腹侧被盖区 M5 毒蕈碱受体以性别特异性方式介导努力-选择反应和伏隔核多巴胺。
Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner .
机构信息
Department of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
Department of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.)
出版信息
J Pharmacol Exp Ther. 2023 May;385(2):146-156. doi: 10.1124/jpet.122.001438. Epub 2023 Feb 24.
Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 μg and 2 μg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 μM, 10 μM, 30 μM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 μM/side) coadministration with physostigmine (2 μg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.
努力相关选择的优化在抑郁症中受到损害。乙酰胆碱（ACh）和多巴胺（DA）与抑郁症有关，腹侧被盖区（VTA）中 ACh 张力的调节会影响大鼠与情绪相关的行为反应。然而，VTA ACh 是否介导努力选择行为尚不清楚。在努力选择任务中，大鼠可以选择按压固定比率 5（FR5）的杠杆来获得更偏好的食物，或者自由选择不太偏好的食物。VTA 给予毒蕈碱乙酰胆碱酯酶抑制剂（physostigmine）（1μg 和 2μg/侧）可减少对更偏好食物的 FR5 反应，而不影响对不太偏好食物的消费。VTA 输注 M5 毒蕈碱受体负变构调节剂 VU6000181（3μM、10μM、30μM/侧）不会影响杠杆按压或饲料消耗。然而，VU6000181（30μM/侧）与 physostigmine（2μg/侧）共同给药可减轻 physostigmine 诱导的雌性和雄性大鼠杠杆按压的减少，并显著提高雄性大鼠的杠杆按压水平超过载体基线水平。在体内伏安法实验中，VTA 联合给予 physostigmine 和 VU6000181 对雌性大鼠伏隔核核心（NAc）中的诱发性瞬态 DA 释放没有显著影响。在雄性大鼠中，与单独给予载体、physostigmine 或 VU6000181 相比，VTA 联合给予 physostigmine 和 VU6000181 增加了 NAc 中的诱发性瞬态 DA 释放。这些数据表明，VTA M5 受体在介导 VTA 胆碱能对努力选择行为的影响和调节 DA 释放方面具有关键作用和潜在的性别差异。 意义陈述：努力选择障碍在抑郁症中观察到，而目前可用的抗抑郁药对抑郁症的治疗效果往往不佳。在努力选择行为的临床前模型中，检查了腹侧被盖区（VTA）乙酰胆碱毒蕈碱 M5 受体的作用。使用 M5 受体的选择性负变构调节剂 VU6000181，我们展示了 VTA M5 受体在努力选择和调节伏隔核核心多巴胺释放中的作用。这项研究支持 M5 受体作为治疗抑郁症的靶点。
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