Effects of WAY 100635 on antipsychotic-induced catalepsy in 5-HT depleted animals: a role for tonic activation of 5-HT(1A) receptors.

We recently observed that the 5-hydroxytryptamine (5-HT)(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cycloh exanecarboxamide (WAY 100635) enhanced antipsychotic-induced catalepsy, which we hypothesized to be due to a blockade of tonic 5-HT(1A) receptor activation. Here, we examined this hypothesis by studying the effects of WAY 100635 in animals that were depleted of 5-HT by repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester. Depletion of 5-HT abolished the enhancement by WAY 100635 of catalepsy induced by low doses of the antipsychotics nemonapride and raclopride, in agreement with the hypothesis that WAY 100635 enhances catalepsy by blocking tonic 5-HT(1A) receptor activation. Given the predictive validity of catalepsy, these findings indicate that 5-HT(1A) receptor blockade may enhance the extrapyramidal side-effects of antipsychotics in humans.