THE DOSE-RESPONSE CHARACTERISTICS OF RAT ORAL DYSKINESIAS WITH CHRONIC HALOPERIDOL OR CLOZAPINE ADMINISTRATION

Whether the pathophysiology and treatment of neuroleptic-induced oral dyskinesias in rats parallel that for tardive dyskinesia in humans rem ains a question. To address the issue further, Sprague Dawley rats wer e treated for 6 months with multiple oral doses of haloperidol (1.5 an d 3.0mg/kg/day) or clozapine (10, 20, and 30mg/kg/day) and compared wi th water treated animals. The rate of oral dyskinesias was monitored a t study start and monthly by trained raters who were blind to treatmen t group. All haloperidol-treated rats developed oral dyskinesias at a significantly higher rate than rats treated with water (p = 0.0007) or those treated with clozapine (p = 0.0017). Each dose of haloperidol p roduced significantly higher rates of oral dyskinesias than did any do se of clozapine and did so in an apparent dose-sensitive manner. Cloza pine lacked a dose-sensitive relationship with the oral dyskinesias, a nd failed to show a significant difference in rate from control rats a t any dose. Plasma levels of haloperidol with these doses were in the human therapeutic range; with clozapine only the highest dose produced plasma levels in the human therapeutic range. These data show little association between rat oral dyskinesias and clozapine treatment, wher eas a strong association is present with haloperidol. The data are, th ereby, consistent with the clinical association of tardive dyskinesia with typical neuroleptics like haloperidol but not with the atypical n euroleptic clozapine.