History of cigarette smoking is associated with higher limbic GABAA receptor 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 GABA(A) receptor availability in volunteers with a history of cigarette smoking using [(11)C]Ro15 4513 positron emission tomography (PET). Eight [(11)C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, α1 and α5 GABA(A) receptor subtype [(11)C]Ro15 4513 V(T) values were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [(11)C]Ro15 4513 spectral frequency as well as α1 and α5 GABA(A) receptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [(11)C]Ro15 4513 V(T) values 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 [(11)C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher α5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABA(A) receptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABA(A) receptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABA(A) receptor 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.