Orphanin FQ and behavioral sensitization to cocaine.

The recently identified endogenous ligand for the ORL-1 (opioid receptor-like) receptor, orphanin FQ, has been shown to induce hypolocomotion and to decrease extracellular dopamine levels in the nucleus accumbens (N.Acc) after intraventricular (ICV) administration. This study investigated the effect of intraventral tegmental area (VTA) administration of orphanin FQ on the hyperlocomotor effects of peripheral cocaine administration and on the development of behavioral sensitization to cocaine. The administration of cocaine (40 mg/kg IP) once daily for 3 days to male Sprague-Dawley rats resulted in an enhanced locomotor response to a subsequent challenge of cocaine (10 mg/kg IP) 5 days later. The bilateral administration of orphanin FQ (10 microg/side or 30 microg/side) into the VTA 5-10 min prior to the administration of cocaine (40 mg/kg IP) produced a transient (15-30 min) decrease in the hyperlocomotor response to cocaine on day 1 but not on days 2 and 3 of the sensitization paradigm. Such orphanin FQ pretreatment on days 1-3 had no effect on the development of a sensitized response to cocaine (10 mg/kg IP) 5-7 days after the last orphanin FQ injection. However, repeated intra-VTA administration of orphanin FQ (30 microg/side) alone for 3 days resulted in a sensitized response to a single dose of cocaine (10 mg/kg IP) given 5-7 days later. These results indicate that orphanin FQ decreases the activity of mesolimbic dopamine neurons via an action in the VTA, an effect that is both transient and demonstrates rapid tolerance, and consequently, is insufficient to prevent the development of cocaine sensitization. The ability of the peptide to induce cocaine sensitization when administered alone despite its acute inhibitory effects is unique and requires further study to elucidate the mechanisms responsible.