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

IF 3.3 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-10-04 DOI:10.1007/s00213-025-06924-6

Michael J Lehane, Gregory C Sartor

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引用次数: 0

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.

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低剂量氯胺酮和(2R,6R)-羟诺氯胺酮对持久羟考酮戒断相关情感行为的影响

理由：在阿片类药物使用障碍（OUD）的受试者中，情感性症状在阿片类药物停止后持续很长时间，并导致治疗结果不佳。（2R,6R）-羟诺氯胺酮（HNK）是一种氯胺酮代谢物，已成为一种有前景的速效和长效抗抑郁药，但其在长期羟考酮戒断期间减轻情感性症状的潜力及其作用机制尚不清楚。目的：探讨(2R,6R)-HNK和氯胺酮对羟考酮戒断期情感样行为的影响，并探讨其作用机制。方法：将雄性和雌性C57BL/6 N小鼠连续8天注射生理盐水或递增剂量的羟考酮，然后延长停药30天。在戒断第1天或第29天，小鼠在戒断第30天进行社会互动、蔗糖偏好或悬尾试验之前，分别给予生理盐水、（2R、6R）-HNK （10 mg/kg, s.c）或氯胺酮（10 mg/kg, s.c）。此外，为了确定AMPA受体信号传导是否对治疗效果是必要的，在不同队列的小鼠中，在(2R,6R)-HNK或氯胺酮之前施用NBQX （AMPA受体拮抗剂）。结果：戒断第1天给予(2R,6R)-HNK和氯胺酮在所有行为测试中都能相似程度地逆转羟考酮诱导的缺陷，NBQX预处理在悬尾测试中减弱了这种作用，但在社会互动或蔗糖偏好测试中没有减弱。当戒断第29天给予氯胺酮或(2R,6R)-HNK时，两种处理都缓解了尾巴悬浮试验的缺陷，但对其他行为没有影响。结论：这些发现表明(2R,6R)-HNK和氯胺酮在缓解羟考酮戒断的情感性症状方面具有治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.