The effect of chronic oxytocin treatment during abstinence from methamphetamine self-administration on incubation of craving, reinstatement, and anxiety.

Methamphetamine (METH) abuse is characterised by chronic relapse and anxiety, for which there are no effective pharmacotherapies. Acute treatment with the neuropeptide oxytocin has shown therapeutic potential for METH addiction and has social and anxiolytic effects in METH-naïve rats. However, the effects of chronic oxytocin treatment in METH-experienced rats are unknown. This study investigated the effects of repeated oxytocin treatment during abstinence from METH self-administration on incubation of cue-induced relapse, yohimbine- and METH-induced reinstatement, trait anxiety, and social interaction. Male and female Sprague-Dawley rats self-administered intravenous METH for 2 h/day (12 days) and then on short-access (2 h/day; ShA) or long-access (6 h/day; LgA) sessions (10 days). Rats underwent 30 days of drug abstinence, during which they received 15 days of intraperitoneal oxytocin (1 mg/kg) or saline (days 6-20) injections. Anxiety and social interaction were tested on days 25-28, and incubation was assessed by testing cue-induced relapse on days 2 and 30. Rats underwent extinction after the final cue-relapse test, followed by yohimbine- and METH-primed reinstatement. LgA, but not ShA rats exhibited incubation of METH-craving and enhanced METH-primed reinstatement in both sexes, and enhanced yohimbine-induced reinstatement in females. Importantly, chronic oxytocin attenuated incubation and METH-primed reinstatement in both sexes, and yohimbine-induced reinstatement in females, although only in LgA rats. LgA produced a heightened anxiety phenotype, which was partially rescued by chronic oxytocin treatment. Using a translatable addiction model, these findings demonstrate the therapeutic efficacy of chronic oxytocin after METH self-administration and supports the clinical utility of oxytocin for METH addiction in both sexes.