Chronic Administration Of Clozapine Research Articles

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.

Effect of chronic clozapine administration on [ 3H]MK801-binding sites in the rat brain: a side-preference action in cortical areas

We studied modifications in [ 3H]MK801-binding sites in the rat brain after chronic clozapine. We found a 20–30% reduction of [ 3H]MK801-binding sites in the anterior cingulate, frontoparietal motor and frontoparietal somatosensory cortices on the left side but none on the right. We also demonstrated a 20% bilateral increase of N-methyl- d-aspartate (NMDA) receptors in the dentate gyrus of the hippocampus. No changes were found in the prefrontal cortex, caudate-putamen, nucleus accumbens, hippocampus or olfactory tubercle.

The CCK-A receptor antagonist devazepide but not the CCK-B receptor antagonist L-365,260 reverses the effects of chronic clozapine and haloperidol on midbrain dopamine neurons

In this study, we examined the effects of the cholecystokinin-A (CCK-A) antagonist devazepide (MK 329) and the CCK-B antagonist L-365,260 to reverse the decrease in the number of spontaneously active dopamine (DA) cells in the ventral tegmental area and substantia nigra pars compacta after chronic haloperidol (HAL) or clozapine (CLOZ) treatment. The intravenous administration of devazepide (2 micrograms/kg) but not L-365,260 (2 micrograms/kg) reversed the reduction in the number of spontaneously active A9 and A10 DA cells produced by chronic HAL. Furthermore, devazepide also reversed the decrease in the number of spontaneously active A10 DA cells produced by chronic CLOZ administration. Overall, these results suggest that CCK-A but not CCK-B receptors play an important role in mediating or maintaining the chronic antipsychotic drug-induced effect on midbrain DA cells.

Selective inhibition of mesolimbic dopamine release following chronic administration of clozapine: involvement of α 1-noradrenergic receptors demonstrated by in vivo voltammetry

The release of dopamine (DA) in vivo was compared in the striatum and nucleus accumbens following chronic (21 day) administration of clozapine (CLOZ) and repeated coadministration of haloperidol (HAL) and the α 1-noradrenergic (NE) receptor antagonist prazosin. Treatment with HAL reduced basal DA release in both brain regions, whereas treatment with CLOZ decreased basal DA release only in the accumbens. Chronic coadministration of HAL and prazosin resulted in decreased DA release in accumbens but not striatum. These results suggest that the α 1-NE receptor blocking properties of CLOZ may, in part, mediate its differential actions on nigrostriatal and mesolimbic DA release, an effect which may in addition contribute to its paucity of extrapyramidal side effects.

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat

Comparison has been made of the effects of brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1–12 months with haloperidol (1.4–1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24–27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5–1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. B max for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. B max for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. B max for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 μM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitvity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.