PDF(Pubmed)
Abstract：
The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signalling would reduce the reinforcing properties of morphine and decrease behaviours associated with opioid misuse. By employing intravenous self-administration in mice, we studied the effects of GAT358, a functionally-biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse-like behaviour and motivation to work for morphine infusions. GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under a fixed ratio 1 schedule of reinforcement. GAT358 also decreased morphine-seeking behaviour after forced abstinence. Moreover, GAT358 dose dependently decreased the motivation to obtain morphine infusions under a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration was reward specific. Furthermore, GAT58 did not produce motor ataxia in the rotarod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.
摘要：
内源性大麻素系统与奖励系统相互作用，以调节对自然增强剂的反应，以及滥用药物。先前的临床前研究表明，直接阻断CB1大麻素受体（CB1R）可以作为治疗物质使用障碍的潜在药理学方法。但是由于严重的精神病副作用，这种策略在临床试验中失败了。已经出现了替代策略以通过开发变构调节剂来规避直接CB1结合的副作用。我们假设CB1R信号的负变构调节会降低吗啡的增强特性并减少与阿片类药物滥用相关的行为。通过对小鼠进行静脉内自我给药，我们研究了GAT358，一种功能偏置的CB1R负变构调节剂（NAM），吗啡摄入量，类似复发的行为和为吗啡输注工作的动机。在吗啡自我给药的维持阶段，GAT358在固定比例1的强化方案下减少了吗啡输注的摄入量。GAT358还减少了强制禁欲后的吗啡寻求行为。此外，GAT358剂量依赖性地降低了在渐进的强化比例下获得吗啡输注的动机。引人注目的是，GAT358在相同的渐进比例任务中不影响为食物奖励而工作的动机，这表明GAT358在减少阿片类药物自我给药方面的作用是奖励特异性的。此外，GAT58在转杆试验中没有产生运动性共济失调。我们的结果表明，CB1RNAMs降低了吗啡的增强特性，并且可以代表安全减少阿片类药物滥用的可行治疗途径。
