Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 μg, 1 μg and 2 μg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 μM, 10 μM, 30 μM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.

中文翻译：

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检查毒蕈碱 M5 受体在 VTA 胆碱能调节大鼠抑郁样和焦虑相关行为中的作用。


乙酰胆碱与情绪障碍有关，包括抑郁和焦虑。人类和啮齿动物的胆碱能张力增加会产生促抑郁和焦虑样作用。通过蔗糖偏好测试 (SPT)、高架十字迷宫 (EPM) 和强迫游泳测试 (FST) 测量，腹侧被盖区 (VTA) 的胆碱能受体可介导雄性大鼠的这些反应。然而，这些效应尚未在女性中进行过研究，并且介导胆碱能张力增加的促抑郁和焦虑样行为效应的 VTA 毒蕈碱受体亚型尚不清楚。我们首先检查了雄性和雌性大鼠 VTA 胆碱能张力增加的行为影响，然后确定 VTA 毒蕈碱 M5 受体是否介导这些影响。 VTA 输注乙酰胆碱酯酶抑制剂毒扁豆碱（0.5 μg、1 μg 和 2 μg/侧）对男性和女性的 SPT、EPM 和 FST 产生快感缺失样、焦虑样、促抑郁样反应。在女性中，VTA 给予毒蕈碱 M5 选择性负变构调节剂 VU6000181（0.68 ng、2.3 ng、6.8 ng/侧，3 μM、10 μM、30 μM/侧输注）不会改变 SPT、EPM 或 FST 行为。然而，在男性 VTA 内单独输注 VU6000181 减少了 FST 不动的时间。此外，在雄性和雌性大鼠中，VU6000181与毒扁豆碱共同输注，在SPT、EPM和FST中减弱了单独VTA毒扁豆碱诱导的促抑郁和类焦虑行为反应。总之，这些数据揭示了 VTA M5 受体在调节 VTA 胆碱能张力增加的快感缺乏、焦虑和抑郁样行为效应中的关键作用。