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Neuropharmacology
Volume 122
, 1 August 2017, Pages 244-253
Invited review
Emerging pharmacotherapies for alcohol use disorder

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Barbara J. Mason Ph.D.

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https://doi.org/10.1016/j.neuropharm.2017.04.032
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Highlights

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Early drug development for AUD focused on blocking the motivation to seek alcohol.
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A new focus is reversing motivational dysregulation associated with protracted abstinence.
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Validated animal models provide targets to normalize brain stress/reward systems in AUD.
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Human lab models of protracted abstinence provide POC screening of potential drugs for AUD.
Abstract

The identification of different stages within the alcohol use disorder (AUD) cycle that are linked to neurocircuitry changes in pathophysiology associated with the negative emotional states of abstinence has provided a view of medication development for AUD that emphasizes changes in the brain reward and stress systems. Alcohol use disorder can be defined as a chronic relapsing disorder that involves compulsive alcohol seeking and taking, loss of control over alcohol intake, and emergence of a negative emotional state during abstinence. The focus of early medications development was to block the motivation to seek alcohol in the binge/intoxication stage. More recent work has focused on reversing the motivational dysregulations associated with the withdrawal/negative affect and preoccupation/anticipation stages during protracted abstinence. Advances in our understanding of the neurocircuitry and neuropharmacological mechanisms that are involved in the development and maintenance of the withdrawal/negative affect stage using validated animal models have provided viable targets for future medications. Another major advance has been proof-of-concept testing of potential therapeutics and clinical validation of relevant pharmacological targets using human laboratory models of protracted abstinence. This review focuses on future targets for medication development associated with reversal of the loss of reward function and gain in brain stress function that drive negative reinforcement in the withdrawal/negative affect stage of addiction. Basic research has identified novel neurobiological targets associated with the withdrawal/negative affect stage and preoccupation/anticipation stage, with a focus on neuroadaptive changes within the extended amygdala that account for the transition to dependence and vulnerability to relapse.
This article is part of the Special Issue entitled “Alcoholism”.
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Section snippets

Conceptual framework for medications development in alcohol use disorder

Alcohol Use Disorder (AUD) is a chronic, relapsing disorder that has been characterized by a compulsion to seek and take alcohol, the loss of control over alcohol intake, and the emergence of a negative emotional state (e.g., dysphoria, anxiety, and irritability) that defines a motivational withdrawal syndrome when access to alcohol is prevented. Moderate to severe AUD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (American Psychiatric Association, 2013),
Clinical trials: challenges and opportunities

Double-blind, placebo-controlled trials with random assignment to treatments are the accepted standard for determining drug efficacy in AUD. A primary challenge is obtaining access to an investigational compound with an approved Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) so that the drug can be tested in humans (see Koob et al., 2009, for further information regarding INDs for medications for the treatment of addiction), or identifying a drug
Human laboratory studies: screening drugs that target the withdrawal/negative affect stage in alcohol use disorder

Human laboratory studies are a potentially powerful means of exploring treatment targets for specific components of the AUD cycle, independent of expensive and lengthy double-blind, placebo-controlled trials. Using the AUD cycle framework (Fig. 1), human laboratory studies provide validated measures for each of the stages of AUD and have heuristic value for predicting potential treatment efficacy in these domains (Koob et al., 2009). In particular, accumulating data demonstrate the predictive
Neurobiological mechanisms in alcohol use disorder that are relevant to novel targets for the development of medications associated with protracted abstinence

As noted above and previously reviewed, two processes are hypothesized to form the neurobiological basis for the withdrawal/negative affect stage: loss of function in the reward systems and recruitment of the brain stress systems in the extended amygdala (Koob and Mason, 2016, Tunstall et al., 2017). The extended amygdala has been conceptualized to be composed of several basal forebrain structures, including the bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA),
Summary and conclusions

The thesis of this review is that medications development for AUD can benefit from use of a heuristic framework for stages of the AUD cycle linked to neurocircuitry and that dysregulation in the brain reward and stress systems that result in the symptoms of acute and protracted abstinence during the withdrawal/negative affect and preoccupation/anticipation stages of the AUD cycle are a neglected focus for drug development for AUD. Much previous work on medications for AUD focused on blocking
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