Effects of the kappa-opioid receptor antagonist nor-binaltorphimine on methamphetamine-vs-food choice in male rhesus monkeys

Background: Kappa-opioid receptors (KOR) are hypothesized to be involved in mediating ongoing methamphetamine self-administration. Previous rat studies have demonstrated that treatment with the KOR antagonist nor-binaltorphimine (nor-BNI) decreases methamphetamine self-administration. However, KOR antagonist effects on methamphetamine self-administration in nonhuman primates are unknown.

Methods: Operant behavior was maintained under a concurrent schedule of banana-flavored pellets (fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined 7 days before and for up to 28 days following 10mg/kg, intramuscular nor-BNI treatment.

Results: Under continuous saline treatment conditions, methamphetamine-maintained a dose-dependent increase in choice over the alternative food reinforcer. 10mg/kg nor-BNI failed to attenuate methamphetamine choice and trended towards increased methamphetamine choice. Methamphetamine choice returned to pre-nor-BNI treatment levels by 21 or 28 days in all 3 monkeys.

Conclusions: The present results do not support the hypothesis that the KOR/dynorphin system robustly modulates methamphetamine self-administration and that KOR antagonists should be considered as methamphetamine use disorder pharmacotherapies. In contrast, these results suggest KOR antagonism may increase methamphetamine reinforcement through blockade of methamphetamine-induced dynorphin release and consequent feedback inhibition.