Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications
Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications
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DOI：
10.1007/7854_2021_294
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发表时间：
2022-01-01
期刊：
影响因子：
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通讯作者：
Felger, Jennifer C.
中科院分区：
文献类型：
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作者：
Bekhbat, Mandakh;Treadway, Michael T.;Felger, Jennifer C.
快感缺乏，其特征是缺乏动机，兴趣或体验快乐的能力，是抑郁症和其他精神疾病的突出症状，并与标准治疗反应差有关。炎症及其对大脑的影响是一种因其在快感缺乏中的潜在作用而受到越来越多关注的病理生理学途径。已经可靠地发现，向人类和实验室动物给予外源性炎症刺激会影响参与奖励处理的神经递质和神经回路，包括腹侧纹状体和腹内侧前额叶皮层，与动机降低有关。此外，包括荟萃分析在内的大量文献描述了抑郁症和其他涉及快感缺乏的精神疾病患者中炎症增加的显著比例，如外周和中枢神经系统中炎性细胞因子、急性期蛋白、趋化因子和粘附分子升高所证明的。这种内源性炎症可能由许多来源引起，包括压力、肥胖或代谢功能障碍、遗传和生活方式因素，其中许多也是精神疾病的风险因素。与涉及外周炎症刺激外源性给药的实验室研究一致，神经影像学研究进一步证实，抑郁症中内源性炎症增加与涉及腹侧纹状体和腹内侧前额叶皮层的奖赏回路内的功能连接减少和激活减少相关，与快感缺乏相关。在这里，我们回顾了炎症和快感缺乏之间关系的最新证据，同时强调了翻译和机械工作，描述了炎症对多巴胺和谷氨酸等神经递质的合成、释放和再摄取的影响，这些神经递质影响了驱动动机缺陷的回路。然后，我们将深入了解针对炎症或其对大脑和行为的下游影响的新型药理学策略。这些概念的有意义的翻译，通过适当设计的试验，针对高炎症和transdiagnosis的快感缺乏症状的精神病患者的治疗进行了讨论。
Anhedonia, characterized by a lack of motivation, interest, or ability to experience pleasure, is a prominent symptom of depression and other psychiatric disorders and has been associated with poor response to standard therapies. One pathophysiologic pathway receiving increased attention for its potential role in anhedonia is inflammation and its effects on the brain. Exogenous administration of inflammatory stimuli to humans and laboratory animals has reliably been found to affect neurotransmitters and neurocircuits involved in reward processing, including the ventral striatum and ventromedial prefrontal cortex, in association with reduced motivation. Moreover, a rich literature including meta-analyses describes increased inflammation in a significant proportion of patients with depression and other psychiatric illnesses involving anhedonia, as evident by elevated inflammatory cytokines, acute phase proteins, chemokines, and adhesion molecules in both the periphery and central nervous system. This endogenous inflammation may arise from numerous sources including stress, obesity or metabolic dysfunction, genetics, and lifestyle factors, many of which are also risk factors for psychiatric illness. Consistent with laboratory studies involving exogenous administration of peripheral inflammatory stimuli, neuroimaging studies have further confirmed that increased endogenous inflammation in depression is associated with decreased activation of and reduced functional connectivity within reward circuits involving ventral striatum and ventromedial prefrontal cortex in association with anhedonia. Here, we review recent evidence of relationships between inflammation and anhedonia, while highlighting translational and mechanistic work describing the impact of inflammation on synthesis, release, and reuptake of neurotransmitters like dopamine and glutamate that affects circuits to drive motivational deficits. We will then present insight into novel pharmacological strategies that target either inflammation or its downstream effects on the brain and behavior. The meaningful translation of these concepts through appropriately designed trials targeting therapies for psychiatric patients with high inflammation and transdiagnostic symptoms of anhedonia is also discussed.