Neural and Neuroendocrine response to compulsive alcohol motivation

摘要 强迫性饮酒动机和失控饮酒是酗酒/重度酗酒和 长期饮酒，但导致这种过度饮酒的机制还没有得到很好的研究。 过量饮酒导致下丘脑-垂体肾上腺(HPA)轴的神经内分泌适应 奖赏和动机通路的神经变化可能导致强迫性酒精动机 和失控的酒精摄入量。在初步研究中，我们发现在暴饮暴食/重度(BH)相对于中度非 狂欢(MD)社交饮酒者改变压力并提示相关的皮质醇反应和高主观酒精 渴望在酒精品尝测试(ATT)中预测强迫性酒精动机和摄入量，这里用作一种 强迫饮酒动机和摄入量的内隐测验。此外，高酒精摄入量会导致 皮质醇反应和高酒精渴求仅见于BH组，而MD组未见。扩展到 根据这些结果，我们建议开发一种利用多波段动脉自旋标记(Asl)的神经成像方法。 结合同时的神经内分泌和呼吸酒精水平的测量来验证这一假设 高酒精刺激和摄入会导致皮质醇反应增加和更多的背侧纹状体血液 流畅性反过来又预测了主观渴望和强制饮酒动机和摄入量的增加 酗酒/酗酒(BH)相对于中度(MD)社交饮酒者。32名MD和32名BH社交饮酒男子 女性(21-45岁；性别平等)将在神经成像会议上进行研究，以解决以下问题 具体目标：具体目标1：评估主观和行为酒精动机和摄入量 大鼠纹状体和腹内侧额前皮质、HPA轴和α-淀粉酶反应的变化 暴饮组、重度SD组和中度SD组的无酒精啤酒和酒精啤酒品尝条件。特定的 目的2：评估饮酒量和呼气酒精水平升高是否预示皮质醇和脑血流量增加 BH组腹侧和背侧纹状体的反应与MD组比较。具体目标3：审查 皮质醇和纹状体CBF增加以及vmPFC CBF降低是否预示着主观渴望和 扫描后酒精品尝试验中的饮酒动机和摄入量。探索性目标：探索性别差异 上述目的并评估酒精和皮质醇在BH和MD患者大脑连接性中的相关变化 组。使用最先进的神经成像技术，该项目承诺开发和验证 多方法神经和神经内分泌成像方案评估酒精相关性糖皮质激素 信号在强迫性酒精动机中起着作用。成功完成这些目标可能会带来新的 测试预防和治疗酒精中毒的新疗法的方法。

ABSTRACT Compulsive alcohol motivation and loss of control alcohol intake are hallmark features of binge/heavy and chronic alcohol use but the mechanisms that drive this excessive alcohol consumption are not well studied. Excessive alcohol use leads to neuroendocrine adaptations in the hypothalamic-pituitary adrenal (HPA) axis and neural changes in the reward and motivation pathways which may lead to compulsive alcohol motivation and loss of control alcohol intake. In preliminary studies we find in binge/heavy (BH) relative to moderate non- binge (MD) social drinkers that altered stress and cue related cortisol responses and high subjective alcohol craving predicts compulsive alcohol motivation and intake in the alcohol taste test (ATT), used here as an implicit test of compulsive alcohol motivation and intake. Furthermore, high alcohol intake led to an increased and sensitized cortisol response and high alcohol craving only in the BH and not the MD group. Expanding on these results, we propose to develop a neuroimaging approach utilizing multiband, arterial spin labelling (ASL) measurement combined with simultaneous neuroendocrine and breath alcohol levels to test the hypothesis that high alcohol motivation and intake leads to increased cortisol responses and greater dorsal striatal blood flow which in turn predicts increased subjective craving and compulsive alcohol motivation and intake in binge/heavy (BH) relative to moderate (MD) social drinkers. Thirty-two MD and 32 BH socially drinking men and women (ages 21-45; equal gender) will be studied in a neuroimaging session to address the following specific aims: Specific Aim 1: To assess subjective and behavioral alcohol motivation and intake, CBF changes in the striatum and ventromedial prefrontal cortex (VmPFC), HPA axis and alpha-amylase response in the non-alcoholic and alcoholic beer taste test conditions in binge heavy and moderate SD groups. Specific Aim 2: To evaluate if alcohol amount and ascending breath alcohol levels predict increased cortisol and CBF response in the ventral and dorsal striatum in the BH compared to MD group. Specific Aim 3: To examine whether increased cortisol and striatal CBF and lower VmPFC CBF predict increased subjective craving and alcohol motivation and intake in post-scan alcohol taste test. Exploratory Aims: To explore sex differences in the above aims and also assess alcohol- and cortisol-related changes in brain connectivity in BH and MD groups. Using state-of-the-art neuroimaging technologies, this project promises to develop and validate a multimethod neural and neuroendocrine imaging protocol to assess whether alcohol-related glucocorticoid signaling plays a role in compulsive alcohol motivation. Successful completion of the aims could lead to new approaches for testing novel therapeutics in prevention and treatment of alcoholism.