Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders

Abstract

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.

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…Regardless, the discovery that acute combined exposure to EtOH and stress further enhance plasma endotoxin, and increased microglial responses in key brain regions could contribute to the stress and alcohol interaction increasing risks of AUD. Stress has been implicated in exacerbating binge/heavy drinking, motivation to drink, and the chronic relapsing nature of AUD (Blaine and Sinha, 2017; Stephens and Wand, 2012). We report here that stress and EtOH exposure interact through changes in blood endotoxin and microglial activation.…”

“…Both alcohol and stress increase stress hormone levels and activity of brain stress systems (Koob et al., 2004). Stress and the release of stress hormones by the hypothalamic–pituitary–adrenal (HPA) axis have been implicated in binge/heavy drinking, motivation to drink, and the chronic relapsing nature of AUD (Blaine and Sinha, 2017; Stephens and Wand, 2012). Release of stress hormones is also linked to increased alcohol drinking, responses to alcohol cues, risk of relapse, and positive subjective responses to alcohol (Blaine and Sinha, 2017; Stephens and Wand, 2012).…”

“…Stress and the release of stress hormones by the hypothalamic–pituitary–adrenal (HPA) axis have been implicated in binge/heavy drinking, motivation to drink, and the chronic relapsing nature of AUD (Blaine and Sinha, 2017; Stephens and Wand, 2012). Release of stress hormones is also linked to increased alcohol drinking, responses to alcohol cues, risk of relapse, and positive subjective responses to alcohol (Blaine and Sinha, 2017; Stephens and Wand, 2012). Interestingly, alcohol and stress both impact innate immune signaling, which has been suggested to contribute to AUDs (Crews et al., 2017; de Timary et al., 2017).…”

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…There are several recent reviews from 2016-2018 providing the details of other important stress responsive systems (like Corticotrophin Releasing Factor, Neuropeptide Y, and glucocorticoid receptor, etc.) from preclinical evidence to the recent clinical trials [Koob and Mason, 2016;Mantsch et al, 2016;Blaine and Sinha, 2017;Mason, 2017;Robinson and Thiele, 2017;Spierling and Zorrilla, 2017;Tunstall et al, 2017;Pomrenze et al, 2017]. The main focus in this mini-review is several other important stress responsive systems, which recently has not been reviewed, like arginine vasopressin/V1b receptors (Part I), and proopiomelanocortin/β-endorphin (Part II).…”

Indicators of Red Blood and T-Lymphocytes in Patients With Alcoholism; Protective Potential of Lithium Ascorbate

“…Напротив, относительное количество зрелых Т-лимфоцитов в 1 точке обследова-ния было повышено по отношению к кон-тролю, что может быть обусловлено вклю-чением компенсаторных механизмов при стрессе, поскольку длительное потребление алкоголя и его отмена является мощным стрессором [13,14]. Проведены предварительные экспери-менты по влиянию аскорбата лития на экс-прессию поверхностных рецепторов лим-фоцитов больных алкоголизмом.…”