Methyleugenol counteracts anorexigenic signals in association with GABAergic inhibition in the central amygdala. (October 2018)

• Record Type: Journal Article
• Authors: Zhu, Tailin; Yan, Yuhua; Deng, Shining; Liu, Yan-Mei; Fan, Hui-Ran; Ma, Bingke; Meng, Bo; Mei, Bing; Li, Wei-Guang; Li, Fei
• Is Part Of: Neuropharmacology. Volume 141(2018)
• Page Start: 331
• Page End: 342
• Publication Date: 2018-10
• Subjects: Anorexigenic -- Methyleugenol -- GABAergic transmission -- GABA(A) receptor -- Central amygdala; AAV adeno-associated virus -- ACSF artificial cerebrospinal fluid -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- BMI bicuculline methiodide -- BLA basolateral amygdala -- CCK cholecystokinin -- CeA central amygdala -- CeL central lateral division of central amygdala -- CeM central medial division of central amygdala -- CNQX 6-cyano-7-nitroquinoxaline-2, 3-dione -- Ctrl control -- D-APV D(−)-2-Amino-5-phosphonopentanoic acid -- DAPI 4, 6-Diamidino-2-phenylindole dihydrochloride hydrate -- DIO double-floxed inverted orientation -- DMSO dimethyl sulfoxide -- EDTA ethylenediaminetetraacetic acid -- GABA γ-aminobutyric acid -- GABAAR A type γ-aminobutyric acid receptor -- GFP green fluorescent protein -- HEPES N-hydroxyethylpiperazine-N-2-ethanesulphonic acid -- i.p. intraperitoneal -- LiCl lithium chloride -- LPB lateral parabrachial nucleus -- mBLA medial part of basolateral amygdala -- ME methyleugenol -- NC negative control -- PBS phosphate buffer solution -- PKC-δ protein kinase C-δ -- PTX picrotoxin -- sIPSC spontaneous inhibitory postsynaptic current -- NMDA N-methyl-d-aspartate; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.08.034
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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 (GABAA Rs), 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 GABAA Rs in the CeA. Indeed, viral-mediated, the CeA region-specific genetic knockdown of the γ2 subunit of GABAA Rs 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. Graphical abstract: Highlights: Methyleugenol enhances GABAergic transmission and represses neuronal excitability of the CeA. Methyleugenol increases feeding but does not affect basal activity in mice. Methyleugenol counteracts anorexigenic signals of satiety or sickness. Effect of methyleugenol is associated with GABAergic inhibition in CeA.