CATALEPSY AS A RODENT MODEL FOR DETECTING ANTIPSYCHOTIC-DRUGS WITH EXTRAPYRAMIDAL SIDE-EFFECT LIABILITY

The predictive validity of catalepsy as a rodent model for detecting t he extrapyramidal side effects (EPS) of antipsychotic drugs was recent ly questioned when the novel antipsychotic savoxepine produced little catalepsy in rodents while producing significant EPS in schizophrenic patients. Because catalepsy is viewed as an important model for predic ting EPS, we decided to re-evaluate the effects of savoxepine. Savoxep ine, clozapine, haloperidol, olanzapine, ORG 5222, raclopride, and ris peridone were examined in two tests for catalepsy (grid and bar tests) in male Sprague-Dawley rats. The ability to antagonize amphetamine-in duced hypermotility was also examined, since this measure is believed to predict clinical efficacy. With the exception of clozapine, all dru gs produced dose-dependent catalepsy in both tests. For each drug, the minimum effective dose for producing catalepsy was greater than or eq ual to the ED(50) for antagonizing amphetamine-induced hyperactivity ( defined as the dose producing a 50% reduction in hyperactivity). Cloza pine resulted in the widest separation of effective doses in the catal epsy and activity models, Raclopride produced the next largest separat ion while the remaining drugs resulted in only a one- or two-fold dose separation between the two behavioral tests. The results with haloper idol and clozapine are consistent with the clinical effects of these d rugs (severe versus mild EPS). The ratios of effective doses in catale psy and activity for the remaining novel drugs are also consistent wit h preliminary clinical findings indicating some EPS with each of these compounds. Thus, catalepsy remains a suitable rodent model for detect ing compounds with EPS liability in humans.