Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China; Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Developmental and Behavioral Pediatric Department, Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Shanghai Institute for Pediatric Research, Xin Hua Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Neuropharmacology. 2018 Oct;141:331-342. doi: 10.1016/j.neuropharm.2018.08.034. Epub 2018 Aug 29.
Feeding can be inhibited by satiety, sickness, or food unpalatability. The central nucleus of the amygdala (CeA) has been considered the key region for processing multiple anorexigenic signals, although the detailed cellular and molecular mechanisms remain largely unclear. Here we identify that methyleugenol (ME), a novel agonist of A type ionotropic γ-aminobutyric acid receptors (GABARs), significantly counteracts the anorexigenic effects caused by satiety or sickness in association with GABAergic inhibition in the CeA. Electrophysiologically, ME enhanced GABAergic transmission and repressed neuronal excitability of the CeA. Behaviorally, ME increased feeding but not affect locomotor activity and basal anxiety in naïve mice. Notably, both systemic and CeA-specific delivery of ME significantly rescued satiety- or sickness-induced inhibition of feeding. The effects of ME were mainly dependent on the GABARs in the CeA. Indeed, viral-mediated, the CeA region-specific genetic knockdown of the γ2 subunit of GABARs largely abolished the above pharmacological effects, while its re-expression in a subpopulation of GABAergic neurons in the CeA, that produce protein kinase C-δ (PKC-δ), recovered the effects of ME on anorexigenic signals. Taken together, these results reveal a novel molecular mechanism for counter-anorexigenic signals dependent on GABAergic inhibition in the CeA, suggesting the possibility of ME as a leading compound for anorexia treatment.
摄食可被饱腹感、疾病或食物适口性差所抑制。虽然中央杏仁核（CeA）已被认为是处理多种厌食信号的关键区域，但详细的细胞和分子机制仍不清楚。在这里，我们发现甲基丁香酚（ME），一种新型的 A 型离子型γ-氨基丁酸受体（GABARs）激动剂，与 CeA 中的 GABA 能抑制作用一起，显著对抗饱腹感或疾病引起的厌食作用。电生理学上，ME 增强了 GABA 能传递并抑制了 CeA 的神经元兴奋性。行为上，ME 增加了摄食，但不影响未处理小鼠的运动活性和基础焦虑。值得注意的是，ME 的全身和 CeA 特异性给药都显著挽救了饱腹感或疾病引起的摄食抑制。ME 的作用主要依赖于 CeA 中的 GABARs。事实上，病毒介导的 CeA 区域特异性 GABARsγ2 亚基的基因敲低在很大程度上消除了上述药理学作用，而其在 CeA 中产生蛋白激酶 C-δ（PKC-δ）的 GABA 能神经元亚群中的重新表达则恢复了 ME 对厌食信号的作用。总之，这些结果揭示了 CeA 中依赖 GABA 能抑制的抗厌食信号的新分子机制，表明 ME 作为治疗厌食症的先导化合物的可能性。
