Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
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To investigate the effects of various chemical classes of antipsychotic drugs: haloperidol, thioridazine, pimozide and clozapine, on the G-protein-activated inwardly rectifying K(+) (GIRK) channels, we carried out Xenopus oocyte functional assays with GIRK1 and GIRK2 mRNAs or GIRK1 and GIRK4 mRNAs. In oocytes co-injected with GIRK1 and GIRK2 mRNAs, application of each of the various antipsychotic drugs immediately caused a reduction of inward currents through the basally active GIRK channels. These responses were not observed in the presence of 3 mM Ba(2+), which blocks the GIRK channels. In addition, in uninjected oocytes, none of the drugs tested produced any significant current response. These results indicate that all the antipsychotic drugs tested inhibited the brain-type GIRK1/2 heteromultimeric channels. Furthermore, similar results were obtained in oocytes co-injected with GIRK1 and GIRK4 mRNAs, indicating that the antipsychotic drugs also inhibited the cardiac-type GIRK1/4 heteromultimeric channels. All the drugs tested inhibited, in a concentration-dependent manner, both types of GIRK channels with varying degrees of potency and effectiveness at micromolar concentrations. Only pimozide caused slight inhibition of these channels at nanomolar concentrations. We conclude that the various antipsychotic drugs acted as inhibitors at the brain-type and cardiac-type GIRK channels. Our results suggest that inhibition of both types of GIRK channels by these drugs underlies some of the side effects, in particular seizures and sinus tachycardia, observed in clinical practice. (+info)
Dissociation of haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex.
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The aim of the present study was to compare the effects of the typical antipsychotic haloperidol and the atypical antipsychotics clozapine and olanzapine on both extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) as well as electrical activity of mesoprefrontal DA (mPFC-DA) neurons. Extracellular single unit recordings and microdialysis experiments were carried out in different groups of chloral hydrate anesthetised rats under identical experimental conditions. Intravenous administration of haloperidol, clozapine, and olanzapine increased the firing rate and burst activity of antidromically-identified mPFC-DA neurons; maximal increase in firing rate of approximately 140, 155, and 70 %, was produced by haloperidol, clozapine, and olanzapine at doses of 0.2, 2.5, and 1 mg/kg, i.v., respectively. Intravenous administration of the same doses increased extracellular DA levels in mPFC by 20%, 190%, and 70%, respectively. Moreover, while haloperidol and olanzapine increased extracellular levels of the deaminated DA metabolite DOPAC, by 60% and 40%, respectively, clozapine was totally ineffective. The D1 receptor antagonist SCH 23390 modified neither DA output nor neuronal firing. To determine whether the effect of the three antipsychotics on DA release might depend on a direct action on the mPFC, rats were perfused locally via inverse dialysis in the mPFC at concentrations ranging from 10(-6) to 10(-4)M. While clozapine and olanzapine increased extracellular DA concentrations by up to 400% of basal level, haloperidol was totally ineffective. The results obtained from this study indicate that the rank potency of the three antipsychotics in stimulating the firing rate of DA neurons projecting to mPFC, correlates with their affinity for D2 receptors and doses used clinically. On the other hand, their stimulating effect on DA release does not correlate with their effect on neuronal firing but depends on a direct action on the mPFC. (+info)
Intracellular modulation of NMDA receptor function by antipsychotic drugs.
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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. (+info)
Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine.
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Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes neutropenia and agranulocytosis in 3 and 0.8% of patients, respectively. Clozapine undergoes bioactivation to a chemically reactive nitrenium ion, which has been shown to cause neutrophil cytotoxicity. To define further the mechanism of cell death, we have investigated the toxicity of clozapine, its stable metabolites, and its chemically reactive nitrenium ion to neutrophils and lymphocytes. Clozapine was able to induce neutrophil apoptosis at therapeutic concentrations (1-3 microM) only when it was bioactivated to the nitrenium ion. The parent drug caused apoptosis at supratherapeutic concentrations (100-300 microM) only. Neutrophil apoptosis induced by the nitrenium ion, but not by the parent drug itself, was inhibited by antioxidants and genistein and was accompanied by cell surface haptenation (assessed by flow cytometry) and glutathione depletion. Dual-color flow cytometry showed that neutrophils that were haptenated were the same cells that underwent apoptosis. No apoptosis of lymphocytes was evident with the nitrenium ion or the parent drug, despite the fact that the former caused cell surface haptenation, glutathione depletion, and loss of membrane integrity. Demethylclozapine, the major stable metabolite in vivo, showed a profile that was similar to, although less marked than that observed with clozapine. N-oxidation of clozapine or replacement of the nitrogen (at position 5) by sulfur produced compounds that were entirely nontoxic to neutrophils. In conclusion, the findings of the study expand on potential mechanisms of clozapine-induced cytotoxicity, which may be of relevance to the major forms of toxicity encountered in patients taking this drug. (+info)
The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin.
