Cortical γ-Aminobutyric Acid Type A–Benzodiazepine Receptors in Recovery From Alcohol Dependence

Staley, Julie K.; Gottschalk, Christopher; Petrakis, Ismene L.; Gueorguieva, Ralitza; O’Malley, Stephanie S.; Baldwin, Ronald M.; Jatlow, Peter; Verhoeff, Nicolaas Paul L.G.; Perry, Edward; Weinzimmer, David; Frohlich, Erin; Ruff, Elizabeth; Dyck, Christopher H. van; Seibyl, John; Innis, Robert B.; Krystal, John H.

doi:10.1001/archpsyc.62.8.877

Cited by 44 publications

(31 citation statements)

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“…This difference normalized after one month of abstinence. Frontal isotope uptake corresponded with severity of alcohol withdrawal and the number of days since the last drink (Staley et al, 2005). Therefore either the expression of GABA A receptors increased with chronic drinking in line with the findings in postmortem brain samples (Lewohl et al, 1997) and subsequently declined with abstinence, or GABA A receptors increased in acute withdrawal before gradually declining.…”

Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Cosupporting

confidence: 75%

“…Either drug may increase the rewarding effects and/or reduce the aversive effects (such as withdrawal) of the other. In contrast to the non-smoking alcoholics described above, GABA A receptor binding and GABA levels in alcoholic smokers did not differ from controls at one week of abstinence Staley et al, 2005). Moreover, a 1 H-MRS study in non-alcoholics showed no difference in cortical GABA levels between smokers and non-smokers (Epperson et al, 2005).…”

Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Comentioning

confidence: 69%

“…A single-photon emission computed tomographic scan (SPECT) imaging study showed that at one week of abstinence from alcohol, binding of 123 I-iomazenil to GABA A BZ receptors was higher throughout the brain, including the hippocampus and amygdala, but particularly in the frontal cortex, in alcoholic non-smokers compared with controls (Staley et al, 2005). This difference normalized after one month of abstinence.…”

Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Comentioning

confidence: 99%

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The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

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Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Cosupporting

confidence: 75%

Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Comentioning

confidence: 69%

Section: Plasticity Of Gaba a Receptor Subunits In Chronic Ethanol Comentioning

confidence: 99%

See 1 more Smart Citation

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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“…In early recovery, there is a transitional phase, during which deficits in GABA A receptor signaling are thought to contribute to withdrawal-related cortical hyperexcitability and low-affinity high-conductance receptors are recruited to reestablish the cortical balance of excitation and inhibition. The recruitment of the additional GABA A receptors was demonstrated by a transient increase in ligand binding over the first week of alcohol withdrawal (17). In this same cross-sectional study (17), a subset of smokers did not show similar time-dependent alterations during early recovery.…”

mentioning

confidence: 86%

“…The recruitment of the additional GABA A receptors was demonstrated by a transient increase in ligand binding over the first week of alcohol withdrawal (17). In this same cross-sectional study (17), a subset of smokers did not show similar time-dependent alterations during early recovery. Moreover, GABA A receptor availability was positively correlated with alcohol withdrawal symptoms in nonsmokers but not smokers, suggesting that smoking may have suppressed withdrawal Significance Alcohol dependence and tobacco smoking are highly comorbid.…”

mentioning

confidence: 86%

Tobacco smoking interferes with GABA _A receptor neuroadaptations during prolonged alcohol withdrawal

Cosgrove

McKay

Esterlis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the effects of tobacco smoking on neuroadaptations in GABA A receptor levels over alcohol withdrawal will provide critical insights for the treatment of comorbid alcohol and nicotine dependence. We conducted parallel studies in human subjects and nonhuman primates to investigate the differential effects of tobacco smoking and nicotine on changes in GABA A receptor availability during acute and prolonged alcohol withdrawal. We report that alcohol withdrawal with or without concurrent tobacco smoking/nicotine consumption resulted in significant and robust elevations in GABA A receptor levels over the first week of withdrawal. Over prolonged withdrawal, GABA A receptors returned to control levels in alcohol-dependent nonsmokers, but alcohol-dependent smokers had significant and sustained elevations in GABA A receptors that were associated with craving for alcohol and cigarettes. In nonhuman primates, GABA A receptor levels normalized by 1 mo of abstinence in both groups-that is, those that consumed alcohol alone or the combination of alcohol and nicotine. These data suggest that constituents in tobacco smoke other than nicotine block the recovery of GABA A receptor systems during sustained alcohol abstinence, contributing to alcohol relapse and the perpetuation of smoking.alcohol dependence | tobacco smoking | neuroimaging | GABA A receptors | translational A lcohol dependence and tobacco smoking are highly comorbid (1). Alcohol-dependent smokers who quit drinking but continue smoking may have a reduced severity of alcohol withdrawal and relapse risk (2) compared with alcohol-dependent smokers who stop smoking and drinking at the same time (3-5). This has led to some complacency in the field about treating the addiction to nicotine in alcohol-dependent smokers, and few treatment settings provide any systematic tobacco treatment (6). However, a large part of the morbidity and mortality from alcohol dependence can be attributed to concurrent tobacco smoking (7), and a large number of alcohol-dependent individuals in treatment express a desire to quit smoking (8). Understanding the involvement of tobacco smoking in the neuroadaptations and behavioral changes that occur during alcohol withdrawal will provide critical insights to direct treatment strategies.Given the multiple molecular targets for alcohol in the brain and numerous constituents of tobacco smoke, it is likely that the neurobiology of this comorbidity is complex. However, the γ-aminobutyric acid (GABA) system may be an important point of convergence of the effects of tobacco smoke and alcohol in the brain. For example, nicotine reinforcement has been critically linked to activation of GABA neurons (9), and alcohol appears to both directly stimulate extrasynaptic GABA A receptors with relatively high affinity (10) and to indirectly stimulate the release of GABA and neurosteroids (11), such as allopregnanolone, that also stimulate extrasynaptic GABA A receptors (12, 13). Alcohol and neurosteroids can act at synaptic GABA A receptors, but the af...

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