SIGNALING MECHANISMS IN DOPAMINE RECEPTOR SYNERGISM

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DESCRIPTION (provided by applicant): Dopamine plays important roles in the neural regulation of movement, motivation, memory, cognition, mood, and neuroendocrine integration. Abnormal dopamine function is associated with the expression or progression of diverse neurological and psychiatric diseases, including Parkinson disease, dyskinesias, schizophrenia, drug addiction, and Tourette disorder. The long-term objective of this research is to clarify the mechanisms by which extracellular dopamine actions are conveyed across the cell membrane to modulate cellular function and behavior in the normal or diseased brain. It is well known that stimulation of dopamine D1-like receptors is linked to the activation of intracellular adenylate cyclase (AC) activity, whereas stimulation of D2-like receptors inhibits AC activity. This conventional view of dopamine receptor function, however, has not consistently accounted for numerous observations that the coactivation of D1-like and D2-like receptors produces mostly synergistic, rather than oppositional, functional effects. There is compelling evidence, however, that D2-like receptors can mobilize other signaling pathways, including intracellular calcium, independent of AC inhibition, and that D1-like receptors can stimulate phosphoinositide (PI) hydrolysis independent of AC stimulation. Based on these findings and other preliminary data, we have proposed a model of dopamine receptor synergism wherein Dl-like agonist stimulation of PI hydrolysis in consonance with D2-like agonist inhibition of AC and/or facilitation of intracellular calcium mobilization, can lead to synergistic functional outcomes at the cellular or behavioral levels. The proposed research will test the validity of this model within the intact brain using known behavioral indices of D1-like/D2-like receptor synergism. The effects of variously selective D1-like agonists on in vivo PI hydrolysis will be correlated with the behavioral effects of the agonists given alone or in combination with the D2-like agonist quinpirole. The role of specific D2-like receptor subtypes in the synergistic interactions also will be assessed. The results are expected to substantially clarify the significance of the PI pathway in dopaminergic function especially as it may relate to the synergistic interactions among D1-like/D2-like agonists. The findings might also yield new insights into the therapeutic mechanisms of dopamine agents that are used in diverse brain disorders, thus facilitating the future development of safer and more efficacious medications for treating or preventing these diseases.