Pathophysiology of schizophrenia: dopamine hypothesis.

Abstract

T he following artide is the second in our series to highlight the role of psychopharmacology in contributing to our theories of the etiologic basis of mental disorders. In parallel to the catecholamine hypothesis of depression (presented in the fall 1995 issue of the Journal, pp. 523533), the dopamine hypothesis for schizophrenia developed and became influential in the 1960s and 1970s. The origins of this hypothesis can be traced back to 1938, when Shube1 first reported on amphetamine-induced psychosis. This phenomenon was not widely accepted until 1958, when Connell1 published a monograph on a study of 42 cases. Carlsson and Lindqvist in 19632 were the first to suggest that the antipsychotic properties of neuroleptic medication were related to monoaminergic receptor blockade in the brain. The notion that dopamine had a specific role in the pathogenesis of psychosis gained support when it was shown that normal subjects and nonschizophrenic psychiatric patients could become psychotic when administered high-dose amphetamine and L-dopa.6 In 1975, Seeman and Lee7 reported that the dosages of 25 neuroleptic drugs required to inhibit electrically stimulated release of tritiated dopamine correlated closely with the average clinical dose required to control psychosis. They suggested that neuroleptics acted at presynaptic dopamine terminals. The following year, Creese, Burt, and Snyder reported in the article reprinted below that the ability of a wide array of antipsychotic medications to compete for tritiated haloperidol binding (at what is now referred to as the D2 receptor) predicted the dosage required to inhibit dopamine-mediated behavior in animals and to control psychosis in humans. Seeman et al. independently reported similar findings in a report that was published in Nature two months later.8 In a telephone interview, Dr. Creese described the historical context in which he conducted his study. Dr. Creese completed his Ph.D. at Cambridge University with Susan Iversen, with whom he had conducted behavior studies in 6-hydroxydopamine-lesioned rats. This crystallized his interest in the molecular mechanisms of dopamine-mediated behaviors. Dr. Creese took a postdoctoral position at Johns Hopkins with Professor Solomon Snyder, who, along with Candace Pert and Gavril Pasternak, had just identified opiate receptors. Dr. Creese described feeling exhilarated and privileged to work at Johns Hopkins, where many exciting discoveries were made in opiate, dopamine, GABA, glycine, muscarinic, adrenergic, and serotonin receptor identification. Dr. Creese used techniques for studying receptor pharmacology pioneered by Snyder to demonstrate definitively that the antipsychotic properties of multiple neuroleptic medications were related to their ability to bind to 1)2 dopamine receptors. Dr. Creese commented that current research in dopamine receptors continues to implicate dopamine in psychotic disorders, but the nature of that interaction now appears more complex. Postmortem studies of schizophrenic brains have found increased D2 receptors; however, the role of neuroleptic exposure has not been eliminated as a possible confounding factor. PET studies have variably found increased D2 binding in drug-naive patients; findings vary depending on the ligand and the mathematical model used for the analysis. A current hypothesis is that schizophrenic subjects may have an increase in the newly discovered D4 receptor, which has a structure and pharmacology similar to those of the 1)2 receptor. Dr. Creese reported that every year there are new discoveries about the complex nature of dopamine receptors, all of which may contribute to more specific and safer treatment of psychosis.