Pharmacogenomics of Alcohol Response and Addiction

Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland 20892-8110, USA.
American Journal of PharmacoGenomics 02/2003; 3(4):217-32. DOI: 10.2165/00129785-200303040-00001
Source: PubMed


Alcoholism is a complex psychiatric disorder that has high heritability (50-60%) and is relatively common; in the US the lifetime prevalence of alcohol dependence is 20% in men and 8% in women. Current psychosocial and pharmacological therapies have relatively modest effects. Treatment is complicated by the fact that alcoholism is often co-morbid with other disorders, including anxiety, depression, and antisocial personality disorder. Approximately 80% of alcoholics smoke cigarettes and there is considerable genetic overlap between nicotine and alcohol addiction. Convergent evidence supports the classification of alcoholics into two broad categories: type 1 - later onset with feelings of anxiety, guilt, and high harm avoidance; and type 2 - early age of onset, usually men, impulsive, antisocial, and with low levels of brain serotonin. The pharmacogenomics of alcohol response is well established; genetic variants for the principal enzymes of alcohol metabolism influence drinking behavior and protect against alcoholism. Vulnerability to alcoholism is likely to be due to multiple interacting genetic loci of small to modest effects. First-line therapeutic targets for alcoholism are neurotransmitter pathway genes implicated in alcohol use. Of particular interest are the 'reward pathway' (serotonin, dopamine, GABA, glutamate, and beta endorphin) and the behavioral stress response system (corticotrophin-releasing factor and neuropeptide Y). Common functional polymorphisms in these genes are likely to be predictive (although each with small effect) of individualized pharmacological responses. Genetic studies, including case-control association studies and genome wide linkage studies, have identified associations between alcoholism and common functional polymorphisms in several candidate genes. Meanwhile, the current pharmacological therapies for alcoholism are effective in some alcoholics but not all. Some progress has been made in elucidating the pharmacogenomic responses to these drugs, particularly in the context of the type 1/type 2 classification system for alcoholics.

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    • "Because of the heterogeneity that occurs among AUD individuals, there has been an effort to categorize them into distinct groups or subtypes that can guide diagnosis, predict prognosis and provide targeted treatments [7] [8]. Subtypes are the expression of a patient's gene polymorphism and phenotypes or endo-phenotypes in different environmental backgrounds [9]. Namely, the concept underlying the identifications of AUD typologies has evolved from the conception of AUD as a disease state (Jellinek gamma and delta) [10] to a personality model supported by genetic epidemiological data (Cloninger type I and type II) [11], and extended into a measure of disease severity determined through cluster analysis, using detailed empirical data derived from in-patient AUD patients (Babor type A and type B) [12]. "
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    ABSTRACT: Almost 10% of the world's population is affected by alcohol use disorder (AUD). The combination between psychosocial intervention and pharmacological treatment seems to be the most effective approach for patients affected by AUD. Among effective drugs useful in the treatment of AUD, GABAB-ergic medications have been tested with encouraging results (i.e. sodium oxybate, baclofen, gabapentin, pregabalin and tiagabine). The present review will summarize available data on these medications.
    Current pharmaceutical design 06/2015; 21(23). DOI:10.2174/1381612821666150619091858 · 3.45 Impact Factor
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    • "cause or worsen cardiovascular diseases and cancer [43] [46]. Stress can also precipitate adverse behaviors, such as depression, rage, anxiety, and addiction [5] [14] [15] [20]. As a result, stress contributes significantly to health care costs [38]. "
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    ABSTRACT: Stress can lead to headaches and fatigue, precipitate addictive be-haviors (e.g., smoking, alcohol and drug use), and lead to cardio-vascular diseases and cancer. Continuous assessment of stress from sensors can be used for timely delivery of a variety of interven-tions to reduce or avoid stress. We investigate the feasibility of continuous stress measurement via two field studies using wireless physiological sensors — a four-week study with illicit drug users (n = 40), and a one-week study with daily smokers and social drinkers (n = 30). We find that 11+ hours/day of usable data can be obtained in a 4-week study. Significant learning effect is ob-served after the first week and data yield is seen to be increasing over time even in the fourth week. We propose a framework to an-alyze sensor data yield and find that losses in wireless channel is negligible; the main hurdle in further improving data yield is the attachment constraint. We show the feasibility of measuring stress minutes preceding events of interest and observe the sensor-derived stress to be rising prior to self-reported stress and smoking events.
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    • "There is mounting evidence for genetic contribution to the development of alcohol (ethanol) use disorders (Ducci & Goldman 2008; Mayfield et al. 2008; Schuckit 2009). Alcohol dependence develops after sustained, excessive consumption, and an important part of genetic diathesis may concern responses to alcohol in pre-dependent individuals (Ducci & Goldman 2008; Enoch 2003; Newlin & Thomson 1990; Schuckit 1994). One such pre-dependent response is tolerance, an important component for clinical diagnosis of alcohol dependence (American Psychiatric Association 2000). "
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    ABSTRACT: Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of this study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2 and HAP3) and low (LAP2 and LAP3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task, which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75 g/kg; Experiment 1) or two (1.75 and 2.0 g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance [when blood ethanol concentrations (BECs) were rising] and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling - BECrising) in HAP mice when compared with LAP mice, which occurred within ∼30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ∼30-60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol.
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