Risperidone has proven to be effective as an antipsychotic drug and has fewer extrapyramidal side-effects than classic neuroleptics. In addition to its dopamine D2receptor antagonistic properties, this antipsychotic agent is a potent 5-HT2receptor antagonist. The atypical antipsychotic, clozapine, also possesses both dopamine D2and 5-HT2receptor affinity next to affinities for other receptors. To gain an insight in the consequences for basal ganglia activity of treatment with these atypical neuroleptics vs. typical neuroleptics, the effects of cumulative doses of risperidone, clozapine and haloperidol on the firing rate of substantia nigra reticulata neurons were studied. Extracellular recordings were performed in chloralhydrate-anaesthetized male Wistar rats. Bath risperidone (50-3200 μg/kg i.v.) and clozapine (100-6400 μg/kg i.v.) dose dependently decreased substantia nigra reticulata activity maximally to 70% of the basal activity. With both treatments, a dose of 800 μg/kg was significantly effective. In contrast, haloperidol (12.5-800 μg/kg i.v.) gradually induced a slight increase in substantia nigra reticulata activity, which was identical to the substantia nigra reticulata activity after saline treatment. Therefore, these results indicate that typical and atypical neuroleptics affect differentially the output of the basal ganglia in the substantia nigra reticulata. To evaluate the involvement of 5-HT2receptors in the effect of risperidone, the 5-HT2receptor agonist, quipazine (0.5 mg/kg i.p.), was administered 15 min preceding risperidone treatment. A 4-fold higher dose of risperidone was needed to significantly affect the substantia nigra reticulata firing rate. Thus, the 5-HT2component of the effect of risperidone is, at least partly, responsible for the difference in effect on substantia nigra reticulata neurons in comparison to haloperidol.
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