Oxytocin modulates behavioral economic and dopaminergic measures of motivation to seek intravenous oxycodone in rats

Abstract

The opioid epidemic persists despite available pharmacotherapies for opioid use disorder (OUD), motivating interest in treatments targeting the motivational and neurochemical substrates of opioid seeking. Peripherally administered oxytocin (OT) attenuates drug seeking and consumption across substances and modulates the mesolimbic dopamine system, yet its effects on opioid seeking and its underlying neurobiology remain poorly characterized. Here we investigated the effects of OT on behavioral and dopaminergic measures of opioid reinforcement using in vivo fiber photometry with the dopamine sensor, GRABDA2m, in the nucleus accumbens (NA) core of male and female rats. Daily OT (15 IU/kg, IP) administered 30 min prior to operant sessions increased demand elasticity for intravenous oxycodone self-administration in males but not females. Acute OT (15 and 45 IU/kg, IP) increased GRABDA2m dopamine signal in the NA core in females, and potentiated oxycodone-evoked dopamine release in both sexes. In a high-effort task, NA core dopamine increased prior to lever presses, and acute OT (15 IU/kg, IP) produced sex-divergent effects on phasic NA core dopamine release during lever pressing, increasing peak signal and area under the curve measures in males. Support vector machine classifiers determined that features of dopamine transients (e.g., mean peak, standard deviation of the amplitude, peak-valley range) before an active lever press distinguished between treatment and sex. Thus, the ability of chronic oxytocin to reduce the motivation to self-administer oxycodone in male rats is independent of oxycodone-induced NA dopamine release but rather may involve dopamine transmission during lever pressing under high effort conditions.