Small molecule NOP agonists reverse locomotor sensitization induced by cocaine in male C57BL/6 mice

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the nociceptin opioid receptor (NOP) has been shown to block cocaine-induced locomotor sensitization in mice and rats, and also reverses this phenomenon when injected intracerebroventricularly in animals with an established sensitized response. In the present study, we determined whether small-molecule NOP agonists would recapitulate this effect after systemic administration. Male C57BL/6 mice treated with cocaine (15 mg/kg) on days 1–3 and showed locomotor sensitization to the same dose of cocaine on day 8 were injected with vehicle or one of the two NOP agonists (AT-202 and AT-524) (but not cocaine) on days 9–11. On day 15, locomotor sensitization was assessed after a cocaine challenge (15 mg/kg). Subchronic administration of the two NOP agonists to sensitized mice significantly decreased the sensitized response on day 15. In a separate experiment conducted in male and female mice lacking the NOP receptor and their wildtype littermates, AT-524 reversed sensitization in male wildtype but not in mice lacking NOP. Further, co-administration of the NOP agonist with cocaine for three days on days 16–18 prevented the development of locomotor sensitization from this cocaine treatment in wild-type but not in NOP −/− mice. However, none of these effects of the NOP agonist was observed in female mice. Together, these results suggest that subchronic repeated administration of small-molecule NOP agonists may block and even reverse adaptive behavioral changes associated with repeated intermittent cocaine treatment in male but not female mice.