Review
Translating the neuroscience of alcoholism into clinical treatments: From blocking the buzz to curing the blues

https://doi.org/10.1016/j.neubiorev.2009.11.018Get rights and content

Abstract

Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.

Section snippets

Introduction: alcohol is different

Although increasingly refined, current theories of addiction largely continue to build on two major sets of discoveries. The first of these are the findings identifying the mesolimbic dopaminergic (DA) pathway as a critical substrate for motivation to engage in exploration of the environment and pursuit of goal oriented behavior. The second set consists of observations that most, if not all, addictive drugs interact with this DA circuitry.

Combining these insights, a succession of theories have

Getting the buzz from alcohol: an opioid–DA cascade

In trying to understand to what extent alcohol interactions with classical reward pathways are a critical substrate for reinforcement of alcohol seeking and intake, several observations need to be made. Already in 1973, a seminal but often overlooked human study suggested a key role for DA in pleasurable and stimulating effects of alcohol in healthy, non-dependent volunteers (Ahlenius et al., 1973). Numerous microdialysis studies in rodents subsequently demonstrated an ability of alcohol to

Curing the blues: extrahypothalamic corticotropin-releasing hormone (CRH)

What, then, maintains excessive alcohol use under conditions when acute rewarding alcohol actions are less important? Clearly, acute tension-reducing or anxiolytic alcohol effects are likely to contribute to social alcohol use. Alcohol actions on GABA-ergic and glutamatergic transmission are major mediators of these acute negatively reinforcing alcohol effects. These mechanisms have recently been reviewed (Spanagel, 2009) and are beyond the scope of the present paper. Because only a minority of

A (not so) new kid on the block: substance P and its NK1 receptor

Clinical translation of preclinical findings validating CRH1 receptors as a target for alcoholism treatment has been slow. This is largely related to issues of medicinal chemistry and is beyond the scope of the present paper. In the meantime, we have explored whether other stress systems might act in parallel with CRH to drive excessive alcohol intake. We have been particularly interested in mechanisms that have been in clinical development for other indications, and therefore might offer

Conclusions

Alcohol use disorders are major causes of morbidity and mortality (Ezzati et al., 2002). Although spontaneous remission occurs, classical studies show that relapse occurs within a 12-month period in almost 2/3 of clinical cases in conventional treatment programs (Hunt et al., 1971). The introduction of the competitive opioid antagonist naltrexone and the functional glutamate antagonist acamprosate provided proof of concept for pharmacotherapy of alcohol addiction, but effect sizes are limited (

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgment

The research from the NIAAA Laboratory of Clinical and Translational Studies reviewed here is supported by intramural NIAAA funding.

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