Perspectives on a Time-dependent Model of Neuroleptic Action

The best support for the hypothesized involvement of central nervous system dopamine systems in the pathophysiology of schizophrenia is the association between the affinity of neuroleptic drugs for the D2 dopamine receptor and their potency as antipsychotics. Discrepancy between the time course of receptor binding and the development of antipsychotic effects, however, limits this model. Preclinical studies have now shown that activation of presynaptic nigrostriatal and mesolimbic dopamine neurons by acute neuroleptic administration is reversed during chronic administration. Clinically, neuroleptic-induced time-dependent reductions in plasma levels of the dopamine metabolite, homovanillic acid (HVA), have been linked to the antipsychotic response in schizophrenic patients. These data support the notion that slowly developing alterations in presynaptic dopamine activity play a role in the mechanism of action of neuroleptic drugs. Differences between plasma and cerebrospinal fluid (CSF) HVA responses to neuroleptic treatment, although not fully explained, may be related to prominent contributions of mesocortical metabolism to CSF levels of HVA. A time-dependent dopaminergic model of neuroleptic action with implications for the pharmacotherapy of schizophrenia is presented.