Academic journal article Alcohol Research

Treatment Implications: Using Neuroscience to Guide the Development of New Pharmacotherapies for Alcoholism

Academic journal article Alcohol Research

Treatment Implications: Using Neuroscience to Guide the Development of New Pharmacotherapies for Alcoholism

Article excerpt

Developing pharmacotherapies to treat alcohol dependence and associated health problems traditionally has been based on gaining a better understanding of the neuroscience underlying alcohol-drinking behavior. To date, three medications have been approved for the treatment of alcohol dependence: disulfiram (Antabuse®), naltrexone (Revia®, Vivitrol®, and Naltrel®), and acamprosate (Campral®). However, these medications have modest efficacy, and there is a great need for newer medications that target different neurochemical systems and which could be used either as adjunctive treatments or to treat subpopulations of drinkers. Furthermore, it also is important to improve current treatment options by understanding and incorporating differences in how people with certain genes respond to medication (i.e., pharmacogenetic differences). KEY WORDS: Alcoholism; alcohol and other drug dependence; treatment; neurochemical systems; neuropharmacology; drug therapy; pharmacotherapy; disulfiram; naltrexone; acamprosate; selective serotonin reuptake inhibitors (SSRIs); topiramate; ondansetron; baclofen; antipsychotics; animal models; human studies

Alcohol dependence and its associated health problems are the third leading cause of morbidity and mortality in the United States. Alcohol dependence is a chronic relapsing disorder and is optimally treated using a combination of psychosocial and pharmacological treatments. Most of the work on medication development to date has focused on four primary areas: treating withdrawal symptoms, reducing consumption of and craving for alcohol, preventing relapse, and treating associated psychiatric problems. Discussion of the treatment of withdrawal from alcohol, which involves a combination of pharmacologic therapy and nutritional and psychosocial support, is beyond the scope of this review. This article focuses on therapeutic agents that reduce alcohol drinking and craving and prevent relapse. These agents were developed using animal models- or a translational approach to understanding the mechanisms of how alcoholism arises and persists from a molecular, neurochemical, and behavioral perspective. Importantly, animal models that assess a wide range of alcoholrelated behaviors, including drinking, dependence, craving, and relapse, have provided an essential foundation for much of this translational research (see reviews by Egli 2005; Lovinger and Crabbe 2005).

Alcohol-drinking behavior is mediated through complex interactions between mechanisms underlying the reinforcing effects of alcohol. Moreover, the positive reinforcing effects of alcohol are mediated through complex interactions between multiple neurochemical systems. These systems target the corticomesolimbic dopaminergic pathway,1 which extends from the ventral tegmental area to the nucleus accumbens and has been shown to be important in the rewarding effects of many drugs, including alcohol. This pathway is indirectly activated by alcohol through the release of other neurotransmitters, including opioids, serotonin, glutamate, ãaminobutyric acid (GABA), and acetylcholine. Following chronic use of alcohol, many of these same neurochemical systems undergo adaptations and attempt to achieve homeostasis when alcohol is withdrawn, which then leads to alcohol withdrawal symptoms and consumption of alcohol for negative reinforcement, or avoidance of withdrawal. Most medications in use or in development for alcoholism treatment act on these neurotransmitter systems (see figure) and, in many instances, are focused on normalizing the alcoholspecific neuroadaptations or blocking alcoholspecific reinforcement. Recent efforts to develop new medications have focused on nonspecific neural mechanisms mediating alcohol drinking, such as stress and motivation/self-control.

Three drugs currently are approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcoholism: disulfiram (Antabuse®), naltrexone (Revia,® Vivitrol,® and Naltrel®), and acamprosate (Campral®). …

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