Blaine Sara K, Sinha Rajita
Department of Psychiatry Yale University School of Medicine, Yale Interdisciplinary Stress Center, 2 Church Street South, Suite 209, New Haven, CT 06519, USA.
Neuropharmacology. 2017 Aug 1;122:136-147. doi: 10.1016/j.neuropharm.2017.01.037. Epub 2017 Feb 1.
In this review, we detail the clinical evidence supporting the role of psychological and physiological stress in instrumental motivation for alcohol consumption during the development of mild to moderate alcohol use disorders (AUDs) and in the compulsive, habitual alcohol consumption seen in severe, chronic, relapsing AUDs. Traditionally, the study of AUDs has focused on the direct and indirect effects of alcohol on striatal dopaminergic pathways and their role in the reinforcing effects of alcohol. However, growing evidence also suggests that alcohol directly stimulates the hypothalamic pituitary adrenal (HPA) axis and has effects on glucocorticoid receptors in extrahypothalamic, limbic forebrain, and medial Prefrontal Cortex (PFC) circuits, which contribute to the development of AUDs and their progression in severity, chronicity, and relapse risk. Evidence indicates HPA axis, glucocorticoid, and PFC dysfunction during protracted withdrawal and under high arousal conditions in those with severe AUDs, and novel evidence is also emerging to suggest HPA axis dysfunction with binge/heavy drinking, which is associated with motivation for alcohol in non-dependent individuals. Specifically, alcohol-associated alterations in HPA axis responses to stress and alcohol cues may serve as interoceptive physiological signals and facilitate conditioning mechanisms to influence alcohol motivation. Thus, this dysfunction may serve as a potential biomarker of both risk and of relapse. Based on this emerging data, we conceptualize and present early evidence for treatment targets that may improve PFC function and/or normalize HPA axis functioning and may be beneficial in the treatment and relapse prevention of AUDs. Finally, we suggest that individual differences in alcohol-related pathophysiology in these circuits may modulate treatment and recovery response, thereby supporting the need for building personalized medicine algorithms to understand and treat AUDs. This article is part of the Special Issue entitled "Alcoholism".
在本综述中，我们详细阐述了临床证据，这些证据支持心理和生理应激在轻度至中度酒精使用障碍（AUDs）发展过程中对饮酒工具性动机的作用，以及在重度、慢性、复发性AUDs中出现的强迫性、习惯性饮酒行为中的作用。传统上，对AUDs的研究主要集中在酒精对纹状体多巴胺能通路的直接和间接影响及其在酒精强化作用中的作用。然而，越来越多的证据还表明，酒精直接刺激下丘脑 - 垂体 - 肾上腺（HPA）轴，并对下丘脑外、边缘前脑和内侧前额叶皮质（PFC）回路中的糖皮质激素受体产生影响，这有助于AUDs的发展及其在严重程度、慢性化和复发风险方面的进展。有证据表明，在严重AUDs患者长期戒断期间和高唤醒状态下，HPA轴、糖皮质激素和PFC功能存在障碍，同时也有新证据表明，暴饮/大量饮酒会导致HPA轴功能障碍，这与非依赖个体的饮酒动机有关。具体而言，酒精相关的HPA轴对应激和酒精线索反应的改变可能作为内感受性生理信号，并促进条件作用机制以影响饮酒动机。因此，这种功能障碍可能作为风险和复发的潜在生物标志物。基于这些新出现的数据，我们构思并展示了早期证据，证明了可能改善PFC功能和/或使HPA轴功能正常化的治疗靶点，这些靶点可能对AUDs的治疗和预防复发有益。最后，我们认为这些回路中与酒精相关的病理生理学个体差异可能调节治疗和恢复反应，从而支持构建个性化医学算法以理解和治疗AUDs的必要性。本文是名为“酒精中毒”的特刊的一部分。
