-A mRNA expression in the mPFC, i.e. a decrease (22%) was found. Of the other drugs tested only haloperidol significantly decreased PPT-A mRNA levels in the NAC shell (14%), in the dorso-lateral CP (19%) and in the medial CP (15%). In view of the differences between amperozide and the other drugs studied, as regards both pre-clinical and clinical characteristics, we suggest that the specific effects of amperozide on PPSOM and PPT-A mRNA in the mPFC may be related to its 5-HT releasing action in the frontal cortex, an effect possibly caused by its alpha2-adrenoceptor blocking activity. This effect, in turn, may be related to an antidepressant-like action that this compound exhibits in animal studies. The decrease in PPT-A mRNA levels seen after the haloperidol treatment is probably due to its potent DA-D2 receptor antagonism and may be related to side-effects, rather than therapeutic effects of this drug.

Effects of serotonergic agents on the up-regulation of dopamine D 2 receptors induced by haloperidol in rat striatum

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D 2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D 2 receptors, while no increase was observed with the atypical antipsychotic drugs clozapine (10 mg/kg) and trans-5-chloro-2-methyl-2,3,3 a,12 b-tetrahydro-1 H-dibenz[2,3:6,7]oxepino[4,5- c]pyrrolidine maleate (ORG 5222; 0.25 mg/kg). Chronic treatment with 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a nonselective serotonin (5-hydroxytryptamine, 5-HT) receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D 2 receptors, while that with (±)-8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), a 5-HT 1A receptor agonist (0.1 mg/kg) had no influence on the dopamine D 2 receptor up-regulation. Coadministration of ritanserin (1 mg/kg), a 5-HT 2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg) attenuated the dopamine D 2 receptor up-regulation. Drug occupation of 5-HT 2A and dopamine D 2 receptors in vivo examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT 2A receptors are highly occupied compared with dopamine D 2 receptors, was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT 2A receptor antagonism versus weak dopamine D 2 receptor blockade may be involved in the absence of up-regulation of dopamine D 2 receptors after chronic treatment with clozapine or ORG 5222.

Dopamine D4 Receptors and Schizophrenia: An Unhappy Ending?

Tremendous interest in the dopamine D4 receptor subtype was generated when it became clear that the atypical antipsychotic drug clozapine binds to it with particularly high affinity. These data, along with the distribution of the D4 receptor in the brain, suggested that a selective D4 receptor antagonist was a suitable target for new antipsychotic drug development. In fact, a novel D4 receptor …

Pharmacological actions of the atypical antipsychotic drug clozapine: a review.

Clozapine [8-chloro- 11-(4-methyl- 1-piperazinyl)-3H-dibenzo (b,e)(1,4) diazepine], or clozaril, is a member of the dibenazepine class of antipsychotic drugs. Initially, studies in animals using a number of neurochemical, biochemical, electrophysiological, and behavioral paradigms indicated that clozapine was markedly different from various typical antipsychotic drugs such as haloperidol and chlorpromazine. Subsequently, clinical studies have shown that clozapine is effective in ameliorating the core symptoms, as well as the negative symptoms, in schizophrenia. However, clozapine has a much lower propensity for inducing neurological side effects after acute or repeated administration compared to various typical neuroleptics. Furthermore, clozapine is therapeutically effective in treating about 30% of schizophrenic patients who are resistant to standard antipsychotic drugs. Based on the above information, clozapine has been designated an atypical antipsychotic drug. However, at this time, it is not entirely clear why clozapine is such a unique antipsychotic drug. To date, there has not been a comprehensive review regarding clozapine's pharmacological profile. Therefore, we will review clozapine's profile in the following areas: 1) affinity for neurotransmitter receptors in the brain; 2) electrophysiology (in vivo, single-cell recording and iontophoresis; in vitro studies); 3) in vivo microdialysis and voltammetry; 4) monoamine turnover or metabolism; 5) intermediate early gene expression; 6) positron emission tomography studies; and 7) molecular biological studies. We will also compare and contrast clozapine's acute and chronic effects, and discuss the merits of various hypotheses that have been put forward to explain clozapine's unique profile.

The effects of antipsychotic drugs on fos protein expression in the prefrontal cortex: Cellular localization and pharmacological characterization

The assessment of immediate-early gene induction has proven to be a useful method for delineating the neural systems that subserve antipsychotic drug actions. In order to differentiate the sites and mechanisms of action of typical and atypical antipsychotic drugs, we examined the effects of antipsychotic drugs on Fos protein expression in the medial prefrontal cortex. The atypical antipsychotic drug clozapine selectively increased the number of neurons that expressed Fos-like immunoreactivity in the prefrontal cortex, targeting the deep layers of the infralimbic and prelimbic cortices. Pyramidal cells were the major cell type in which Fos was expressed. A small number of calbindin-like immunoreactive, but not parvalbumin- or reduced nicotinamide adenine dinucleotide phosphate diaphorase-containing, interneurons also expressed Fos after clozapine challenge. Immunoblot studies revealed that clozapine induced Fos protein in the infralimbic and prelimbic cortices. Other antipsychotic drugs that are D2 receptor antagonists, including haloperidol, raclopride, sulpiride, remoxipride and loxapine, did not alter Fos expression. The clozapine-induced increase in Fos expression was also not attributable to actions at the D1 dopamine receptor, nor to serotonin type 2a/2c receptor antagonism or combined serotonin type 2-D2 dopamine receptor antagonism. The ability of clozapine to block alpha 1-adrenergic or muscarinic cholinergic receptors did not contribute to the unique actions of clozapine. Despite the inability of dopamine receptor antagonists other than clozapine to elicit an increase in Fos expression, both the mixed D1-D2 dopamine agonist apomorphine and the D2-like agonist quinpirole increased Fos protein levels in the prefrontal cortex. However, neither pretreatment with sulpiride to block D2/3/4 dopamine receptors or SCH 23390 to block D1/5 dopamine receptors modified the Fos response to clozapine. Since dopamine receptor antagonist pretreatments did not attenuate the clozapine-elicited Fos expression, but D2 agonists increased cortical Fos expression, clozapine may act in the prefrontal cortex on an as yet undefined dopamine receptor. In contrast to the nucleus accumbens shell, where all antipsychotic drugs increase Fos expression, only clozapine induced Fos in the medial prefrontal cortex. These observations suggest that the ability of clozapine to treat schizophrenic patients who are resistant to the therapeutic benefits of conventional antipsychotic drugs may occur through actions in the prefrontal cortex.