This paper reviews evidence suggesting that nicotine and tobacco smoke profoundly modulate the effects of alcohol on γ-aminobutyric acid (GABA) neuronal function, specifically at the GABA(A)-benzodiazepine receptor (GABA(A)-BZR). The focus of this paper is on recent neuroimaging evidence in preclinical models as well as clinical experiments. First, we review findings implicating the role of alcohol at the GABA(A)-BZR and discuss the changes in GABA(A)-BZR availability during acute and prolonged alcohol withdrawal. Second, we discuss preclinical evidence that suggests nicotine affects GABA neuronal function indirectly by a primary action at neuronal nicotinic acetylcholine receptors. Third, we show how this evidence converges in studies that examine GABA levels and GABA(A)-BZRs in alcohol-dependent smokers and nonsmokers, suggesting that tobacco smoking attenuates the chemical changes that occur during alcohol withdrawal. Based on a comprehensive review of literature, we hypothesize that tobacco smoking minimizes the changes in GABA levels that typically occur during the acute cycles of drinking in alcohol-dependent individuals. Thus, during alcohol withdrawal, the continued tobacco smoking decreases the severity of the withdrawal-related changes in GABA chemistry. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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