Abstract
The most widely accepted hypothesis concerning the pathophysiology of schizophrenia, the dopamine hypothesis, suggests that the symptoms of schizophrenia are mediated in part by a functional hyperactivity in the dopamine system in the brain, primarily at D2-dopamine receptors. Recent data suggest that D1-dopamine receptors may also play a major role in the pathophysiology of schizophrenia. Using positron emission tomography (PET), increased variability and reduced D1-receptor binding have been observed in the basal ganglia and frontal cortex of drug-naive schizophrenia patients. Such alterations have also been found in some in vitro studies. These results suggest that the ratio of D1- over D2-regulated dopamine signaling in some brain regions is reduced in schizophrenia. A clinical trial of SCH 39166, a selective D1-dopamine receptor antagonist, showed no evidence of antipsychotic activity in schizophrenic patients. Instead, it appeared that selective D1-receptor antagonism may have aggravated symptoms. Although these findings do not support the prediction that selective D1-dopamine receptor antagonism produces antipsychotic effects, they do not preclude the possibility that combined D1- and D2-receptor antagonism may act synergistically to ameliorate symptoms in schizophrenia. In addition, clinical evaluation of D1 agonists in schizophrenia should be undertaken.
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