Department of Psychiatry, Yale School of Medicine, New Haven, 06511, CT, USA.
Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Neuropharmacology. 2020 Jul;171:108089. doi: 10.1016/j.neuropharm.2020.108089. Epub 2020 Apr 5.
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.
乙酰胆碱与包括抑郁和焦虑在内的情绪障碍有关。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效应。腹侧被盖区 (VTA) 的胆碱能受体被认为介导了雄性大鼠的这些反应，如蔗糖偏好测试 (SPT)、高架十字迷宫 (EPM) 和强迫游泳测试 (FST) 所示。然而，这些影响尚未在女性中进行过检查，并且 VTA 毒蕈碱受体亚型 (s) 介导增加的胆碱能张力的促抑郁和焦虑样行为效应尚不清楚。我们首先检查了增加的 VTA 胆碱能张力对雄性和雌性大鼠的行为影响，然后确定 VTA 毒蕈碱 M5 受体是否介导了这些影响。VTA 内注射乙酰胆碱酯酶抑制剂毒扁豆碱 (0.5 μg、1 μg 和 2 μg/侧) 在雄性和雌性大鼠中产生了 SPT、EPM 和 FST 上的快感缺失样、焦虑样、促抑郁样反应。在雌性大鼠中，VTA 给予毒蕈碱 M5 选择性负变构调节剂 VU6000181(3 μM、10 μM 和 30 μM/侧 0.68 ng、2.3 ng 和 6.8 ng/侧) 不会改变 SPT、EPM 或 FST 行为。然而，在雄性大鼠中，单独 VU6000181 的 VTA 内注射减少了 FST 上的不动时间。此外，在雄性和雌性大鼠中，VU6000181 与毒扁豆碱的共同输注减弱了 VTA 毒扁豆碱单独引起的 SPT、EPM 和 FST 中的促抑郁和焦虑样行为反应。综上所述，这些数据揭示了 VTA M5 受体在介导 VTA 中增加的胆碱能张力引起的快感缺失、焦虑和抑郁样行为效应中的关键作用。
