Clozapine is an antipsychotic drug with a unique clinical, biochemical and behavioral profile. However, clozapine also produces agranulocytosis, which has led to a vigorous search for other """"""""atypical"""""""" antipsychotics with properties that resemble clozapine. Previous research has indicated that research on tremulous jaw movements in rats may be useful for identifying drugs with motor properties similar to clozapine. Unlike typical antipsychotics, clozapine generally fails to induce tremulous jaw movements in repeated administration procedures. In addition, clozapine acts to suppress the jaw movements induce by the anticholinesterase tacrine. The suppression of tacrine-induced jaw movements by clozapine occurs at a relatively low dose; clozapine suppressed tacrine-induced jaw movements with an ED50 lower than that observed for suppression of lever pressing. Using acute injection procedures, olanzapine and risperidone also were relatively potent at suppressing jaw movements, while haloperidol was ineffective. In studies involving repeated 14 day injection procedures, the rank order of the ratios of the ED50s for suppression of tacrine-induced jaw movements and lever injection procedures, the rank order of the ratios of the ED50s for suppression of tacrine-induced jaw movements and lever pressing was (from lowest to highest) as follows: clozapine < olanzapine < thioridazine < haloperidol. This pattern is consistent with human clinical data on the production of extrapyramidal side effects. Thus, it is reasonable to suggest that behavioral studies involving tremulous jaw movements could be useful for characterizing the pharmacological characteristics that underlie the suppression of jaw movement activity by atypical antipsychotics are uncertain. Although there is considerable evidence indicating that the anticholinergic properties of clozapine may contribute to the motor effects of this drug, less is known about the possible contribution of serotonergic antagonist properties. In view of the studies indicating that 5-HT systems may be involved in mediating some of the motor effects of atypical antipsychotics, the proposed studies will investigate the involvement of 5-HT mechanisms in the suppression of jaw movement activity. The first group of studies will assess the effects of additional antipsychotic drugs that have 5-HT antagonist properties. Tests will be conducted after both acute and repeated dosing procedures. The second group of proposed experiments is designed to investigate the effects of 5-HT2a/2c antagonism on tacrine- and haloperidol-induced jaw movements. The third group of proposed studies will employ intracranial drug injections to determine that brain loci at which 5-HT2a/2c antagonists and atypical antipsychotics suppress jaw movements activity. Taken together, the results of these experiments will help to identify the pharmacological characteristics and brain circuits that underlie the motor effects of clozapine.
