Reevaluation of the mesolimbic hypothesis of antipsychotic drug action.

Conventional neuroleptic drugs are thought to derive their antipsychotic efficacy through influences on the mesolimbic dopamine (DA) system. In contrast, motor side effects of these drugs are suggested to follow from influences on the nigrostriatal DA system. This conceptualization is based on the assumption that behaviors mediated by the mesolimbic DA system are involved in schizophrenia while behaviors controlled by the nigrostriatal system are not. In this article, it is argued that although assumptions about mesolimbic activities may indeed be correct, those concerning the nigrostriatal system certainly are not. This being the case, drugs with mesolimbic-specific activity may not have significant antipsychotic potency and probably will not be free of motor side effects. The current thrust of neuropharmacology, which emphasizes development of drugs with pharmacological specificity rather than anatomical selectivity, is more likely to generate new antipsychotic agents with a reduced risk of motor side effects.