Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
Beijing Hwellso Pharmacuetial Co., Ltd. No.1 Jinguang North Street, Liangxiang Town Industrial Development Are, Fangshan District, Beijing 102488, China.
Behav Brain Res. 2021 Feb 5;399:112971. doi: 10.1016/j.bbr.2020.112971. Epub 2020 Oct 17.
Methamphetamine addiction causes serious public health problems worldwide. However, there is no effective medication licensed for methamphetamine addiction. The endogenous opioid system is considered to be a common substrate in drug addiction due to its regulation of dopamine release. In recent clinical trials, (-)-naltrexone, an opioid receptors and Toll-like receptor 4 antagonist, has exhibited encouraging findings for treating methamphetamine addiction; however, the understanding of its pharmacological mechanisms remains insufficient. By using mice models of behavioral sensitization and conditioned place preference (CPP), the present study was performed to investigate the effects of naltrexone on the methamphetamine-associated properties of incentive salience and reward-related memory, the two crucial factors for the development of addictive process and relapse. We found that naltrexone reduced single methamphetamine-induced hyperlocomotion in mice. In the paradigm of methamphetamine-induced behavioral sensitization paired with contextual cues in mice, naltrexone suppressed the development and expression of locomotor sensitization, suggesting the decrease in incentive salience to methamphetamine and context. In the methamphetamine-induced CPP paradigm in mice, naltrexone attenuated both the expression and methamphetamine-priming reinstatement of CPP response, suggesting the impairment of either contextual cue- or drug-induced retrieval of methamphetamine-associated memory. After the establishment of methamphetamine-induced CPP in mice, naltrexone treatment during the extinction training produced conditioned place adverse response, suggesting that naltrexone facilitated negative affection-associated extinction learning. Taken together, these findings demonstrate that naltrexone could intervene in the properties of incentive salience and reward-related memory in methamphetamine addiction, which may contribute to its therapeutic effects on methamphetamine addicts in clinical studies.
甲基苯丙胺成瘾导致全球范围内严重的公共卫生问题。然而，目前尚无获准用于治疗甲基苯丙胺成瘾的有效药物。内源性阿片系统因其调节多巴胺释放而被认为是药物成瘾的共同基础。在最近的临床试验中，(-)-纳曲酮，一种阿片受体和 Toll 样受体 4 拮抗剂，在治疗甲基苯丙胺成瘾方面显示出令人鼓舞的结果；然而，其药理机制的理解仍然不足。本研究采用行为敏化和条件位置偏爱（CPP）的小鼠模型，旨在研究纳曲酮对与激励性价值和奖赏相关记忆相关的甲基苯丙胺相关特性的影响，这两个因素是成瘾过程和复吸发展的关键因素。我们发现纳曲酮可减少单剂量甲基苯丙胺诱导的小鼠过度活动。在伴有环境线索的甲基苯丙胺诱导的行为敏化的小鼠模型中，纳曲酮抑制运动敏化的发展和表达，表明对甲基苯丙胺和环境的激励性价值降低。在 CPP 范式中，纳曲酮减弱 CPP 反应的表达和甲基苯丙胺引发的复吸，表明对环境线索或药物诱导的与甲基苯丙胺相关记忆的检索受损。在 CPP 范式中，纳曲酮处理在 CPP 表达和甲基苯丙胺引发的复吸过程中都能减弱 CPP 反应，表明纳曲酮能够促进负面情感相关的消退学习。综上所述，这些发现表明，纳曲酮可以干预甲基苯丙胺成瘾中的激励性价值和奖赏相关记忆的特性，这可能有助于其在临床研究中对甲基苯丙胺成瘾者的治疗效果。
