Orphanin FQ-opioid Interactions in the regulation of brain reward systems To elucidate the mechanism(s) by which orphanin FQ modulates the activity of the mesolimbic DA system using an in vivo neurochemical and primary culture electrophysiology approach together with immunocytochemical/in situ hybridization receptor localization studies directed at finding answers to the following specific questions: a. Is the orphanin FQ-induced inhibition of accumbens DA release, observed with microdialysis following i.c.v. administration of the peptide, due to an action in the ventral tegmental area (VTA) and/or nucleus accumbens and are similar effects observed in other DA terminal regions such as the amygdala, caudate and prefrontal cortex? b. Can orphanin FQ receptors be visualized on axonal terminals and/or dendrites of midbrain DA neurons in brain sections or on VTA primary cultured DA neurons? c. If orphanin FQ receptors are expressed on DA cells in culture are they functional in electrophysiological tests and, if so, to what ion channels are they coupled? d. if orphanin FQ does not act directly on DA neurons can orphanin FQ receptors be visualized on neurochemically identifiable axonal terminal inputs to the VTA or nucleus accumbens such as those utilizing glutamate, GABA, substance P or enkephalin? e. Does orphan in FQ influence the release of these transmitters in the VTA or nucleus accumbens and do antagonists to these transmitters block orphanin FQ effects on DA release? 2. To determine the relationship between orphanin FQ and endogenous opioids in the nucleus accumbens-pallidal pathway using a combination of neurochemical and neuroanatomical approaches. a. Does orphanin FQ modulate enkephalin release in the palladium following i.c.v., intra-accumbens or intra-pallidal injection? b. Conversely, is orphanin FQ release in the palladium regulated by opioid receptor agonists? c. Arc orphanin FQ receptors localized on the axonal terminals and/or dendrites of enkephalinergic accumbens-pallidal neurons or are they predominantly post-synaptic in the palladium? d. Conversely, are opioid receptors expressed on orphanin FQ-positive neuronal processes within the palladium? 3. To examine the behavioral effects of orphanin FQ administration and determine the role of DA and opioid systems in mediating these actions. a. Does local administration of orphanin FQ into the VTA or nucleus accumbens induce hypolocomotion as is the behavioral effect reversible with an indirect DA agonist. u Mid is the behavioral effect reversible with an indirect DA agonist? b. Is orphanin FQ-induced vacuous chewing behavior modified by administration of selective D1-like and D2-like receptor agonists and antagonists? c. Is orphanin FQ administered locally into the VTA, nucleus accumbens or palladium aversive? d. Does orphanin FQ counteract the rewarding effects of opiate and psychostimulant drugs injected into these regions in place-preference paradigms?
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