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.