Enhancement of haloperidol-induced catalepsy by nicotine: an investigationof possible mechanisms

Nicotine has been reported to potentiate the cataleptic effect of the dopam ine receptor antagonist haloperidol in rats. This effect is paradoxical, si nce nicotine alone tends to increase nigrostriatal dopamine release. In the present experiments, a pro-cataleptic effect of nicotine was confirmed sta tistically but was small and variable. Three potential mechanisms underlyin g this effect were investigated. (i) Desensitization of brain nicotinic rec eptors appears to make little if any contribution to the pro-cataleptic eff ect of nicotine, insofar as the latter was not mimicked by two centrally ac tive nicotinic antagonists (mecamylamine and chlorisondamine). (ii) Depolar ization inactivation resulting from combined treatment with haloperidol and nicotine does not appear to be critical, since the pro-cataleptic effect o f nicotine was not enhanced by chronic haloperidol administration, a treatm ent designed to enhance depolarization inactivation. (iii) The slow emergen ce and persistence of the acute pro-cataleptic effect of nicotine suggested possible mediation by a nicotine metabolite. However, neither cotinine nor nornicotine, the principal pharmacologically-active metabolites of nicotin e, exerted a significant pro-cataleptic effect. In conclusion, the pro-cata leptic effect of nicotine was weak and variable in the present study, and i ts mechanism remains obscure.