The effects of ketamine on methamphetamine withdrawal-induced anxiety and drug-seeking behaviors in the rat

IF 3.6 2区医学 Q1 PSYCHIATRY

Drug and alcohol dependence Pub Date : 2025-08-30 DOI:10.1016/j.drugalcdep.2025.112861

Marco German Ghilotti, Richardo Petrilli Fortuna, Kofi Osei-Abrefa Ayensu, Danielle R. Stern, Ellen M. Unterwald

{"title":"The effects of ketamine on methamphetamine withdrawal-induced anxiety and drug-seeking behaviors in the rat","authors":"Marco German Ghilotti, Richardo Petrilli Fortuna, Kofi Osei-Abrefa Ayensu, Danielle R. Stern, Ellen M. Unterwald","doi":"10.1016/j.drugalcdep.2025.112861","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>The use of methamphetamine has continued to rise in the US. In addition to facilitating dopamine neurotransmission, methamphetamine indirectly increases glutamate release, which activates N-methyl-<span>D</span>-aspartate receptors (NMDARs). Ketamine is a noncompetitive NMDAR antagonist. Ketamine also has actions on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and promotes synaptogenesis. Thus, we hypothesized that ketamine may be a potential therapeutic to reduce methamphetamine-seeking behaviors and associated negative affect in a rat model.</div></div><div><h3>Methods</h3><div>Male and female rats underwent methamphetamine or saline intravenous self-administration for 10 sessions, followed by extinction training. Rats received ketamine or saline treatment either prior to 10 daily extinction sessions or only prior to the last extinction session. Anxiety-like behaviors were measured 24h after extinction, followed by cue-induced and drug-primed reinstatement two and six days later, respectively.</div></div><div><h3>Results</h3><div>Methamphetamine withdrawal increased anxiety-like behaviors in male rats on the elevated plus maze test compared to rats that self-administered saline. Moreover, anxiety-like behaviors were significantly attenuated by daily ketamine treatment during extinction. Drug-primed, but not cue-induced reinstatement, tested six days after the last extinction session, was significantly attenuated in male rats that received ten or one ketamine injection during extinction compared with rats receiving vehicle during extinction. Ketamine was ineffective in female rats in reducing cue-induced or drug-primed reinstatement.</div></div><div><h3>Conclusions</h3><div>Ketamine may confer sex-specific benefits during methamphetamine withdrawal , particularly by reducing anxiety-like behaviors and attenuating drug-primed reinstatement in males. These results support the potential of ketamine as a targeted adjunct therapy during early methamphetamine abstinence in males.</div></div>","PeriodicalId":11322,"journal":{"name":"Drug and alcohol dependence","volume":"276 ","pages":"Article 112861"},"PeriodicalIF":3.6000,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug and alcohol dependence","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S037687162500314X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

The use of methamphetamine has continued to rise in the US. In addition to facilitating dopamine neurotransmission, methamphetamine indirectly increases glutamate release, which activates N-methyl-D-aspartate receptors (NMDARs). Ketamine is a noncompetitive NMDAR antagonist. Ketamine also has actions on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and promotes synaptogenesis. Thus, we hypothesized that ketamine may be a potential therapeutic to reduce methamphetamine-seeking behaviors and associated negative affect in a rat model.

Methods

Male and female rats underwent methamphetamine or saline intravenous self-administration for 10 sessions, followed by extinction training. Rats received ketamine or saline treatment either prior to 10 daily extinction sessions or only prior to the last extinction session. Anxiety-like behaviors were measured 24 h after extinction, followed by cue-induced and drug-primed reinstatement two and six days later, respectively.

Results

Methamphetamine withdrawal increased anxiety-like behaviors in male rats on the elevated plus maze test compared to rats that self-administered saline. Moreover, anxiety-like behaviors were significantly attenuated by daily ketamine treatment during extinction. Drug-primed, but not cue-induced reinstatement, tested six days after the last extinction session, was significantly attenuated in male rats that received ten or one ketamine injection during extinction compared with rats receiving vehicle during extinction. Ketamine was ineffective in female rats in reducing cue-induced or drug-primed reinstatement.

Conclusions

Ketamine may confer sex-specific benefits during methamphetamine withdrawal , particularly by reducing anxiety-like behaviors and attenuating drug-primed reinstatement in males. These results support the potential of ketamine as a targeted adjunct therapy during early methamphetamine abstinence in males.

查看原文本刊更多论文

氯胺酮对大鼠甲基苯丙胺戒断性焦虑和药物寻求行为的影响

在美国，甲基苯丙胺的使用量持续上升。除了促进多巴胺神经传递外，甲基苯丙胺还间接增加谷氨酸释放，从而激活n -甲基- d -天冬氨酸受体（NMDARs）。氯胺酮是一种非竞争性NMDAR拮抗剂。氯胺酮还能作用于α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs），促进突触发生。因此，我们假设氯胺酮可能是一种潜在的治疗方法，可以减少大鼠模型中寻求甲基苯丙胺的行为和相关的负面影响。方法雄性大鼠和雌性大鼠分别进行10次甲基苯丙胺或生理盐水静脉自我给药，然后进行消失训练。大鼠在每天10次灭绝之前或仅在最后一次灭绝之前接受氯胺酮或生理盐水治疗。在消失24小时后测量焦虑样行为，然后分别在2天和6天后进行线索诱导和药物启动恢复。结果与自我给予生理盐水的大鼠相比，戒断甲基苯丙胺增加了雄性大鼠的焦虑样行为。此外，在消失期间，每日氯胺酮治疗可显著减轻焦虑样行为。在最后一次灭种后6天进行的实验中，在灭种期间接受10次或1次氯胺酮注射的雄性大鼠与在灭种期间接受载具的大鼠相比，药物启动而非线索诱导的恢复明显减弱。氯胺酮在雌性大鼠中对减少线索诱导或药物引发的恢复均无效。结论：在甲基苯丙胺戒断过程中，氯胺酮可能具有性别特异性的益处，特别是在减少男性焦虑样行为和减少药物启动恢复方面。这些结果支持氯胺酮作为男性早期甲基苯丙胺戒断的有针对性辅助治疗的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Drug and alcohol dependence 医学-精神病学

CiteScore

7.40

自引率

7.10%

发文量

409

审稿时长

41 days

期刊介绍： Drug and Alcohol Dependence is an international journal devoted to publishing original research, scholarly reviews, commentaries, and policy analyses in the area of drug, alcohol and tobacco use and dependence. Articles range from studies of the chemistry of substances of abuse, their actions at molecular and cellular sites, in vitro and in vivo investigations of their biochemical, pharmacological and behavioural actions, laboratory-based and clinical research in humans, substance abuse treatment and prevention research, and studies employing methods from epidemiology, sociology, and economics.