γ-Aminobutyric Acid Type A Receptors and Alcoholism

Krystal, John H.; Staley, Julie K.; Mason, Graeme F.; Petrakis, Ismene L.; Kaufman, Joan; Harris, R. Adron; Gelernter, Joel; Lappalainen, Jaakko

doi:10.1001/archpsyc.63.9.957

Cited by 170 publications

(47 citation statements)

References 222 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In both preclinical models of AUDs and in clinical neuroimaging studies, glutamatergic and GABAergic dysfunction have been hypothesized and identified [8–10]. For example, alcohol withdrawal syndrome (AWS) has been postulated to result from the removal of exogenous alcohol on a chronically imbalanced ratio of glutamatergic/GABAergic neurotransmission, which increases the risk for withdrawal seizures due to excessive excitatory neurotransmission [11, 12]. …”

Section: Introductionmentioning

confidence: 99%

Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders

et al. 2015

View full text Add to dashboard Cite

Alcoholic patients suffer from harmful allostatic neuroplastic changes in the brain causing an acute withdrawal syndrome upon cessation of drinking followed by a protracted abstinence syndrome and an increased risk of relapse to heavy drinking. Benzodiazepines have long been the treatment of choice for detoxifying patients and managing alcohol withdrawal syndrome (AWS). Non-benzodiazepine anticonvulsants (NBACs) are increasingly being used both for alcohol withdrawal management and for ongoing outpatient treatment of alcohol dependence, with the goal of either abstinence or harm reduction. This expert narrative review summarizes the scientific basis and clinical evidence supporting the use of NBACs in treating AWS and for reducing harmful drinking patterns. There is less evidence in support of NBAC therapy for AWS, with few placebo-controlled trials. Carbamazepine and gabapentin appear to be the most promising adjunctive treatments for AWS, and they may be useful as monotherapy in select cases, especially in outpatient settings and for the treatment of mild-to-moderate low-risk patients with the AWS. The body of evidence supporting the use of the NBACs for reducing harmful drinking in the outpatient setting is stronger. Topiramate appears to have a robust effect on reducing harmful drinking in alcoholics. Gabapentin is a potentially efficacious treatment for reducing the risk of relapse to harmful drinking patterns in outpatient management of alcoholism. Gabapentin's ease of use, rapid titration, good tolerability, and efficacy in both the withdrawal and chronic phases of treatment make it particularly appealing. In summary, several NBACs appear to be beneficial in treating AWS and alcohol use disorders.

show abstract

Section: Introductionmentioning

confidence: 99%

Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It has been well established that GABA is relevant to alcohol responsiveness, dependence, alcoholism vulnerability, and pharmacological interventions for alcoholism (Krystal et al, 2006). For instance, healthy young adult social drinkers administered alcohol via intravenous infusion exhibit decreased GABA in occipital cortex (OCC), which is consistent with alcohol’s ability to potentiate the GABA system (Gomez et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Altered Anterior Cingulate Neurochemistry in Emerging Adult Binge Drinkers with a History of Alcohol‐Induced Blackouts

Silveri

Cohen‐Gilbert

Crowley

et al. 2014

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background Binge alcohol consumption is associated with multiple neurobiological consequences, including altered neurophysiology, brain structure and functional activation. Magnetic resonance spectroscopy (MRS) studies have demonstrated neurochemical alterations in the frontal lobe of alcohol users, although most studies focused on older, alcohol dependent subjects. Methods In this study, neurochemical data were acquired using MRS at 4T from emerging adults (18–24 years old) who were binge alcohol drinkers (BD, n=23) or light drinkers (LD, n=31). Since binge drinking is also associated with increased prevalence of experiencing an alcohol-induced blackout, BD were stratified into alcohol-induced blackout (BDBO) and non-blackout groups (BDN). Results Overall, BD had significantly lower gamma amino-butyric acid (GABA) and N-acetyl-aspartate (NAA) in the anterior cingulate cortex (ACC) than LD. When stratified by blackout history, BDBO also had lower ACC glutamate (Glu) than LD. No group differences in MRS metabolites were observed in the parietal-occipital cortex. Lower ACC GABA and glutamate remained significant after accounting for lower grey matter content in BD, however NAA differences were no longer evident. In addition, low ACC GABA levels were associated with greater alcohol use consequences, and worse response inhibition and attention/mental flexibility in BD. Conclusions These data indicate that binge drinking affects frontal lobe neurochemistry, more so in those who had experienced an alcohol-induced blackout. Characterization of the neurochemical profiles associated with binge alcohol consumption and blackout history may help identify unique risk factors for the later manifestation of alcohol abuse and dependence, in young individuals who are heavy, frequent drinkers, but who do not meet the criteria for alcohol use disorders.

