Emerging pharmacotherapies for alcohol use disorder

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.

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).…”

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

“…Preclinical studies and early phase clinical trials have focused on a wide variety of potential new treatments for AUD such as targeting neuropeptide, opioid, cannabinoid, nicotinic, dopaminergic, glycinergic, GABAergic and glutamatergic receptors. A few possible new treatments for AUD based on recent research include gabapentin, topiramate, baclofen and varenicline (4,54). The most relevant neurotransmitter systems and thus the appropriate treatment will likely be based on individual differences between patients as well as the target phase of the addiction cycle.…”

“…Withdrawal/negative affect models include hangover anxiety and increased motivation to obtain alcohol in a dependent state that can be induced by alcohol vapor exposure or prolonged IA to alcohol. Finally, anticipation/preoccupation/craving models includes cue-and stress-induced reinstatement of alcohol-seeking behavior (37,54). Research and animal models focusing on these three key stages of AUD has been used to screen several promising targets for possible new treatments for AUD (Figure 3).…”

Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

“…Based on several clinical studies, it can be confirmed that prolonged alcohol use, genetic factors, psychosocial, cognitive, and environmental risk factors could play a role in the individual variability in the development of moderate to severe AUD [4,[6][7][8]. Understanding the mechanisms that underlie individual vulnerability to moderate to severe AUD may help enhance the number of effective treatment strategies for AUD and reduce the economic burden associated with the disorder [9,10].…”