The impact of α3β4 partial agonist AT-1001 on oxycodone withdrawal

Opioid withdrawal remains a major barrier to successful treatment of opioid use disorder. Non-opioid treatments such as clonidine and lofexidine reduce acute somatic symptoms but do not address affective and protracted withdrawal signs. Neuronal nicotinic acetylcholine receptors (nAChRs), particularly the α3β4⁎ subtype, are a promising alternative target implicated in opioid withdrawal. Here we investigated whether AT-1001, a high-affinity α3β4⁎ partial agonist, reduces somatic and affective signs of oxycodone withdrawal in mice.

Male and female C57BL/6J mice were rendered dependent on oxycodone (60mg/kg/day) or vehicle (0.9% saline) via a 7-day osmotic minipump infusion. Twenty-four hours after minipump removal, mice received an acute subcutaneous injection of vehicle, lofexidine (0.5mg/kg), or AT-1001 (0.3, 0.9, or 3mg/kg), followed by assessment of somatic withdrawal signs. In a separate cohort of oxycodone-dependent mice, animals received the highest dose of AT-1001 or lofexidine and were assessed two weeks post-minipump removal for mechanical sensitivity and anxiety-like behaviors (light/dark box assay).

Our results showed that AT-1001 dose-dependently reduced somatic withdrawal signs in oxycodone-treated mice. In contrast to lofexidine, AT-1001 attenuated mechanical hypersensitivity and anxiety-like behavior compared to the vehicle group in oxycodone-dependent mice. Furthermore, AT-1001 had no significant effect on oxycodone-induced antinociception, as evaluated in the warm-water immersion assay.

. Our findings suggest that AT-1001 effectively reduces oxycodone withdrawal signs without altering its antinociceptive effects. This supports α3β4⁎ partial agonists as promising candidates for further development as a safer and more comprehensive opioid withdrawal treatment.