PDF(Pubmed)
Abstract：
The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and reward-related behavior, and their distribution can be altered by long-term heavy drinking. Therefore, AChRs are promising pharmacotherapeutic targets for treating the cognitive symptoms of AUD. In the present study, the procognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than 1 year. The muscarinic AChR antagonist scopolamine was used to disrupt performance of a serial stimulus discrimination and reversal (SDR) task designed to probe cognitive flexibility, defined as the ability to modify a previously learned behavior in response to a change in reinforcement contingencies. The ability of xanomeline and varenicline to remediate the disruptive effects of scopolamine was compared between socially dominant and subordinate monkeys, with lighter and heavier drinking histories, respectively. We hypothesized that subordinate monkeys would be more sensitive to all three drugs. Scopolamine dose-dependently impaired performance on the serial SDR task in all monkeys at doses lower than those that produced nonspecific impairments (e.g., sedation); its potency did not differ between dominant and subordinate monkeys. However, both AChR agonists were effective in remediating the scopolamine-induced deficit in subordinate monkeys but not in dominant monkeys. These findings suggest xanomeline and varenicline may be effective for enhancing cognitive flexibility in individuals with a history of heavy drinking. SIGNIFICANCE STATEMENT: Procognitive effects of two acetylcholine (ACh) receptor agonists were assessed in group-housed monkeys who had several years\' experience drinking ethanol. The muscarinic ACh receptor agonist xanomeline and the nicotinic ACh receptor agonist varenicline reversed a cognitive deficit induced by the muscarinic ACh receptor antagonist scopolamine. However, this effect was observed only in lower-ranking (subordinate) monkeys and not higher-ranking (dominant monkeys). Results suggest that ACh agonists may effectively remediate alcohol-induced cognitive deficits in a subpopulation of those with alcohol use disorder.
摘要：
经常在酒精使用障碍（AUD）患者中观察到的认知障碍部分导致治疗开始和依从性极低。脑乙酰胆碱受体（AChR）介导和调节认知和奖励相关行为，长期大量饮酒可以改变其分布。因此,AChR是用于治疗AUD的认知症状的有希望的药物治疗靶标。在本研究中,两种AChR激动剂的认知前功效，xanomeline和varenicline,在自我服用乙醇超过一年的群居猴子中进行了评估。毒蕈碱AChR拮抗剂东pol碱用于破坏旨在探索认知灵活性的连续刺激辨别和逆转（SDR）任务的性能，定义为响应于加固突发事件的变化而修改先前学习的行为的能力。在优势猴和从属猴之间比较了xanomeline和varenicline治疗东莨菪碱破坏性作用的能力，有更轻和更重的饮酒史，分别。我们假设从属猴子对所有三种药物都更敏感。东莨菪碱剂量依赖性地损害了所有猴子在连续SDR任务中的表现，剂量低于产生非特异性损害的剂量（例如，g,镇静）；其效力在优势猴和从属猴之间没有差异。然而,两种AChR激动剂均可有效修复从属猴的东pol碱诱导的缺陷，但不是在占主导地位的猴子。这些发现表明，xanomeline和varenicline可能对增强有大量饮酒史的个体的认知灵活性有效。重要性声明在有数年饮酒经验的群居猴子中评估了两种乙酰胆碱（Ach）受体激动剂的认知前作用。毒蕈碱ACh受体激动剂xanomeline和烟碱ACh受体激动剂varenicline逆转了毒蕈碱ACh受体拮抗剂东pol碱诱导的认知缺陷。然而,这种效应仅在等级较低(从属)的猴子中观察到,而在等级较高(优势猴)中观察不到.结果表明，ACh激动剂可以有效治疗酒精使用障碍患者亚群中酒精引起的认知缺陷。
