Investigation of the reinforcing potential of samidorphan and naltrexone by fixed and progressive ratio intravenous self-administration testing in heroin-maintained rats

Background: Samidorphan is a novel -opioid antagonist with low intrinsic activity at - and -opioid receptors. Aims: Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 g/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan's relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 g/kg/injection) and heroin (7.5, 15, 25 g/kg/injection) were comparators. Results: All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend (p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significantly lower than all heroin doses. The numbers of self-administered samidorphan and naltrexone injections/session on fixed ratio-5 were not significantly different from one another. The mean inter-injection intervals for heroin were significantly shorter than for saline, whereas those of samidorphan and naltrexone were not. Progressive ratio break-points for samidorphan and naltrexone were not different from saline except for the highest dose of samidorphan. In addition, the progressive ratio break-points for samidorphan were not significantly different from those of naltrexone and were significantly lower than heroin. The samidorphan unit-doses evaluated in self-administration yielded plasma concentrations ranging between 25-109% and 10-45% of the maximum concentration values in humans. Conclusions: Overall, the profiles of samidorphan and naltrexone, which has no abuse liability, were similar in this model.