Sex-specific behavioral and thalamo-accumbal circuit adaptations after oxycodone abstinence

Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences in craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as the intrinsic excitability of NAcSh medium spiny neurons (MSNs), in slices from rats subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence following self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged but not acute abstinence, with females exhibiting higher relapse rates. Prolonged but not acute abstinence led to comparable increases in PVT-NAcSh synaptic strength in both sexes, while inhibitory synaptic transmission in this pathway was not significantly altered at either abstinence time point. Intrinsic excitability of NAcSh MSNs was largely unaltered following oxycodone abstinence in both sexes; however, a trend toward increased spike output was observed in males after prolonged abstinence. Together, these findings suggest that prolonged oxycodone abstinence produces time-dependent and pathway-selective increases in excitatory synaptic strength at PVT-NAcSh inputs, accompanied by sex-specific effects on relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.