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

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 alcohol-related 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 cortico-mesolimbic 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, [gamma]-aminobutyric 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many of these same neurochemical systems undergo adaptations and attempt to achieve homeostasis when alcohol is withdrawn, which then leads to alcohol withdrawal symptoms and consumption of alcohol for negative reinforcement, or avoidance of withdrawal.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 alcohol-specific neuroadaptations or blocking alcohol-specific 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[R]), naltrexone (Revia,[R] Vivitrol,[R] and Naltrel[R]), and acamprosate (Campral[R]). The following sections will describe each of these agents, including their efficacy and the neuroscience underlying treatment response. The article also will discuss other agents that have shown some promise in reducing drinking and finally present preliminary evidence from some exciting investigational agents that still are under evaluation.



Disulfiram has been in use for the treatment of alcoholism since the 1940s. This medication produces an aversive effect by disrupting alcohol metabolism. When alcohol is consumed, it is converted to acetaldehyde, which is further broken down by aldehyde dehydrogenase. Disulfiram inhibits aldehyde dehydrogenase, which leads to an excessive buildup of acetaldehyde and results in many unpleasant effects, including lowered blood pressure, palpitations, nausea, vomiting, headache, and difficult breathing. Anticipation of these aversive effects can be used to discourage drinking.

Although the proposed mechanism of action of disulfiram on alcohol use has been thought to be primarily related to the inhibition of liver aldehyde dehydrogenase, its efficacy also could be related to secondary central nervous system actions, through modulation of catecholamine neurotransmission. …

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