Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.
Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Mol Psychiatry. 2018 Oct;23(10):2029-2038. doi: 10.1038/mp.2017.226. Epub 2017 Nov 14.
Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.
临床前证据表明，胃内分泌细胞合成的肽类激素——ghrelin 是肠-脑轴的关键组成部分，它通过调节中枢奖励和应激途径参与觅酒行为。然而，ghrelin 的给药是否以及如何影响人类的酒精摄入量尚不清楚。本研究首次在一项随机、交叉、双盲、安慰剂对照的人类实验室研究中对此进行了调查。参与者是非治疗性寻求酒精依赖的重度饮酒者。给予 10 分钟静脉内给予 ghrelin/安慰剂（3 mcg/kg）负荷剂量，随后持续给予 ghrelin/安慰剂输注（16.9 ng/kg/min）。在递增比率酒精自我给药实验中，参与者可以通过计算机化酒精输注系统按下按钮接受静脉内酒精。在另一项实验中，当参与者执行一项任务以获得酒精、食物或无奖励的分数时，进行了脑功能磁共振成像。结果表明，与安慰剂相比，静脉内给予 ghrelin 显著增加了自我给予的酒精输注次数（百分比变化：24.97±10.65，P=0.04，Cohen's d=0.74）。与安慰剂相比，参与者在接受 ghrelin 时也更快地开始自我给药（P=0.03）。ghrelin 给药还调节了呼吸酒精浓度与酒精主观效应之间的关系。神经影像学数据显示，ghrelin 增加了杏仁核中与酒精相关的信号（P=0.01），并调节了内侧眶额皮质（P=0.01）和伏隔核（P=0.08）中与食物相关的信号。这些数据表明，ghrelin 信号影响人类的觅酒行为，应作为开发新型酒精使用障碍药物的有前途靶点进一步研究。
