History of cigarette smoking is associated with higher limbic GABAAreceptor availability

Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction. We investigated limbic GABAAreceptor availability in volunteers with a history of cigarette smoking using [11C]Ro15 4513 positron emission tomography (PET). Eight [11C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, [alpha]1 and [alpha]5 GABAAreceptor subtype [11C]Ro15 4513 VTvalues were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [11C]Ro15 4513 spectral frequency as well as [alpha]1 and [alpha]5 GABAAreceptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [11C]Ro15 4513 VTvalues in the presubgenual cingulate and parahippocampal gyrus, and at a trend level in the insula, nucleus accumbens and subgenual cingulate. In six abstinent previous smokers ('ex-smokers'), total [11C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher [alpha]5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABAAreceptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABAAreceptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABAAreceptor availability continues with abstinence indicating that this may be a trait marker for nicotine addiction or that alterations in GABA function associated with cigarette smoking persist.