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Latent inhibition (LI), i.e., retarded conditioning to a stimulus following its nonreinforced preexposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Typical and atypical antipsychotic drugs (APD's) potentiate LI, but to date the model has not dissociated between them. This study demonstrates such a dissociation using haloperidol (0.1 mg/kg), clozapine (5 mg/kg), and ritanserin (0.6 mg/kg) administered in preexposure and/or conditioning. Under conditions which did not yield LI in vehicle controls (40 preexposures and five conditioning trials), both haloperidol and clozapine, but not ritanserin, led to LI when administered in conditioning. Under conditions which led to LI in vehicle controls (40 preexposures and two conditioning trials), clozapine and ritanserin, but not haloperidol, abolished LI when administered in preexposure. It is suggested that LI potentiation via conditioning detects the "typical" action of APD's whereas LI disruption via preexposure detects the "atypical" action of APD's. (+info)
Clozapine- and olanzapine-induced Fos expression in the rat medial prefrontal cortex is mediated by beta-adrenoceptors.
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The atypical neuroleptics, clozapine and olanzapine, have superior therapeutic efficacy against the negative symptoms of schizophrenia, compared with the typical neuroleptics. Recently, it has been suggested that the ability of clozapine and olanzapine to induce Fos expression in the medial prefrontal cortex (mPFC), contribute to their therapeutic efficacy. However, the mechanisms underlying the neuropharmacological effects of clozapine and olanzapine in the mPFC remain elusive. In the present study, we demonstrate that clozapine- and olanzapine-induced Fos expression in the mPFC are inhibited by propranolol. We also show that clozapine and olanzapine induce Fos expression in the locus coeruleus. These results suggest that clozapine and olanzapine increase noradrenaline release by stimulating noradrenergic neuronal activity in the locus coeruleus and, consequently, increased noradrenaline induce Fos expression in the mPFC via beta-adrenergic receptors. This postulated sequence may be one of mechanisms by which clozapine-like atypical neuroleptics are more effective for the negative symptoms of schizophrenia. (+info)
Clozapine augmentation: safety and efficacy.
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While clozapine has been demonstrated to be efficacious in refractory schizophrenia and possibly schizoaffective as well as bipolar disorders, a substantial number of patients still remain unresponsive. One strategy in treating these refractory patients is to augment clozapine with other somatic treatments. This article reviews the efficacy and safety of the combination of clozapine with other somatic treatments. A total of 70 articles were obtained from a manual, as well as computerized (Medline), search of the English language literature from 1978 to March 1998. Few controlled studies exist; most were case reports/series. From these data, the greatest risk of adverse effects seems to be associated with clozapine combined with benzodiazepines, valproate, or lithium, but no currently evaluated combination is absolutely unsafe. In terms of efficacy, the data suggest a number of potential augmentation strategies, although controlled data are few. Combination therapies with clozapine are common in clinical practice, despite a lack of empirical data, and the benefits and risks of these combinations need to be systematically reviewed. (+info)
The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia.
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Several case studies indicate that clozapine use is associated with reductions in the use of nicotine, alcohol, or illicit drugs. Although not designed to assess clozapine, this study explored a posteriori the effects of clozapine on alcohol and drug use disorders among schizophrenia patients. Among 151 patients with schizophrenia or schizoaffective disorder and co-occurring substance use disorder who were studied in a dual-disorder treatment program, 36 received clozapine during the study for standard clinical indications. All participants were assessed prospectively at baseline and every 6 months over 3 years for psychiatric symptoms and substance use. Alcohol-abusing patients taking clozapine experienced significant reductions in severity of alcohol abuse and days of alcohol use while on clozapine. For example, they averaged 54.1 drinking days during 6-month intervals while off clozapine and 12.5 drinking days while on clozapine. They also improved more than patients who did not receive clozapine. At the end of the study, 79.0 percent of the patients on clozapine were in remission from alcohol use disorder for 6 months or longer, while only 33.7 percent of those not taking clozapine were remitted. Findings related to other drugs in relation to clozapine were also positive but less clear because of the small number of patients with drug use disorders. This study was limited by the naturalistic design and the lack of prospective, standardized measures of clozapine use. The use of clozapine by patients with co-occurring substance disorders deserves further study in randomized clinical trials. (+info)