DOPAMINE-LINKED PHOSPHOINOSITIDE METABOLISM IN BRAIN

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We have recently observed that dopamine stimulates the production of phosphoinositide second messengers in rat brain. The dopaminergic effect was mimicked by the selective dopamine D1 receptor agonist, SKF38393, and blocked by the selective D1 receptor antagonist, SCH23390, but not by the selective D2 receptor antagonist, sulpiride. Furthermore, the stimulatory effect of SKF38393 was observed in the striatum, hippocampus, frontal cortex, and amygdala, brain regions which contain significant levels of D1 receptors, but not in the cerebellum. Interestingly, the amygdala which exhibited a marked sensitivity to SKF38393-induced phosphoinositide hydrolysis in our studies, has previously been shown to contain D1-like receptors which do not couple to stimulation of dopamine-linked adenylate cyclase. These findings suggest that some actions of dopamine in the brain are mediated by a subtype of the dopamine receptor that is selectively coupled to phosphoinositide metabolism. This newfound action of dopamine has potential implications for the understanding and treatment of various dopamine-associated neuropathologies, including schizophrenia, parkinsonism, Huntington's chorea, and tardive dyskinesia. To further characterize this dopaminergic effect, we have devised experiments to characterize the receptor involved and possibly identify its selective agonists and antagonists, identify any G proteins that may be involved in the transduction mechanism, determine the relationship between the stimulation of phosphoinositide metabolism and dopamine-stimulated adenylate cyclase, and determine the regional brain distribution of this dopamine-stimulated phosphoinositide response. The findings of this project will help to lay a solid foundation for understanding the role of dopamine in central nervous system function and dysfunction, and for evaluating and possibly redefining various models of dopamine-associated neuropsychiatric disorders.