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

Relationship to Features of Alcohol Dependence and Cigarette Smoking

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

Arch Gen Psychiatry. 2005;62:877-888.

Context  Adaptations in -aminobutyric acid type A (GABA_A)–benzodiazepine receptors contribute to the neurobiology of human alcohol dependence and withdrawal.

Objective  To study GABA_A-benzodiazepine receptor adaptations in subjects with alcohol dependence over the first month of sobriety.

Design  Inpatients who were not receiving medication, were either smokers or nonsmokers, and had alcohol dependence completed 2 iodine I 123–labeled iomazenil single-photon emission computed tomographic scans: 1 scan at a mean ± SD of 4.9 ± 2.5 days of sobriety (n = 23) and 1 scan at a mean ± SD of 29.8 ± 7.6 days of sobriety (n = 20). Participants in a matched group of healthy subjects (n = 15) completed 1 single-photon emission computed tomographic scan.

Participants  Men with alcohol dependence (n = 27) and a matched healthy comparison group (n = 15).

Main Outcome Measures  ¹²³I-iomazenil single-photon emission computed tomographic images were converted to units of distribution volume (regional activity/free ¹²³I-iomazenil) and were analyzed using voxel-based statistical parametric mapping and regions of interest analyses. The relationships between ¹²³I-iomazenil distribution volume, clinical features of alcohol dependence, and smoking status were evaluated.

Results  ¹²³I-iomazenil uptake was elevated in several cortical regions, with a more prominent increase in nonsmokers with alcohol dependence as compared with smokers with alcohol dependence at 1 week of abstinence from alcohol. No significant differences were observed at 4 weeks of abstinence. At 1 week of abstinence, frontal ¹²³I-iomazenil uptake correlated with the severity of alcohol withdrawal and the number of days since the last alcoholic drink was consumed. No significant associations were observed for smokers with alcohol dependence.

Conclusions  These data demonstrate time-dependent regulation of cortical GABA_A-benzodiazepine receptors associated with the recovery from alcohol dependence. Higher GABA_A-benzodiazepine receptor levels during acute withdrawal may reflect a compensation for reduced receptor function, which is thought to contribute to alcohol tolerance and withdrawal. The subsequent decline may reflect "normalization" of GABA_A receptor function with sobriety. Smoking may attenuate GABA_A receptor adaptations associated with alcohol dependence and may contribute to the comorbidity between alcoholism and smoking.

Author Affiliations: Yale University School of Medicine, New Haven, Conn (Drs Staley, Gottschalk, Petrakis, Gueorguieva, O’Malley, Baldwin, Jatlow, Verhoeff, Perry, van Dyck, Seibyl, Innis, and Krystal, Mr Weinzimmer, and Mss Frohlich and Ruff); Veterans Affairs Connecticut Healthcare System, West Haven, Conn (Drs Staley, Petrakis, Baldwin, Verhoeff, Perry, Innis, and Krystal, Mr Weinzimmer, and Mss Frohlich and Ruff); and Institute for Neurodegenerative Disorders, New Haven (Dr Seibyl). Dr Baldwin is now with the Department of Radiology, Vanderbilt University, Nashville, Tenn, Dr Verhoeff is with the University of Toronto, Toronto, Ontario, and Dr Innis is with the Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Md.

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