Effects of acute and repeated clozapine injections on cholinomimetic-induced vacuous jaw movements

Three studies were undertaken to investigate the effects of the atypical neuroleptic clozapine on the vacuous jaw movements induced by cholinergic stimulation in rats. In the first experiment, acute clozapine injections (4.0-16.0 mg/kg) produced a dose-related suppression of the vacuous jaw movements induced by 0.4 mg/kg physostigmine. In the second experiment, acute injections of clozapine (2.0-16.0 mg/kg) also suppressed vacuous jaw movements induced by 4.0 mg/kg pilocarpine in a dose-related manner. The third experiment was designed to compare the effects of acute and repeated administration of 16.0 mg/kg clozapine. In this experiment, there were three groups: one that received 4.0 mg/kg pilocarpine, a second group that received pilocarpine plus an acute injection of 16.0 mg/kg clozapine, and a third group that received injections of 16.0 mg/kg clozapine for 14 consecutive days, including the final day in which they also were injected with pilocarpine. For the third experiment, animals were assessed for the sedative effects of clozapine as well as vacuous jaw movements. The results indicated that either acute or repeated injections of 16.0 mg/kg clozapine reduced vacuous jaw movements relative to rats that received pilocarpine alone, and the two clozapine-treated groups did not differ from each other. The sedation ratings indicated that acute injections of 16.0 mg/kg clozapine produced substantial drowsiness and sedation, whereas rats that had received clozapine for 14 days did not show substantial sedation. These results indicate that clozapine can suppress cholinomimetic-induced vacuous jaw movements. The suppressive effects of clozapine on pilocarpine-induced vacuous jaw movements do not show tolerance within the 14-day period of repeated injections, whereas the sedative effects of clozapine do show tolerance. Thus, these results demonstrate that the suppression of pilocarpine-induced vacuous jaw movements by clozapine is not merely an artifact of clozapine-induced sedation. Because pilocarpine-induced vacuous jaw movements share some characteristics with human parkinsonian symptoms, the present results are consistent with previous reports indicating that repeated injections of clozapine produce anti-parkinsonian effects.