Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation.,Neuropsychopharmacology

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Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation.
Neuropsychopharmacology ( IF 6.6 ) Pub Date : 2018-11-27 , DOI: 10.1038/s41386-018-0281-8
Jonathan M Hailwood ₁ , Christopher J Heath ₂ , Benjamin U Phillips ₁ , Trevor W Robbins ₁ , Lisa M Saksida _{3,

4} , Timothy J Bussey _{1,

3,

4}

Affiliation

Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non-specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort-related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels.

中文翻译：

毒蕈碱乙酰胆碱受体的阻断促进了动机行为并拯救了抗精神病药诱导的动机模型。

对动机行为的破坏是许多神经精神和神经退行性疾病中非常普遍和严重的症状。目前针对这些疾病的治疗选择对动机障碍几乎没有影响或没有影响。我们评估了毒蕈碱乙酰胆碱受体对小鼠动机行为的贡献，作为动机障碍的新药理学目标。非选择性毒蕈碱受体拮抗剂东莨菪碱以及亚型选择性更强的拮抗剂比哌立登 (M1) 和托吡卡胺 (M4) 促进了触摸屏渐进比 (PR) 性能。然而，东莨菪碱和托吡卡胺也会增加非特异性活性水平，而比哌立登没有。一系列对照测试表明，mAChR 拮抗剂的作用对奖励值的变化很敏感，而不是由饱腹感、运动疲劳、食欲或毅力的变化驱动。随后，亚有效剂量的比哌立登能够促进安非他明对 PR 表现的影响，表明能够增强多巴胺能功能。比哌立登和东莨菪碱也能够逆转氟哌啶醇引起的 PR 表现缺陷，但只有比哌立登能够挽救努力相关选择 (ERC) 表现的缺陷。总之，这些数据表明 M1 mAChR 可能是一个新的目标，用于药理学增强努力的努力和随之而来的动机障碍的拯救。反过来，

更新日期：2019-01-26

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