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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Acknowledgements
Work described in this review was supported by grants from the National Institutes of Health (NIMH) MH44814 and the Swedish Medical Research Council (MRF) 03560 and by an unrestricted educational grant from Hoechst Marion Roussel.
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Sedvall, G., Karlsson, P. Pharmacological Manipulation of D1-Dopamine Receptor Function in Schizophrenia. Neuropsychopharmacol 21 (Suppl 2), S181–S188 (1999). https://doi.org/10.1016/S0893-133X(99)00104-9
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DOI: https://doi.org/10.1016/S0893-133X(99)00104-9
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