Delineating the Role of Benzodiazepine Receptors in Alcohol and Nicotine Dependence

Julie K. Staley, Ph.D

Yale University

Funded in March, 2003: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

ABSTRACT

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Delineating the Role of Benzodiazepine Receptors in Alcohol and Nicotine Dependence

A central role for aberrant GABAergic function in alcohol dependence has been appreciated for decades. In contrast, the role of GABA systems in cigarette smoking has been poorly studied. The paucity of studies on the regulation of GABA systems by tobacco smoke is shocking, given the high rate of comorbidity between alcoholism and tobacco smoking. Alcohol, like benzodiazepines (BDZ), facilitates GABA function. In contrast, cigarette smoke contains beta carbolines that block the actions of BDZ at GABA-A receptors, suggesting that tobacco smoking opposes the effects of alcohol at the GABA receptor and facilitates tolerance to the effects of alcohol. In the present proposal, we seek to test the hypothesis that the benzodiazepine receptor is differentially regulated between alcoholic nonsmokers and alcoholic smokers during withdrawal and that the regulatory changes in benzodiazepine receptor availability will correlate with the severity of alcohol withdrawal.

This hypothesis will be addressed by imaging the BDZ receptor using [123I]Iomazenil SPECT in 1) alcoholic nonsmokers that quit drinking, 2) alcoholic smokers that quit drinking and continue smoking, and 3) alcoholic smokers that quit drinking and smoking simultaneously within 24 h and 6-10 days after their last alcohol drink and/or last cigarette. [123I]Iomazenil will be administered by bolus plus constant infusion. Three serial SPECT emission images (12 minutes each) will be obtained 5.5-6.5 h after the beginning of the infusion using a Prism 300XP camera. A transmission scan (15 minutes) will be obtained in the presence of a 20 mCi 57Co line source and used to correct the emission scans for photons which are absorbed by the tissue. An MRI will be obtained and used to correct SPECT images for differences in gray tissue volume. Within subject and group differences will be assessed using both a region of interest analysis and a voxel by voxel based analysis (Statistical Parametric Mapping, SPM).

The findings from these studies will delineate the regulatory changes that occur in the BDZ receptor during acute withdrawal from alcohol in the absence and presence of tobacco smoking and during acute withdrawal from both alcohol and tobacco smoke, and the relationship of these changes to the severity of alcohol withdrawal symptoms. The findings from these studies will guide future pharmacotherapeutic approaches towards treating alcohol dependence and dual alcohol and nicotine dependence.

HYPOTHESIS

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Goals:
1. To determine if higher BDZ receptor availability is a marker of active alcohol dependence or a correlate of acute withdrawal in alcoholic nonsmokers.  We hypothesize that alcoholic nonsmokers will exhibit lower BDZ receptor availability within 24 h of their last drink and increased BDZ receptor availability after 1 wk of alcohol withdrawal and that BDZ receptor availability will correlate with the severity of alcohol withdrawal symptoms. To test this hypothesis, alcoholic nonsmokers will be asked to participate in two [123I]Iomazenil SPECT scans; the first within 24 h of the last drink (prior to the development of alcohol withdrawal symptoms); and the second after 5-8 days of abstinence.

2. To determine if continued tobacco smoking during alcohol withdrawal suppresses the rebound in BDZ receptor availability and if smoking during alcohol withdrawal enhances the severity of alcohol withdrawal symptoms. We hypothesize that alcoholic smokers that continue to smoke after alcohol detoxification will have “normal” BDZ receptor availability, in contrast to alcoholic smokers who quit drinking and smoking who will demonstrate increased BDZ receptors similar to alcoholic nonsmokers. We also hypothesize that alcoholic smokers who continue to smoke will demonstrate greater severity of alcohol withdrawal symptoms compared to alcoholic smokers who quit smoking and drinking. To address this hypothesis, alcoholic smokers will be asked to quit drinking and to continue smoking, while another alcoholic smokers will be asked to quit drinking and smoking. Each AS will be asked to participate in two [123I]Iomazenil SPECT scans, the first within 24 h of their last drink and the second at 5-8 days after their last drink. 

SELECTED PUBLICATIONS

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Meyerhoff D.J., Tizabi Y., Staley J.K., Durazzo T.C., Glass J.M., and Nixon S.J.  Smoking comorbidity in alcoholism: neurobiological and neurocognitive consequences.  Alcohol Clin Exp Res. 2006 Feb;30(2):253-64.

Staley J.K., Gottschalk C., Petrakis I.L., Gueorguieva R., O’Malley S., Baldwin R.M., Jatlow P., Verhoeff N.P., Perry E., Weinzimmer D., Frohlich E., Ruff E., van Dyck C.H., Seibyl J.P., Innis R.B., and Krystal J.H.  Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking.  Arch Gen Psychiatry. 2005 Aug;62(8):877-88.