Interactions between neuroleptics and 5-HT1A ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects

Rationale: Combining neuroleptics with 5-HT_1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or are better tolerated. Objective: To examine 1) the ability of 5-HT_1A ligands to alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time in the paw test) and extrapyramidal side-effects (forelimb retraction time in the paw test; catalepsy tests), 2) the role of intrinsic activity at 5-HT_1A receptors in the modulatory effects of 5-HT_1A ligands, and 3) the generality of the interactions across neuroleptics. Methods: The effects of different doses of 5-HT_1A ligands with intrinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 100135) administered together with a fixed, high dose of the neuroleptics haloperidol, risperidone, and tropapride were examined in the paw test and on catalepsy. Results: Firstly, the 5-HT_1A agonists 8-OH-DPAT and ipsapirone attenuated the extrapyramidal-like effects of haloperidol and risperidone more than their therapeutic-like effects; this was not observed for tropapride, where all of its effects were markedly attenuated. Secondly, neither the weak 5-HT_1A agonist WAY 100135 nor the silent antagonist WAY 100635 attenuated the effects of neuroleptics. Thirdly, neuroleptics apparently differed in their sensitivity to interactions with 5-HT_1A agonists inasmuch as 8-OH-DPAT and ipsapirone attenuated the effects of tropapride on hindlimb retraction times more than those of haloperidol or risperidone. Conclusions: The present data suggest that 5-HT_1A agonists with intermediate or high, but not low, intrinsic activity may abolish the extrapyramidal effects of neuroleptics. Together with results of previous studies, it appears that 5-HT_1A agonists alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied. Received: 29 June 1998/Final version: 6 November 1998