Razidlo John A, Fausner Skylar M L, Ingebretson Anna E, Wang Liuchang C, Petersen Christopher L, Mirza Salahudeen, Swank Isabella N, Alvarez Veronica A, Lemos Julia C
Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, Minnesota 55455.
Medical Discovery Team on Addiction, Medical School, University of Minnesota, Minneapolis, Minnesota 55455.
J Neurosci. 2022 Sep 7;42(36):6917-6930. doi: 10.1523/JNEUROSCI.1424-21.2022.
There are five cloned muscarinic acetylcholine receptors (M1-M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1-M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here, we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration-response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia assayed using the sucrose preference test or on stress-coping strategy assayed using the forced swim test. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in response to environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety. The basic physiological and behavioral functions of the muscarinic M5 receptor remain understudied. Furthermore, its presence on dopamine neurons, relatively restricted expression in the brain, and recent crystallization make it an attractive target for therapeutic development. Yet, most preclinical studies of M5 receptor function have primarily focused on substance use disorders in male rodents. Here, we characterized the role of M5 receptors in potentiating dopamine transmission in the nucleus accumbens, finding impaired functioning after stress exposure. Furthermore, we show that M5 receptors can modulate exploratory behavior in a sex-specific manner, without affecting hedonic behavior. These findings further illustrate the therapeutic potential of the M5 receptor, warranting further research in the context of treating mood disorders.
有五种克隆的毒蕈碱型乙酰胆碱受体（M1 - M5）。其中，毒蕈碱5型受体（M5）是唯一定位于腹侧被盖区和黑质多巴胺能神经元的受体。与M1 - M4不同，M5受体在大脑中的表达相对受限，这使其成为一个有吸引力的治疗靶点。在此，我们对雄性和雌性小鼠伏隔核中M5依赖的多巴胺传递增强以及伴随的探索行为进行了深入表征。我们发现M5受体通过直接作用于伏隔核内的终末来增强多巴胺传递。使用毒蕈碱激动剂氧化震颤素，我们揭示了独特的浓度 - 反应曲线以及对重复强迫游泳应激或束缚应激暴露的敏感性。我们发现M5受体的组成性缺失减少了在开放场中心的探索，同时仅在雄性小鼠中损害了正常的习惯化。此外，M5缺失减少了对显著刺激的探索，特别是在高新奇性条件下，但对使用蔗糖偏好试验测定的享乐行为或使用强迫游泳试验测定的应激应对策略没有影响。我们得出结论，M5受体对于与环境互动以及根据环境线索更新行为输出至关重要，特别是在雄性小鼠中。情绪和焦虑障碍的一个主要特征是与环境脱离。这些数据表明增强M5受体活性可能是改善这些抑郁和焦虑症状的有用治疗靶点。毒蕈碱M5受体的基本生理和行为功能仍未得到充分研究。此外，它在多巴胺能神经元上的存在、在大脑中相对受限的表达以及最近的结晶使其成为治疗开发的有吸引力的靶点。然而，大多数关于M5受体功能的临床前研究主要集中在雄性啮齿动物的物质使用障碍上。在此，我们表征了M5受体在增强伏隔核多巴胺传递中的作用，发现应激暴露后功能受损。此外，我们表明M5受体可以以性别特异性方式调节探索行为，而不影响享乐行为。这些发现进一步说明了M5受体的治疗潜力，值得在治疗情绪障碍的背景下进行进一步研究。
