Orphanin FQ (OFQ), has been identified as the endogenous ligand of the opioid receptor-like (ORL-1) receptor. Although this peptide and its receptor show structural similarities to their opioid counterparts, OFQ has been shown to exert counter-opioid effects in the brain. OFQ has been reported to decrease motor behavior and extracellular levels of dopamine in the nucleus accumbens following intracerebroventricular injection. These data suggest that OFQ may be important in the regulation of endogenous """"""""reward"""""""" pathways. We propose to evaluate the acute and chronic actions of this peptide on cocaine-induced dopamine release in the forebrain using microdialysis in freely moving rats, concomitant with measurement of motor behavior, and to determine the site of action of OFQ along the mesocorticolimbic axis. Repeated intermittent cocaine administration induces a phenomenon of behavioral and neurochemical sensitization which may be important in cocaine craving and addiction. This is associated with an increased dopamine release response in the nucleus accumbens. In addition to changes in dopamine release, hyperactivity of glutamatergic neurons has also been implicated in the effects of cocaine. Indeed, the development of cocaine sensitization (mediated in the ventral tegmental area, VTA) can be prevented by NMDA receptor antagonists. Since, in addition to its action on dopamine systems, OFQ has also been shown to inhibit glutamate release in some brain regions, we hypothesize that OFQ may prove particularly potent in blocking cocaine sensitization. We therefore propose to examine the effect of OFQ on cocaine-induced behavioral sensitization and accompanying changes in glutamate and dopamine release in the VTA and nucleus accumbens. The studies proposed will further our understanding of the role of this new peptide in the modulation of reward circuitry in general and on cocaine actions on these pathways in particular. Based on these findings, it may be possible in the future to develop anti- craving compounds for use in the treatment of psychostimulant abuse.