show abstract

“…Such conditioned withdrawal reactions [49,50,51,52] suggest that contextual cues elicit counteradaptive mechanisms that are specifically directed against the sedative effects of the drug of abuse. Indeed, cessation of chronic consumption of a GABAergic drug is accompanied by conditioned withdrawal symptoms and a strong urge to consume the drug [17,41]. Similar reactions have been described by about one third of all detoxified alcohol-dependent patients [17].…”

Section: Learning Mechanisms and The Neurobiological Correlates Undermentioning

confidence: 89%

“…On the symptom level, this can lead to development of tolerance towards excessive drug intake. Once alcohol intake is suddenly stopped during detoxification, GABA A receptors do not recover immediately, but appear to remain downregulated several days or even weeks after detoxification [40,41]. Such a delayed recovery of GABA A receptors following acute cessation of alcohol intake impairs neural inhibition (e.g.…”

Section: Key Clinical Symptoms Of Addiction and Their Underlying Neurmentioning

confidence: 99%

“…Such a delayed recovery of GABA A receptors following acute cessation of alcohol intake impairs neural inhibition (e.g. in cortical areas) and can facilitate epileptic seizures [15,41]. Therefore, upregulated excitatory glutamatergic receptors on the one hand and downregulated inhibitory GABA A receptors on the other hand can contribute to a disbalance between inhibition and excitation in the central nervous system and can thus manifest as withdrawal symptoms.…”

Section: Key Clinical Symptoms Of Addiction and Their Underlying Neurmentioning

confidence: 99%

See 1 more Smart Citation

Too Difficult to Stop: Mechanisms Facilitating Relapse in Alcohol Dependence

et al. 2014

View full text Add to dashboard Cite

Background: In alcohol and other substance dependencies, patients often suffer relapse despite better knowledge and their intention to remain abstinent. A variety of neurotransmitter systems and their respective alterations due to the chronic drug intake are involved in mechanisms that facilitate relapse. It has been postulated that these neurotransmitter systems are related to changes in motivational and learning mechanisms, and engender a shift from goal-directed to habitual behavior in dependent patients that facilitates drug-seeking behavior. Methods: We review learning mechanisms facilitating relapse, as identified and tested to date. We focus on studies examining the interaction between alcohol-related changes in monoaminergic neurotransmission and their respective effects on pavlovian and operant learning mechanisms in alcohol dependence. Results: Animal experiments and first human studies suggest that chronic alcohol intake impairs goal-directed behavior and facilitates habitual drug intake. Key symptoms of alcohol dependence such as tolerance development, withdrawal, craving and reduced control of alcohol intake can be explained by alcohol-induced alteration of dopaminergic neurotransmission and its GABAergic and glutamatergic modulation and their respective effects on pavlovian and operant conditioning as well as pavlovian-to-instrumental transfer. Conclusion: Chronic alcohol intake impairs neurotransmitter systems that regulate prefrontal-striatal circuits and interfere with goal-directed decision-making and the acquisition of new, non-drug-related behavior patterns. Alcohol craving induced by pavlovian conditioned cues can facilitate habitual drug intake. Such learning mechanisms and their alterations by chronic alcohol intake might be targeted by specific interventions.

show abstract

γ-Aminobutyric Acid Type A Receptors and Alcoholism

Cited by 170 publications

References 222 publications

Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders

Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders

Altered Anterior Cingulate Neurochemistry in Emerging Adult Binge Drinkers with a History of Alcohol‐Induced Blackouts

Too Difficult to Stop: Mechanisms Facilitating Relapse in Alcohol Dependence

Contact Info

Product

Resources

About