The long term objective of this project is to understand the biochemical mechanisms involved in the selective alteration of dopaminergic function. In the present studies we plan to examine the behavioral & biochemical effects of chronically treating mice with selective D1 and D2 agonists. We will determine these effects in normal mice and in mice in which a dopaminergic system has been made supersensitive to dopaminergic agonists. The system used to study altered dopaminergic function is the well characterized model of mice with unilateral lesions of the corpus striatum induced by injecting 6-hydroxdopamine. These lesions result in a supersensitive turning behavior in response to dopamine agonists. Our preliminary studies show that it is possible to reverse this behavioral supersensitivity in mice by the continuous administration of apomorphine or selective dopaminergic agonists.
The aims of this proposal are: a) to characterize more fully the effects of these agonists, b) to determine the differential involvement of D1 and D2 dopaminergic systems in dopaminergically mediated behaviors in normal and supersensitive mice and to determine the biochemical correlates of both the dopaminergic supersensitivity and the reversal of this effect induced by the dopamine agonists. Accordingly we will examine the correspondence between altered dopaminergic behavior and: a) the density and properties of postsynaptic D1 and D2 receptors; b) biochemical dopaminergic functions that are coupled to the D1 and D2 receptors--namely, dopamine-stimulated adenylate cyclase activity and inhibition of the release of acetylcholine, respectively; and c) certain post- receptor events that may be responsible for altered dopaminergic function--namely, the activity of calmodulin and the phosphorylation of striatal proteins. The results of these studies should increase our basic understanding of dopaminergic function and ultimately suggest different target sites or novel pharmacotherapies for ameliorating neurologic or psychiatric disorders that involve abnormal dopaminergic activity.
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