Collins Sean M, O'Connell Christopher J, Reeder Evan L, Norman Sophia V, Lungani Kainat, Gopalan Poornima, Gudelsky Gary A, Robson Matthew J
Division of Pharmaceutical Sciences, University of Cincinnati James L. Winkle College of Pharmacy, Cincinnati, OH, United States.
Department of Biological Sciences, University of Cincinnati College of Arts and Sciences, Cincinnati, OH, United States.
Front Pharmacol. 2022 Jul 15;13:930346. doi: 10.3389/fphar.2022.930346. eCollection 2022.
Various forms of traumatic brain injury (TBI) are a leading cause of disability in the United States, with the generation of neuropsychiatric complications such as depression, anxiety, social dysfunction, and suicidality being common comorbidities. Serotonin (5-HT) signaling is linked to psychiatric disorders; however, the effects of neurotrauma on normal, homeostatic 5-HT signaling within the central nervous system (CNS) have not been well characterized. We hypothesize that TBI alters specific components of 5-HT signaling within the CNS and that the elucidation of specific TBI-induced alterations in 5-HT signaling may identify novel targets for pharmacotherapies that ameliorate the neuropsychiatric complications of TBI. Herein, we provide evidence that closed-head blast-induced mild TBI (mTBI) results in selective alterations in cortical 5-HT receptor signaling. We find that mTBI increases cortical 5-HT receptor sensitivity and radioligand binding at time points corresponding with mTBI-induced deficits in social behavior. In contrast, characterizations of 5-HT receptor function revealed no effect of mTBI. Notably, we find that repeated pharmacologic activation of 5-HT receptors post-injury reverses deficits in social dominance resulting from mTBI. Cumulatively, these studies provide evidence that mTBI drives alterations in cortical 5-HT receptor function and that selective targeting of TBI-elicited alterations in 5-HT receptor signaling may represent a promising avenue for the development of pharmacotherapies for TBI-induced generation of neuropsychiatric disorders.
各种形式的创伤性脑损伤（TBI）是美国致残的主要原因，神经精神并发症如抑郁、焦虑、社交功能障碍和自杀倾向是常见的合并症。血清素（5-HT）信号传导与精神疾病有关；然而，神经创伤对中枢神经系统（CNS）内正常的、稳态的5-HT信号传导的影响尚未得到充分表征。我们假设TBI会改变CNS内5-HT信号传导的特定成分，阐明TBI诱导的5-HT信号传导的特定改变可能会识别出改善TBI神经精神并发症的药物治疗新靶点。在此，我们提供证据表明，闭合性头部爆炸所致的轻度TBI（mTBI）会导致皮质5-HT受体信号传导的选择性改变。我们发现，在与mTBI诱导的社交行为缺陷相对应的时间点，mTBI会增加皮质5-HT受体敏感性和放射性配体结合。相比之下，5-HT受体功能的表征显示mTBI没有影响。值得注意的是，我们发现损伤后反复对5-HT受体进行药物激活可逆转mTBI导致的社会优势缺陷。总的来说，这些研究提供了证据，表明mTBI会导致皮质5-HT受体功能改变，选择性靶向TBI引起的5-HT受体信号传导改变可能是开发治疗TBI所致神经精神疾病药物的一个有前景的途径。
