0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Perspectives |

γ-Aminobutyric Acid Type A Receptors and Alcoholism:  Intoxication, Dependence, Vulnerability, and Treatment

John H. Krystal, MD; Julie Staley, PhD; Graeme Mason, PhD; Ismene L. Petrakis, MD; Joan Kaufman, PhD; R. Adron Harris, PhD; Joel Gelernter, MD; Jaakko Lappalainen, MD, PhD
Arch Gen Psychiatry. 2006;63(9):957-968. doi:10.1001/archpsyc.63.9.957.
Text Size: A A A
Published online

Context  Alcohol facilitates γ-aminobutyric acid (GABA) function, and GABA type A (GABAA) receptor–facilitating agents suppress alcohol withdrawal symptoms. Advances in molecular neuroscience, genetics, and neuroimaging provide new insights into the role of brain GABA systems in short- and long-term alcohol effects.

Objective  To review the role of brain GABA systems in alcohol response, alcohol dependence, alcoholism vulnerability, and alcoholism pharmacotherapy.

Design  Literature review.

Results  Alcohol increases GABA release, raises neurosteroid levels, and may potently enhance the function of a GABAA receptor subclass that shows high affinity for GABA and neurosteroids, relative insensitivity to benzodiazepines, low chloride conductance, and an extrasynaptic location. Variation in GABAA receptor subunit genes may contribute to the vulnerability to alcoholism, particularly in the context of environmental risk factors. Alcohol dependence is associated with time-dependent changes in brain GABAA receptor density and subunit gene expression levels that contribute to a withdrawal-related deficit in GABAA receptor function. However, cortical GABA levels are not reduced during acute withdrawal. Benzodiazepine-assisted detoxification enhances a phasic component of GABA function. However, novel treatments target the tonic component of GABA neurotransmission mediated by benzodiazepine-insensitive GABAA receptors. Smoking attenuates withdrawal-related disturbances in brain GABA function, perhaps contributing to comorbid nicotine and alcohol dependence. The GABA systems show recovery with long-term sobriety.

Conclusions  Recent research deepens our understanding of the role of GABA systems in alcohol action, alcohol dependence, and the vulnerability to alcoholism. Also, GABAA receptor subtype–selective treatments merit exploration for reducing withdrawal symptoms and drinking in alcohol-dependent individuals.

Figures in this Article

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

First Page Preview

View Large
First page PDF preview

Figures

Place holder to copy figure label and caption
Figure 1.

Range of ethanol concentrations with modulatory effects at selected ionotropic receptors. Each bar is black up to the concentration at which ethanol produces 50% of its maximum effect (EC50) or the concentration at which ethanol produces a 50% inhibition of ligand binding to a receptor target (IC50) (ie, the boundary of the black and gray sections of the bars). The ranges primarily reflect electrophysiologic data reviewed by Grant and Lovinger4 (where additional details related to the EC50 or IC50 values can be found). The figure has been modified to include studies reviewed in the text and to be consistent with a recent review.5 The clinical consequences of intoxication, also from Grant and Lovinger,4 vary across individuals depending on the initial level of alcohol sensitivity and extent of alcohol tolerance. 5-HT3 indicates serotonin type 3; GABAA, γ-aminobutyric acid type A; NMDA, N-methyl-D-aspartate.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Relationship between the duration of sobriety and the volume of distribution of iodine I123-labeled iomazenil (123I-iomazenil) in the medial frontal cortex (mFC) (open circles) and cerebellum (CB) (filled circles) in recovering alcohol-dependent nonsmoking (mFC: r = 0.72, P = .04; and CB: r = 0.93, P = .001) (A) and smoking (B) patients. The 123I-iomazenil volume of distribution provides a measure related to the density of the benzodiazepine binding site of γ-aminobutyric acid type A receptors. Each dot represents data from an individual. Data are from Staley et al.142

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

The general trajectory of selected γ-aminobutyric acid type A (GABAA) receptor subunits during alcohol dependence and the initiation of sobriety. The results of several studies considered in this review are summarized. The gross estimate of the percentage of GABAA receptors bearing a given subunit is based on the reported percentage of receptor subtypes in the brain from Whiting7 and on the quantitative time-dependent description of GABAA receptor subunit gene expression levels during ethanol withdrawal from Sanna et al.97 In the basal state, the synaptic GABAA receptors bearing the α1-3, β2-3, and γ2 subunits dominate. With the development of alcohol dependence, synaptic and extrasynaptic receptor subunit composition changes, with α4,6 subunits replacing α1-3 subunits and γ2 subunits replacing δ subunits. The GABAA receptors associated with alcohol dependence are less functional than the array associated with the basal state. In response, synaptic forms of GABAA receptors are recruited during acute withdrawal. The recent single-photon emission computed tomography data suggest that there is a transitional period during the late phase of acute withdrawal in which receptors associated with alcohol dependence are still present but the synaptic receptors are reemerging. This transitional period is associated with increased GABAA receptor density. As the transition to the basal array of GABAA receptor is completed (1 week to 1 month of sobriety), the GABAA receptor contribution to acute and protracted alcohol withdrawal is presumed to be completed. It is possible, however, that intracellular disturbances downstream of GABAA receptors may have a more protracted time course than that presented in this figure.

Graphic Jump Location

Tables

References

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 92

Sign in

Create a free personal account to sign up for alerts, share articles, and more.

Purchase Options

• Buy this article
• Subscribe to the journal

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature
Alcohol Abuse or Dependence

The Rational Clinical Examination
Make the Diagnosis: Alcohol Abuse

brightcove.createExperiences();