The effects of low-dose ketamine and (2R,6R)-Hydroxynorketamine on affective behaviors associated with protracted oxycodone withdrawal

Michael J Lehane; Gregory C Sartor

doi:10.1007/s00213-025-06924-6

The effects of low-dose ketamine and (2R,6R)-Hydroxynorketamine on affective behaviors associated with protracted oxycodone withdrawal

Psychopharmacology (Berl). 2025 Oct 4. doi: 10.1007/s00213-025-06924-6. Online ahead of print.

Authors

Michael J Lehane^{1

2

3}, Gregory C Sartor^{4

5

6}

Affiliations

¹ Center for Addiction Science and Innovation (CASI), University of Connecticut, Storrs, CT, 06269, USA.
² Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA.
³ Institute for the Brain and Cognitive Sciences (IBACS), University of Connecticut, Storrs, CT, 06269, USA.
⁴ Center for Addiction Science and Innovation (CASI), University of Connecticut, Storrs, CT, 06269, USA. gregory.sartor@uconn.edu.
⁵ Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA. gregory.sartor@uconn.edu.
⁶ Institute for the Brain and Cognitive Sciences (IBACS), University of Connecticut, Storrs, CT, 06269, USA. gregory.sartor@uconn.edu.

PMID: 41045335
DOI: 10.1007/s00213-025-06924-6

Abstract

Rationale: In subjects with opioid use disorder (OUD), affective symptoms persist long after opioid cessation and contribute to poor treatment outcomes. (2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite, has emerged as promising rapid-acting and long-lasting antidepressants, but its potential to reduce affective symptoms during protracted oxycodone withdrawal and the mechanism of action remain unclear.

Objective: The objective of this study is to investigate the effects of (2R,6R)-HNK and ketamine on affective-like behaviors during oxycodone withdrawal and evaluate the underlying mechanism.

Methods: Male and female C57BL/6 N mice were injected with saline or escalating dose of oxycodone for eight consecutive days followed by 30 days of protracted withdrawal. On withdrawal day 1 or 29, mice were treated with saline, (2R,6R)-HNK (10 mg/kg), s.c.), or ketamine (10 mg/kg, s.c.) prior to the social interaction, sucrose preference, or tail suspension test on withdrawal day 30. Additionally, to determine if AMPA receptor signaling was necessary for the treatment effect, NBQX (AMPA receptor antagonist) was administered prior to (2R,6R)-HNK or ketamine in a different cohort of mice.

Results: Both (2R,6R)-HNK and ketamine reversed oxycodone-induced deficits to a similar degree in all behavior tests when administered on withdrawal day 1, and pre-treatment with NBQX attenuated this effect in the tail suspension test but not the social interaction or sucrose preference tests. When ketamine or (2R,6R)-HNK was administered on withdrawal day 29, both treatments alleviated deficits in the tail suspension test but lacked effects in other behaviors.

Conclusions: These findings demonstrate the therapeutic potential of (2R,6R)-HNK and ketamine in alleviating affective symptoms of oxycodone withdrawal.

Keywords: (2R,6R)-Hydroxynorketamine; AMPA receptor; Affective symptoms; Ketamine; Opioid use disorder; Oxycodone; Protracted withdrawal.

Grants and funding

Connecticut Institute for the Brain and Cognitive Sciences/Connecticut Institute for the Brain and Cognitive Sciences