Neuroleptics, Dopamine, and Schizophrenia

Abstract

Neuroleptic drugs have provided not only the most efficacious form of treatment for schizophrenia but also a unique pharmacologic probe for discerning its pathophysiology. The link between the antipsychotic effects of neuroleptics and dopamine systems continues to be supported by current research. Recent preclinical and clinical studies suggest that time-delayed changes in DA neuronal function may more closely relate to the therapeutic effects of neuroleptics than does their relatively immediate effect of DA receptor blockade. The use of levels of plasma HVA as a noninvasive reflector of DA function provides a research strategy for longitudinal studies of neuroleptic effects in schizophrenia. Preliminary evidence suggests that neuroleptic-induced changes in levels of plasma HVA may be of value as an in vivo marker for neuroleptic antipsychotic effects. The recent identification and characterization of the mesocortical DA system, which links the midbrain to frontal areas of the cerebral cortex, represents a significant development in the neurobiology of CNS DA systems. The behavioral implications of the functional neuroanatomy of the mesocortical system, its relative unresponsiveness to neuroleptic agents, and the possibility of modulatory effects on the mesolimbic DA system render the mesocortical system a particularly important area of research with etiologic and pharmacotherapeutic implications for schizophrenia. The accumulating evidence indicating structural brain abnormalities in a significant number of schizophrenic patients has renewed interest in classical neuropathologic approaches to understanding its etiology. Although current evidence does not uniformly support the hypothesis of two schizophrenia types reflecting DA and non-DA forms of the illness, the postulate is useful as an attempt to integrate recent findings into a conceptual framework. Better understanding of the biochemical basis for heterogeneity of neuroleptic response and systematic data relating this responsivity to morphologic brain changes constitute an important direction for schizophrenia research.