Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder

Malizia, Andrea L.; Cunningham, Vincent J.; Bell, Caroline; Liddle, Peter F.; Jones, Terry; Nutt, David

doi:10.1001/archpsyc.55.8.715

Cited by 335 publications

(177 citation statements)

References 69 publications

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“…Thus, although it appears that the nicotine per se does not directly affect GABA A receptor levels, we cannot exclude the possibility that other behavioral components of tobacco smoking are also relevant to our findings. Based on previous work demonstrating lower GABA A receptor levels in individuals with anxiety disorders versus healthy controls (27) and our previous finding that smoking appears to disrupt the negative relationship between anxiety symptoms and GABA A receptor levels in healthy controls (28), we might speculate that continued smoking impacts changes in GABA A receptor levels during alcohol withdrawal by modulating anxiety at a behavioral and a molecular level. Interestingly, a recent study reports higher levels of GABA A receptors in the amygdala and nucleus accumbens in ex-smokers compared with those who never smoked (29).…”

Section: Discussionmentioning

confidence: 84%

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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Section: Discussionmentioning

confidence: 84%

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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“…Any potential global differences would have been removed by the global normalization. Interestingly, in panic disorder, which is related to PTSD a global reduction of [ 11 C]flumazenil binding was also found throughout the brain, 39 suggesting that the GABAergic system is indeed involved in these anxiety disorders.…”

Section: Discussionmentioning

confidence: 99%

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

et al. 2007

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c-Aminobutyric acid (GABA A ) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA A receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA A receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA A receptor complex in veterans with and without PTSD using [ 11 C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [ 11 C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [ 11 C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [ 11 C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABA A receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

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“…[10][11][12][13][14] In patients with panic disorder a deficit of GABA receptors has been shown in several brain areas, including OFC. 38 Decreased GABA-receptor clustering resulted in enhanced anxiety, which was demonstrated in an animal model. 39 Our post-hoc analysis examined what chemicals in OFC were mostly changed in relation to anxiety, and identified multiple neurotransmitters and other chemicals: NAA (as a precursor of a neurotransmitter N-acetyl-aspartyl-glutamate, which after breakdown produces excitatory neurotransmitter aspartate; this chemical was changed the most); GABA (as an inhibitory neurotransmitter); Gln (as a precursor of the excitatory neurotransmitter glutamate); Glc (as an energy substrate); and Ins (as a second messenger that liberates Ca 2+ from the endoplasmic reticulum and is involved in recognition of chemical signals).…”

Section: Molecular Psychiatrymentioning

confidence: 99%

Anxiety in healthy humans is associated with orbital frontal chemistry

Grachev

Apkarian

2000

Mol Psychiatry

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Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder

Abstract: These results must be considered preliminary but are congruous with previous clinical psychopharmacologic evidence of involvement of the benzodiazepine-GABA(A) receptor and demonstrate that decreased flumazenil binding at this site may underlie panic disorder.

Cited by 335 publications

References 69 publications

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

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

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

Anxiety in healthy humans is associated with orbital frontal chemistry

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Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder

Abstract: These results must be considered preliminary but are congruous with previous clinical psychopharmacologic evidence of involvement of the benzodiazepine-GABA(A) receptor and demonstrate that decreased flumazenil binding at this site may underlie panic disorder.

Cited by 335 publications

References 69 publications

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

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

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

Anxiety in healthy humans is associated with orbital frontal chemistry

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Product

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

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