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 remains a question. To address the issue further, Sprague Dawley rats were treated for 6 months with multiple oral doses of haloperidol (1.5 and 3.0 mg/ kg/day) or clozapine (10, 20, and 30 mg/kg/day) and compared with water treated animals. The rate of oral dyskinesias was monitored at study start and monthly by trained raters who were blind to treatment 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 produced significantly higher rates of oral dyskinesias than did any dose of clozapine and did so in an apparent dose-sensitive manner. Clozapine lacked a dose-sensitive relationship with the oral dyskinesias, and failed to show a significant difference in rate from control rats at 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, whereas a strong association is present with haloperidol. The data are, thereby, consistent with the clinical association of tardive dyskinesia with typical neuroleptics like haloperidol but not with the atypical neuroleptic clozapine.
Gao
X M
XM
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, USA.
Hashimoto
T
T
Cooper
T B
TB
Tamminga
C A
CA
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects; D003024:Clozapine / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006220:Haloperidol / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D003024:Clozapine; D006220:Haloperidol