Lee Ming Tatt, Peng Wei-Hao, Hsu Tien-Wei, Chu Tian-Huei, Teng Yu-Ning, Wu Cheng-Chun, Lee Yung-Kuo, Lan Yu-Yan, Ho Yu-Cheng
Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia.
Center of Research for Mental Health and Wellbeing, UCSI University, Cheras, Kuala Lumpur, Malaysia.
J Psychopharmacol. 2025 Jul 24:2698811251351611. doi: 10.1177/02698811251351611.
Major depressive disorder (MDD) is a prevalent psychiatric illness, significantly contributing to disability and suicide rates. While dysfunctions in neurotransmission, notably monoaminergic transmission, are commonly attributed to MDD, involvement of the glutamatergic system in comorbid depressive disorders suggests its potential as a target for antidepressant therapy. Despite evidence of diminished glutamatergic neuron activity in the midbrain ventrolateral periaqueductal gray (vlPAG) in rodent models of depression-which projects to the ventral tegmental area (VTA), a region regulating depression-like behaviors-the precise neurocircuit mechanisms within the vlPAG remain unclear.
To investigate dysregulation of glutamatergic transmission in the vlPAG and its role in depression-like behavior, we combined behavioral testing, pharmacological manipulation, retrograde tracing, and electrophysiological recording in male C57BL/6 mice.
Mice receiving intravlPAG infusion of the mGlu2/3 receptor antagonist LY341495 exhibited reversal of depression-like behaviors. Chronic restraint stress (CRS) elicited depression-like behavior, whereas intravlPAG administration of LY341495 reversed these behaviors. VTA-projecting vlPAG neurons exhibited reduced frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and decreased neuronal excitability. Blocking mGlu2/3 receptors, which act as autoreceptors inhibiting glutamate release, in the vlPAG rescued these effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione prevented LY341495-induced reversal of depression-like behaviors.
This provides the first direct evidence that blockade of mGlu2/3 receptors in the vlPAG ameliorates depression-like behavior, highlighting their role in regulating vlPAG-VTA neurocircuits implicated in MDD pathophysiology.
重度抑郁症（MDD）是一种常见的精神疾病，对残疾率和自杀率有显著影响。虽然神经传递功能障碍，尤其是单胺能传递功能障碍，通常被认为与MDD有关，但谷氨酸能系统在合并性抑郁症中的作用表明其可能成为抗抑郁治疗的靶点。尽管在抑郁症啮齿动物模型中，中脑腹外侧导水管周围灰质（vlPAG）中的谷氨酸能神经元活动减少，该区域投射到腹侧被盖区（VTA），而VTA是一个调节类似抑郁行为的区域，但vlPAG内确切的神经回路机制仍不清楚。
为了研究vlPAG中谷氨酸能传递的失调及其在类似抑郁行为中的作用，我们在雄性C57BL/6小鼠中结合了行为测试、药物操作、逆行追踪和电生理记录。
接受vlPAG内注射mGlu2/3受体拮抗剂LY341495的小鼠表现出类似抑郁行为的逆转。慢性束缚应激（CRS）引发了类似抑郁的行为，而vlPAG内给予LY341495可逆转这些行为。投射到VTA的vlPAG神经元表现出自发性兴奋性突触后电流（sEPSCs）的频率和幅度降低，神经元兴奋性降低。阻断作为自身受体抑制谷氨酸释放的mGlu2/3受体可挽救这些效应。此外，vlPAG内微量注射L型电压依赖性钙通道（VDCC）阻滞剂维拉帕米、原肌球蛋白相关激酶B（TrkB）受体拮抗剂ANA-12、雷帕霉素复合物1抑制剂雷帕霉素的哺乳动物靶点以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮可预防LY341495诱导的类似抑郁行为的逆转。
这提供了首个直接证据，表明阻断vlPAG中的mGlu2/3受体会改善类似抑郁的行为，突出了它们在调节与MDD病理生理学相关的vlPAG-VTA神经回路中的作用。
