ENDOCYTOSIS OF MESOLIMBIC OPIOID AND DOPAMINE RECEPTORS

$82,095P01FY2007DANIH

University Of California, San Francisco, San Francisco CA

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Abstract

During these studies morphine was observed to have unexpected effects on the endocytic membrane[unreadable] trafficking of the mu opioid receptor (MOR) in physiologically relevant medium spiny neurons in the rat[unreadable] Nucleus Accumbens and in primary culture, and unexpected regulatory effects on endosome recruitment of[unreadable] non-visual (beta-) arrestins were also observed in dendrites of these neurons. The proposed studies seek to[unreadable] elucidate the mechanistic basis of MOR regulatory effects in medium spiny neurons, and to test specific[unreadable] hypotheses regarding possible regulatory functions on opioid and co-expressed dopamine receptors relevant[unreadable] to mesolimbic dopamine function and the rewarding effects of opioid drugs. The Specific Aims of the[unreadable] proposed studies are to:[unreadable] (1) Define mechanisms of morphine-induced endocytosis of MOR and endosome recruitment of beta-arrestins[unreadable] in medium spiny neurons. The proposed studies seek to elucidate the mechanistic basis of these[unreadable] unprecedented morphine effects. The hypothesis to be tested is that MOR endocytosis and endosome[unreadable] recruitment of beta-arrestin is a consequence of specific cytoplasmic phosphorylation(s) in MOR.[unreadable] (2) Identify mechanisms of D1 dopamine receptor regulation in relevant MOR-expressing neurons. MOR-expressing[unreadable] medium spinal neurons are major targets of VTA dopaminergic signaling via co-expressed D1[unreadable] receptors (D1R). Preliminary studies suggest that drug-mediated activation of MOR, by essentially[unreadable] 'sequestering' beta-arrestins on endosomes, may attenuate arrestin-dependent D1R endocytosis induced by[unreadable] dopamine. This hypothesis will be tested using site-directed mutagenesis and established co-transfection[unreadable] methods in rat striatal neurons.[unreadable] (3) Utilize live cell imaging methods to visualize drug effects on relevant receptor and arrestin trafficking[unreadable] events in real time. GFP tagging and live cell imaging methods to the regulated trafficking of MOR in rat[unreadable] striatal neurons, focusing on spatial aspects of MOR recycling following drug-mediated activation.[unreadable]

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