Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA; Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA; Columbia VA Health Care System, Columbia, SC, USA.
Brain Behav Immun. 2021 Aug;96:63-72. doi: 10.1016/j.bbi.2021.05.010. Epub 2021 May 16.
Clinical studies indicate that obese individuals have an increased risk of developing co-morbid depressive illness and that these patients have reduced responses to antidepressant therapy, including selective serotonin reuptake inhibitors (SSRIs). Obesity, a condition of chronic mild inflammation including obesity-induced neuroinflammation, is proposed to contribute to decreases in synaptic concentrations of neurotransmitters like serotonin (5HT) by decreasing 5HT synthesis in the dorsal raphe nucleus (DRN) and/or affecting 5HT reuptake in DRN target regions like the hippocampus. In view of these observations, the goal of the current study was to examine inflammatory markers and serotonergic dynamics in co-morbid obesity and depression. Biochemical and behavioral assays revealed that high-fat diet produced an obesity and depressive-like phenotype in one cohort of rats and that these changes were marked by increases in key pro-inflammatory cytokines in the hippocampus. In real time using fast scan cyclic voltammetry (FSCV), we observed no changes in basal levels of hippocampal 5HT; however responses to escitalopram were significantly impaired in the hippocampus of obese rats compared to diet resistant rats and control rats. Further studies revealed that these neurochemical observations could be explained by increases in serotonin transporter (SERT) expression in the hippocampus driven by elevated neuroinflammation. Collectively, these results demonstrate that obesity-induced increases in neuroinflammation adversely affect SERT expression in the hippocampus of obese rats, thereby providing a potential synaptic mechanism for reduced SSRI responsiveness in obese subjects with co-morbid depressive illness.
临床研究表明，肥胖个体患合并性抑郁疾病的风险增加，并且这些患者对包括选择性 5-羟色胺再摄取抑制剂（SSRIs）在内的抗抑郁治疗的反应降低。肥胖是一种慢性轻度炎症状态，包括肥胖引起的神经炎症，据推测，它通过降低背侧中缝核（DRN）中 5-羟色胺（5HT）的合成和/或影响 DRN 目标区域（如海马）中的 5HT 再摄取，导致神经递质 5HT 的突触浓度降低。鉴于这些观察结果，目前研究的目的是检查合并肥胖和抑郁时的炎症标志物和 5-羟色胺能动力学。生化和行为测定表明，高脂肪饮食使一组大鼠产生肥胖和抑郁样表型，这些变化的特征是海马中的关键促炎细胞因子增加。使用快速扫描循环伏安法（FSCV）实时观察，我们没有发现海马 5HT 的基础水平有变化；然而，与饮食抵抗大鼠和对照大鼠相比，肥胖大鼠的海马对依他普仑的反应明显受损。进一步的研究表明，这些神经化学观察结果可以通过由神经炎症升高引起的海马中 5-羟色胺转运蛋白（SERT）表达增加来解释。总之，这些结果表明，肥胖引起的神经炎症增加会对肥胖大鼠海马中的 SERT 表达产生不利影响，从而为肥胖伴合并性抑郁疾病患者中 SSRI 反应性降低提供了潜在的突触机制。
