Positive Allosteric Modulation of α5-GABAA Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle.
Positive Allosteric Modulation of α5-GABAA Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle.
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DOI：
10.1093/ijnp/pyac035
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发表时间：
2022-08-16
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高达64%的被诊断患有创伤后应激障碍（PTSD）的患者会经历精神病，这可能归因于异常的多巴胺神经元活动。我们先前已经证明，α5-GABAAR的正变构调节剂可以选择性地降低海马活动，并逆转用于研究精神分裂症的啮齿动物模型中的精神病样生理和行为改变;然而，这种方法是否转化为PTSD模型仍有待阐明。我们利用为期2天的不可避免的足部电击（IS）程序诱导雄性Sprague-Dawley大鼠的应激相关病理生理学。我们在对照组和IS处理组大鼠中使用体内电生理学和行为测量，评价了腹侧海马（vHipp）内给药GL-II-73（α5-GABAAR）或α5亚基病毒过表达的影响。IS显著增加腹侧被盖区多巴胺神经元群体活性，或自发放电的多巴胺神经元数量（n = 6; P = .016），与用于研究精神病的多种啮齿动物模型中的观察结果一致。IS还诱导感觉运动门控缺陷，通过减少惊吓的前脉冲抑制来衡量（n = 12; P = 0.039）。有趣的是，GL-II-73的vHipp内给药完全逆转了IS诱导的多巴胺神经元群体活性增加（n = 6; P = 0.024）和前脉冲抑制缺陷（n = 8; P = 0.025），而vHipp中α5亚基的病毒过表达无效。我们的研究结果表明，在啮齿动物模型中，增加α5-GABAAR功能的药物干预，而不是α5本身的过度表达，可以逆转与PTSD相关的应激诱导的缺陷，为治疗PTSD中的共病精神病提供了潜在的治疗干预位点。
Up to 64% of patients diagnosed with posttraumatic stress disorder (PTSD) experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABAARs can selectively decrease hippocampal activity and reverse psychosis-like physiological and behavioral alterations in a rodent model used to study schizophrenia; however, whether this approach translates to a PTSD model remains to be elucidated. We utilized a 2-day inescapable foot shock (IS) procedure to induce stress-related pathophysiology in male Sprague-Dawley rats. We evaluated the effects of intra-ventral hippocampus (vHipp) administration GL-II-73, an α5-GABAAR, or viral overexpression of the α5 subunit, using in vivo electrophysiology and behavioral measures in control and IS-treated rats. IS significantly increased ventral tegmental area dopamine neuron population activity, or the number of dopamine neurons firing spontaneously (n = 6; P = .016), consistent with observation in multiple rodent models used to study psychosis. IS also induced deficits in sensorimotor gating, as measured by reduced prepulse inhibition of startle (n = 12; P = .039). Interestingly, intra-vHipp administration of GL-II-73 completely reversed IS-induced increases in dopamine neuron population activity (n = 6; P = .024) and deficits in prepulse inhibition (n = 8; P = .025), whereas viral overexpression of the α5 subunit in the vHipp was not effective. Our results demonstrate that pharmacological intervention augmenting α5-GABAAR function, but not α5 overexpression in itself, can reverse stress-induced deficits related to PTSD in a rodent model, providing a potential site of therapeutic intervention to treat comorbid psychosis in PTSD.
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