Negative emotional states that are associated with excessive alcohol intake, particularly anxiety-like states, have been linked to opponent processes in the central nucleus of the amygdala (CeA), affecting stress-related transmitters and monoamines. This study extends these observations to include endocannabinoid signaling in alcohol-dependent animals. Rats and mice were exposed to chronic intermittent alcohol with vapor inhalation or liquid diet to induce dependence. In vivo microdialysis was used to estimate interstitial concentrations of endocannabinoids [N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG)] and amino acids (glutamate and GABA) in rat CeA. Additionally, we evaluated the inhibition of endocannabinoids clearance enzymes [monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase] on anxiety-like behavior and alcohol consumption in alcohol-dependent rats and mice. Results revealed that alcohol dependence produced decreases in baseline 2-AG dialysate levels and increases in baseline levels of glutamate and GABA. Acute alcohol abstinence induced an enhancement of these dependence-induced effects and the levels of 2-AG and GABA were restored upon alcohol re-exposure. Additional studies showed that the increased CeA 2-AG levels induced by restraint stress and alcohol self-administration were blunted in alcohol-dependent rats. Pharmacological studies in rats and mice showed that anxiety-like behavior and alcohol consumption were increased in alcohol-dependent animals, and these behavioral effects were attenuated mainly by MAGL inhibitors [MJN110 (10 and 20 mg/kg) in rats and JZL184 (1 and 3 mg/kg) in mice]. The present results suggest a key role for endocannabinoid signaling in motivational neuroadaptations during alcohol dependence, in which a deficiency in CeA 2-AG signaling in alcohol-dependent animals is linked to stress and excessive alcohol consumption.

中文翻译：

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杏仁核中的内源性大麻素信号不足会导致酒精依赖相关的焦虑样行为和过量饮酒。

与过量饮酒有关的负性情绪状态，尤其是与焦虑有关的状态，已与杏仁核（CeA）中央核中的对手进程相关联，影响与压力相关的递质和单胺。这项研究将这些发现扩展到包括酒精依赖性动物中的内源性大麻素信号传导。将大鼠和小鼠暴露于慢性间歇性酒精中，并进行蒸气吸入或流质饮食以诱导依赖性。体内微透析用于评估大鼠CeA中内源性大麻素[N-花生四烯酸乙醇胺（anandamide; AEA）和2-花生四烯酰甘油（2-AG）]和氨基酸（谷氨酸和GABA）的间质浓度。此外，我们评估了内源性大麻素清除酶[单酰基甘油脂肪酶（MAGL）和脂肪酸酰胺水解酶]对焦虑依赖性行为和酒精依赖大鼠和小鼠饮酒的抑制作用。结果显示，酒精依赖导致基线2-AG透析液水平降低，而谷氨酸和GABA基线水平升高。急性戒酒会增强这些依赖性诱导的作用，并且再次接触酒精后可恢复2-AG和GABA的水平。进一步的研究表明，在依赖酒精的大鼠中，由于束缚压力和酒精自我管理而引起的CeA 2-AG水平升高受到抑制。在大鼠和小鼠中进行的药理研究表明，酒精依赖型动物的焦虑样行为和饮酒量增加，这些行为作用主要被MAGL抑制剂[大鼠的MJN110（10和20 mg / kg）和小鼠的JZL184（1和3 mg / kg）]减弱。目前的结果表明，在依赖酒精的过程中，内源性大麻素信号传导在动机神经适应中起着关键作用，其中依赖酒精的动物中CeA 2-AG信号传导的缺乏与压力和过度饮酒有关。