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

Rationale: Combining neuroleptics with 5-HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the deve lopment of new compounds that have greater therapeutic potential and/or are better tolerated. Objective: To examine 1) the ability of 5-HT1A ligands t o alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time in the paw test) and extrapyramidal si de-effects (forelimb retraction time in the paw test. catalepsy tests), 2) the role of intrinsic activity at 5-HT1A receptors in the modulatory effect s of 5-HT1A ligands, and 3) the generality of the interactions across neuro leptics. Methods: The effects of different doses of 5-HT1A ligands with int rinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 10013 5) administered together with a fixed. high dose of the neuroleptics halope ridol, risperidone. and tropapride were examined in the paw test and on cat alepsy. Results: Firstly the 5-HT1A agonists 8-OH-DPAT and ipsapirone atten uated the extrapyramidal-like effects of haloperidol and risperidone more t han their therapeutic-like effects: this was not observed for tropapride. w here all of its effects were markedly attenuated. Secondly. neither the wea k 5-HT1A 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-HT1A agonists inasmuch as 8-OH-DPA T and ipsapirone attenuated the effects of tropapride on hindlimb retractio n times more than those of haloperidol or risperidone. Conclusions: The pre sent data suggest that 5-HT1A agonists with intermediate or high, but not l ow intrinsic activity may abolish the extrapyramidal effects of neuroleptic s. Together with results of previous studies, it appears that 5-HT1A agonis ts alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied.