Koob GF. A role for GABA mechanisms in the motivational effects of alcohol. Biochem Pharmacol 68: 1515-1525

Department of Neuropharmacology, The Scripps Research Institute, 1055 North Pines Road, La Jolla, CA 92037, USA.
Biochemical Pharmacology (Impact Factor: 5.01). 11/2004; 68(8):1515-25. DOI: 10.1016/j.bcp.2004.07.031
Source: PubMed


Low doses of ethanol have been hypothesized to act directly via proteins that form ligand-gated receptor channels, such as the gamma-aminobutyric acid (GABA) receptor complex, to allosterically alter function, particularly in specific brain areas such as those hypothesized to be involved in ethanol reinforcement. At the pharmacological level, one can antagonize the effects of ethanol with GABA antagonists, particularly its sedative, anxiolytic-like and acute reinforcing actions. Brain sites involved in the GABAergic component of ethanol reinforcement include the ventral tegmental area, elements of the extended amygdala (including the central nucleus of the amygdala), and the globus pallidus. Chronic administration of ethanol sufficient to produce dependence and increased ethanol intake are associated with increased GABA release in the amygdala and increased sensitivity to GABA agonists. A hypothesis is proposed that GABAergic interactions with the brain stress neurotransmitter corticotropin-releasing factor in specific elements of the extended amygdala may be an important component for the motivation for excessive drinking associated with the transition from social drinking to addiction.

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    • "Third, GABA receptor genes confer increased risk for substance use disorders through disinhibition coupled with heightened response to environmental cues (Beuten et al. 2005; Enoch 2008; Grucza and Bierut 2005; Koob 2004). The GABA system plays a major role in impulsivity and increased craving in response to stress (Dai et al. 2009; Enoch et al. 2006; Villafuerte et al. 2012). "

    American Journal of Sociology 01/2016; In Press. · 3.17 Impact Factor
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    • "GABAARs mediate several important effects of alcohol. Considerable evidence indicates that GABAARs are the major target of EtOH in the CNS28,29,30,31,32. Some studies show that short-term alcohol exposure increases the inhibitory effect of GABAARs; however, many factors determine whether GABAARs respond to short-term alcohol exposure33. "
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    ABSTRACT: Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents.
    Acta Pharmacologica Sinica 07/2014; 35(8). DOI:10.1038/aps.2014.50 · 2.91 Impact Factor
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    • "It can for example, act on the GABA-releasing (i.e., presynaptic) neuron, causing an increase in GABA release; or it can act on the signal-receiving (i.e., postsynaptic) neuron facilitating the activity of the GABAA receptor. The consumption of alcohol is suppressed by compounds that interfere with the actions of the GABAA receptor (i.e., GABAA receptor antagonists) as well as compounds that stimulate the GABAB receptor (i.e., GABAB agonists) in the nucleus accumbens, ventral pallidum, bed nucleus of the stria terminalis and amygdala.[15] "
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    ABSTRACT: Recent advances in the study of alcoholism have thrown light on the involvement of various neurotransmitters in the phenomenon of alcohol addiction. Various neurotransmitters have been implicated in alcohol addiction due to their imbalance in the brain, which could be either due to their excess activity or inhibition. This review paper aims to consolidate and to summarize some of the recent papers which have been published in this regard. The review paper will give an overview of the neurobiology of alcohol addiction, followed by detailed reviews of some of the recent papers published in the context of the genetics of alcohol addiction. Furthermore, the author hopes that the present text will be found useful to novices and experts alike in the field of neurotransmitters in alcoholism.
    Indian Journal of Human Genetics 05/2014; 20(1). DOI:10.4103/0971-6866.132750
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