Cannabinoid CB1 receptors (CB1Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB1R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB1R antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.

中文翻译：

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大麻素 CB1 受体中性拮抗剂 AM4113 在大鼠中抑制海洛因自我给药，而不会产生抑郁副作用。

大麻素 CB1 受体 (CB1Rs) 已被证明是治疗成瘾药物开发的一个有希望的目标。然而，SR141716A（利莫那班，一种选择性 CB1R 拮抗剂/反向激动剂）用于治疗肥胖和戒烟的临床试验由于抑郁、焦虑和自杀倾向等不良副作用而失败。最近的临床前研究表明，中性 CB1R 拮抗剂 AM4113 可能在尼古丁自我给药模型中保留 SR141716A 的治疗性抗成瘾作用，并且可能具有较少的不良副作用。然而，关于 AM4113 是否对其他滥用药物（如阿片类药物和精神兴奋剂）也有效，以及它是否在实验动物中产生类似于 SR141716A 的抑郁副作用，我们知之甚少。在这项研究中，我们证明了 AM4113（3 和 10 mg/kg）的全身给药剂量依赖性地抑制静脉内海洛因的自我给药，而不是可卡因或甲基苯丙胺，而 SR141716A（3 和 10 mg/kg）剂量依赖性地抑制自我给药海洛因和甲基苯丙胺，但不是可卡因。在脑电刺激奖励 (BSR) 范例中，SR141716A（3 和 10 mg/kg）剂量依赖性地增加 BSR 刺激阈值（即降低刺激奖励），但 AM4113 在相同剂量下对 BSR 没有影响，表明 SR141716A 可能会产生厌恶效果，而 AM4113 可能不会。总之，这些研究结果表明，中性 CB1R 拮抗剂（如 AM4113）值得进一步研究，作为一类新的基于 CB1R 的药物，用于治疗阿片类药物成瘾，而不会产生类似 SR141716A 的厌恶作用。