Activation of nociceptin receptor attenuates methamphetamine motivation and relapse in rats: Involvement of phosphorylated CREB and Akt in the nucleus accumbens

Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide (N/OFQ) and its nociceptin opioid receptor (NOP) in alcohol and cocaine reward. However, the effects of NOP agonists on methamphetamine (MAP) reinforcement, motivation, and relapse remain uncertain. In this study, we evaluated the effects of Ro 64-6198, a selective NOP agonist, on MAP reinforcement, motivation, and relapse in rats. Rats underwent a fixed-ratio 1 (FR1) training to establish stable MAP intravenous self-administration (0.05 mg/kg/infusion) for 12 days, and the motivation for MAP was quantified using a progressive-ratio (PR) schedule, while the relapse was assessed through cue- and MAP-primed reinstatement after abstinence. Western blot analysis was employed to measure the relative expression of phosphorylated CREB, ERK, and Akt in the nucleus accumbens (NAc) following drug priming. Acute treatment of Ro 64-6198 (1 mg/kg) significantly reduced the motivated behavior for MAP under PR testing (P vs. vehicle). Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues, respectively (P P < 0.05). These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc. Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors, positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.