AT-202, a Nociceptin Receptor Agonist, Blocks Drug- and Stress-Induced Reinstatement of Extinguished Cocaine Conditioned Place Preference

Abstract

Central administration of nociceptin/orphanin FQ (N/OFQ), the endogenous agonist peptide ligand for the nociceptin (NOP) receptor, has been shown to block conditioned place preference (CPP) of a variety of abused drugs, including psychostimulants such as cocaine and amphetamine. However, small-molecule NOP agonists have not been extensively examined for their effects on acquisition and reinstatement of psychostimulant CPP. We have previously shown that a small-molecule NOP agonist AT-202 (formerly SR16835) attenuates acquisition of morphine CPP. In the present study we examined the effects of AT-202 on acquisition and drug-primed or stress-induced reinstatement of cocaine CPP. To establish CPP, testing was conducted over six consecutive days resulting in three drug and three vehicle pairing sessions. To assess the effects on drug reinstatement following the first CPP test, separate groups of animals underwent daily extinction sessions during which animals were exposed to both compartments for 15 min. When animals had satisfied the extinction criterion, they were tested for reinstatement of extinguished cocaine CPP. Cocaine at doses of 5-30 mg/kg, produced robust CPP. Following acquisition of cocaine CPP and subsequent extinction, a cocaine prime reinstated extinguished drug seeking similar to the levels observed during the first CPP test. AT-202 pretreatment prior to the lowest dose of cocaine (5 mg/kg) did not alter the acquisition of cocaine CPP. We further established that AT-202 alone did not reinstate extinguished cocaine CPP. Notably, however, AT-202 blocked reinstatement of cocaine CPP when given as a pretreatment prior to a priming injection of cocaine. We also examined the effects of AT-202 on stress-induced reinstatement of extinguished cocaine CPP, using forced swim and a chemical stressor, yohimbine, to induce stress. Both forced swim and yohimbine (2 mg/kg) reinstate extinguished cocaine CPP to similar levels obtained during the first CPP test. AT-202 given as a pretreatment to forced swim and yohimbine, blocked reinstatement of extinguished cocaine CPP. These results show that even though AT-202 does not block acquisition of cocaine CPP, it is able to block reinstatement of both ‘drug-primed’ and ‘stress-induced’ cocaine CPP. These findings provide preliminary evidence that the NOP receptor agonists may be useful as pharmacotherapies to treat psychostimulant addiction and may be especially valuable in relapse prevention.