Differential effects of typical and atypical neuroleptics on alpha-noradrenergic and dopaminergic postsynaptic receptors

Abstract

Mezilamine (2-methylamino-4- N-methylpiperazino-5-methylthio-6-chloropyrimidine), a new antidopaminergic agent, is more effective, in vitro and in vivo, in competing for the binding of [ 3H]-haloperidol in rat tuberculum olfactorium than in rat striatum. Such effects, similar to atypical neuroleptics (clozapine, sulpiride), are opposite to classical neuroleptics like chlorpromazine or UK 177 (2-benzilamino-4- N-methylpiperazino-5-methylthio-6-chloropyrimidine). Mezilamine displaces 10 times more [ 3H]-clonidine binding than [ 3H]-WB 4101 binding in rat cerebral cortex and such a preference for α-agonist rather than antagonist sites is also opposite to most neuroleptics, including UK 177. A combination of phenoxybenzamine and mezilamine causes catalepsy and produces a preferential acceleration of striatal dopamine turnover whereas mezilamine alone is more effective on the mesolimbic system. Such results suggest that α-agonist activity in combination with antidopaminergic properties may limit the extrapyramidal effects and induce a selective neuroleptic action in the mesolimbic system.