Biochemical alterations produced by neuroleptics in man: studies of plasma homovanillic acid in schizophrenic patients.

Abstract

Despite the enormous growth of neuroscience over recent decades, neuroleptic drugs remain overwhelmingly the most important pharmacological treatment for schizophrenia and psychosis in general. The understanding that these antipsychotic agents block dopamine neurotransmission was first suggested by the observation by Carlsson and Lindqvist (1963) that dopamine (DA) metabolites markedly increase in the brain following the acute administration of neuroleptic. The hypothesis that the antipsychotic actions of neuroleptics are linked to this inhibition of dopamine neurotransmission is most strongly supported by the close correlations observed between the binding affinities of a series of neuroleptic drugs for non-adenylcyclase-linked DA (D2) receptors in rat (Creese et al. 1976; Seeman et al. 1976) and human brains (Richelson and Nelson 1984) and their antipsychotic potencies. An apparent weakness of this hypothesis, however, is the discrepancy between the rapid onset of DA receptor blockade, which occurs within hours following neuroleptic administration, and the delay, usually weeks, necessary to achieve maximum therapeutic effects (Baldessarini 1980). It has now been shown by means of biochemical and electrophysiological techniques that the enhancement of DA turnover which follows acute neuroleptic administration is reversed during chronic administration in nigrostriatal and mesolimbic DA neurons (Roth 1983; Bunney 1984). Mesocortical DA neurons, however, differ as they show diminished responsivity to both DA agonists and antagonists, a phenomenon it is thought may be related to a lack of autoreceptors (Bannon and Roth 1983).