Attenuation of cocaine and heroin seeking by μ-opioid receptor antagonism

Abstract

RationaleEvidence has implicated the endogenous opioids, in particular μ-opioid receptors, in emotional behavior and regulation of reward circuits, especially in the context of heroin addiction and hedonic responses to ingestive rewards. The μ-opioid receptor antagonist naltrexone (NTX) has been reported to be effective in preventing relapse to alcoholism and in reducing alcohol and cocaine craving during abstinence.ObjectivesThe aim of the present experiments was to investigate the effects of a novel selective μ-opioid receptor antagonist GSK1521498 on cocaine and heroin seeking and the primary reinforcement of drug self-administration behavior.MethodsRats were first trained to self-administer cocaine or heroin and then to seek the drugs over prolonged periods of time under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a drug-associated conditioned reinforcer. On a stable baseline, animals were treated with either GSK1521498 (0.1, 1, 3 mg/kg; IP) or NTX (0.1, 1, 3 mg/kg; SC) before each test session.ResultsCocaine seeking was dose-dependently decreased following GSK1521498 treatment. However, the same treatment had no effect on cocaine self-administration under a continuous reinforcement schedule. Treatment with NTX had a less pronounced but similar effect. GSK1521498, but not NTX, dose-dependently reduced heroin seeking both before and after infusion of the drug although both increased heroin self-administration under continuous reinforcement.ConclusionsThese data suggest that GSK1521498, by reducing opioid receptor signaling at the μ-opioid receptor, may have therapeutic potential to reduce the propensity to seek cocaine or heroin and, additionally, to diminish the consequence of an initial relapse to heroin taking.