The role of withdrawal-related phenomena in development and maintenance of alcohol addiction remains under debate. A “self-medication” framework postulates that emotional changes are induced by a history of alcohol use, persist into abstinence, and are a major factor in maintaining alcoholism. This view initially focused on negative emotional states during early withdrawal: these are pronounced, occur in the vast majority of alcohol dependent patients, and are characterized by depressed mood and elevated anxiety. This concept lost popularity with the realization that, in most patients, these symptoms abate over 3 – 6 weeks of abstinence, while relapse risk persists long beyond this period. More recently, animal data have established that a prolonged history of alcohol dependence induces more subtle neuroadaptations. These confer altered emotional processing that persists long into protracted abstinence. The resulting behavioral phenotype is characterized by excessive voluntary alcohol intake and increased behavioral sensitivity to stress. Emerging human data support the clinical relevance of negative emotionality for protracted abstinence and relapse. These developments prompt a series of research questions: 1) Are processes observed during acute withdrawal, while transient in nature, mechanistically related to those that remain during protracted abstinence? 2) Is susceptibility to negative emotionality in acute withdrawal in part due to heritable factors, similar to what animal models have indicated for susceptibility to physical aspects of withdrawal? 3) To what extent is susceptibility to negative affect that persists into protracted abstinence heritable?

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Dysregulation of pain neurocircuitry and neurochemistry has been increasingly recognized as playing a critical role in a diverse spectrum of diseases including migraine, fibromyalgia, depression, and PTSD. Evidence presented here supports the hypothesis that alcohol dependence is among the pathologies arising from aberrant neurobiological substrates of pain. In this review, we explore the possible influence of alcohol analgesia and hyperalgesia in promoting alcohol misuse and dependence. We examine evidence that neuroanatomical sites involved in the negative emotional states of alcohol dependence also play an important role in pain transmission and may be functionally altered under chronic pain conditions. We also consider possible genetic links between pain transmission and alcohol dependence. We propose an allostatic load model in which episodes of alcohol intoxication and withdrawal, traumatic stressors, and injury are each capable of dysregulating an overlapping set of neural substrates to engender sensory and affective pain states that are integral to alcohol dependence and comorbid conditions such as anxiety, depression, and chronic pain.

More than 76 million people worldwide are estimated to have diagnosable Alcohol Use Disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The U.S. Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism’s (NIAAA’s) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: 1) to make the drug development process more efficient; 2) to identify more efficacious medications, personalize treatment approaches, or both, and 3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options, and ultimately lessen the impact of this devastating disorder.

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case–control analysis (N=908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N=3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N=81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N=22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P=0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P=0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.