Effects of WAY 100635 on antipsychotic-induced catalepsy in 5-HT depleted animals: a role for tonic activation of 5-HT1A receptors

We recently observed that the 5-hydroxytryptamine (5-HT)(1A) receptor antag onist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cycloh exanecarboxamide (WAY 100635) enhanced antipsychotic-induced catalepsy, whi ch we hypothesized to be due to a blockade of tonic 5-HT1A receptor activat ion. Here, we examined this hypothesis by studying the effects of WAY 10063 5 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 o f the antipsychotics nemonapride and raclopride, in agreement with the hypo thesis that WAY 100635 enhances catalepsy by blocking tonic 5-HT1A receptor activation. Given the predictive validity of catalepsy, these findings ind icate that 5-HT1A receptor blockade may enhance the extrapyramidal side-eff ects of antipsychotics in humans. (C) 2000 Elsevier Science B.V. All rights reserved.