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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 μ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors.

AIMS:
Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 μg/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 μg/kg/injection) and heroin (7.5, 15, 25 μg/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.

Ref: J Psychopharmacol 33(3): 383-391, 2019.

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Experimental

Abuse & Dependence, CNS

Author

Smith SL, Dean RL, Todtenkopf MS, Heal DJ

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