Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment.
Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment.
复制标题
酒精依赖个体对 GABA-B 受体激动的神经内分泌反应：门诊和人体实验室联合实验的结果。
DOI：
10.1016/j.neuropharm.2018.04.011
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发表时间：
2018
影响因子：
4.7
通讯作者：
Leggio,Lorenzo
中科院分区：
文献类型：
--
作者：
Farokhnia,Mehdi;Sheskier,MikelaB;Lee,MaryR;Le,AprilN;Singley,Erick;Bouhlal,Sofia;Ton,Timmy;Zhao,Zhen;Leggio,Lorenzo
γ-氨基丁酸 (GABA) 是神经系统中主要的抑制性神经递质，在调节饮酒、食物摄入和应激反应的生物行为过程中发挥着重要作用。通过使用正构激动剂（例如巴氯芬）和正变构调节剂，代谢型 GABA-B 受体已被研究为酒精使用障碍的潜在治疗靶点。 GABA-B 受体的药理学操作与酒精摄入相结合是否以及如何影响摄食和压力相关的神经内分泌途径仍然未知。在本随机、双盲、安慰剂对照研究中，34 名酒精依赖者在自然门诊环境中接受巴氯芬（30 毫克/天）或安慰剂一周，然后进行对照实验室实验，其中包括酒精提示反应、固定剂量启动和自我给药程序。采集血样，并测量以下神经内分泌标志物：生长素释放肽、瘦素、胰淀素、胰高血糖素样肽-1 (GLP-1)、胰岛素、催乳素、促甲状腺激素、生长激素、皮质醇和促肾上腺皮质激素 (ACTH)。在门诊阶段，巴氯芬显着增加酰基生长素释放肽（p=0.01）、瘦素（p=0.01）、胰淀素（p=0.004）和GLP-1（p=0.02）的血液浓度。在实验室实验中发现胰岛淀粉样多肽 (p=0.001) 和胰岛素 (p=0.03) 具有显着的药物×时间点相互作用效应，GLP-1 (p=0.06) 和 ACTH (p=0.10) 具有趋势水平的相互作用效应。在本研究中，与安慰剂相比，巴氯芬对饮酒没有影响（p≥0.05）。与之前的研究一起，这些发现揭示了 GABA 能系统和 GABA-B 受体在酒精、进食和压力相关行为的共同神经生物学中的作用。
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals received baclofen (30 mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue-reactivity, fixed-dose priming, and self-administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon-like peptide-1 (GLP-1), insulin, prolactin, thyroid-stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl-ghrelin (p= 0.01), leptin (p= 0.01), amylin (p= 0.004), and GLP-1 (p= 0.02). Significant drug × time-point interaction effects for amylin (p= 0.001) and insulin (p= 0.03), and trend-level interaction effects for GLP-1 (p= 0.06) and ACTH (p= 0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (p's ≥ 0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA-B receptors in the shared neurobiology of alcohol-, feeding-, and stress-related behaviors.