Addiction Biology Unit, Molecular Targets and Medication Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Postdoctoral Research Associate Training (PRAT) Fellow, National Institute of General Medical Sciences, Bethesda, MD, USA.
Neuropsychopharmacology. 2024 Oct;49(11):1678-1688. doi: 10.1038/s41386-024-01861-y. Epub 2024 Apr 10.
Preclinical research has demonstrated the efficacy of CB1 receptor (CB1R) antagonists in reducing drug-taking behavior. However, clinical trials with rimonabant, a CB1R antagonist with inverse agonist profile, failed due to severe adverse effects, such as depression and suicidality. As a result, efforts have shifted towards developing novel neutral CB1R antagonists without an inverse agonist profile for treating substance use disorders. Here, we assessed AM6527, a CB1R neutral antagonist, in addiction animal models. Our findings revealed that AM6527 did not affect cocaine self-administration under fixed-ratio reinforcement schedules but dose-dependently inhibited it under progressive-ratio reinforcement schedules. Additionally, AM6527 dose-dependently inhibited heroin self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and oral sucrose self-administration under a fixed-ratio reinforcement schedule, as well as cocaine- or heroin-triggered reinstatement of drug-seeking behavior in rats. However, chronic AM6527 administration for five consecutive days significantly inhibited heroin self-administration only during the initial two days, indicating tolerance development. Notably, AM6527 did not produce rewarding or aversive effects by itself in classical electrical intracranial self-stimulation and conditioned place preference tests. However, in optical intracranial self-stimulation (oICSS) maintained by optogenetic stimulation of midbrain dopamine neurons in DAT-cre mice, both AM6527 and rimonabant dose-dependently inhibited dopamine-dependent oICSS behavior. Together, these findings suggest that AM6527 effectively reduces drug-taking and seeking behaviors without rimonabant-like adverse effects. Thus, AM6527 warrants further investigation as a potential pharmacotherapy for opioid and cocaine use disorders.
临床前研究已经证明了 CB1 受体 (CB1R) 拮抗剂在减少药物使用行为方面的疗效。然而，由于严重的不良反应，如抑郁和自杀倾向，一种具有反向激动剂特征的 CB1R 拮抗剂利莫那班的临床试验失败了。因此，人们努力开发新型具有中性 CB1R 拮抗剂特征且无反向激动剂特征的药物，用于治疗物质使用障碍。在这里，我们评估了 AM6527，一种 CB1R 中性拮抗剂，在成瘾动物模型中的作用。我们的研究结果表明，AM6527 不会影响可卡因在固定比率强化时间表下的自我给药，但会在递增比率强化时间表下剂量依赖性地抑制可卡因的自我给药。此外，AM6527 剂量依赖性地抑制了海洛因在固定比率和递增比率强化时间表下的自我给药以及在固定比率强化时间表下的口服蔗糖自我给药，以及可卡因或海洛因引发的大鼠药物寻求行为的复吸。然而，连续五天给予 AM6527 会显著抑制仅在最初两天内的海洛因自我给药，表明产生了耐受。值得注意的是，AM6527 本身在经典的电颅内自我刺激和条件性位置偏好测试中不会产生奖励或厌恶作用。然而，在 DAT-cre 小鼠中通过中脑多巴胺神经元的光遗传学刺激维持的光颅内自我刺激 (oICSS) 中，AM6527 和利莫那班都剂量依赖性地抑制了多巴胺依赖性的 oICSS 行为。总之，这些发现表明 AM6527 有效地减少了药物使用和寻求行为，而没有利莫那班样的不良反应。因此，AM6527 值得进一步研究，作为治疗阿片类药物和可卡因使用障碍的潜在药物治疗方法。
