Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability

Abstract

The predictive validity of catalepsy as a rodent model for detecting the extrapyramidal side effects (EPS) of antipsychotic drugs was recently 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 predicting EPS, we decided to re-evaluate the effects of savoxepine. Savoxepine, clozapine, haloperidol, olanzapine, ORG 5222, raclopride, and risperidone were examined in two tests for catalepsy (grid and bar tests) in male Sprague-Dawley rats. The ability to antagonize amphetamine-induced hypermotility was also examined, since this measure is believed to predict clinical efficacy. With the exception of clozapine, all drugs produced dose-dependent catalepsy in both tests. For each drug, the minimum effective dose for producing catalepsy was greater than or equal to the ED50 for antagonizing amphetamine-induced hyperactivity (defined as the dose producing a 50% reduction in hyperactivity). Clozapine resulted in the widest separation of effective doses in the catalepsy and activity models. Raclopride produced the next largest separation while the remaining drugs resulted in only a one- or two-fold dose separation between the two behavioral tests. The results with haloperidol and clozapine are consistent with the clinical effects of these drugs (severe versus mild EPS). The ratios of effective doses in catalepsy and activity for the remaining novel drugs are also consistent with preliminary clinical findings indicating some EPS with each of these compounds. Thus, catalepsy remains a suitable rodent model for detecting compounds with EPS liability in humans.

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

“…The high percentage of colocalization of both NGFI-B and RXRg1 transcripts after haloperidol treatment in the StDL, a brain region involved in the control of locomotor behaviors, suggest that these effects may take place in the same striatal cell population. Haloperidol-induced catalepsy is thought to reproduce acute EPS observed in humans (Hoffman and Donovan, 1995). Our results demonstrate that the cataleptic behavior induced by dopamine D 2 antagonists is strongly reduced in NGFI-B-deficient mice.…”

Animal models for predicting the efficacy and side effects of antipsychotic drugs

“…The forelimbs are spread and the time the animal remains in this position is measured. 54 The catalepsy test is frequently used in drug screening to evaluate the liability of potential antipsychotics to induce extrapyramidal side effects. Generally, the doses required to induce catalepsy occupy approximately 80% of D2 receptors in the striatum, being higher than those efficacious in models predictive of antipsychotic efficacy, which requires around 65-70% occupation.…”

Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: Relevance to animal models of antipsychotic drugs

“…Forty-eight rats were randomly assigned to one of seven groups (n = 6/vehicle group, n = 7 for other groups): vehicle (water, sc or ip) + vehicle (saline, sc), vehicle (water, sc) + Donovan, 1995;Sams-Dodd, 1999;Swerdlow et al, 2000;Weiner, 2003). Because of the limitation of acute treatment regimen, none of these models provides a relevant model of time course of antipsychotic effect.…”