Alcohol Addiction: An Enigma among Us

Abstract

Current evidence is providing a view of the actions of ethanol that indicates that this simple two-carbon molecule demonstrates significant specificity in its actions. Even within ethanol-sensitive systems such as the GABAA and NMDA receptors, differential sensitivity is apparent and based on the subunit composition of these receptors. Additionally, posttranslational modification, particularly the phosphorylation state, of certain GABAA and NMDA receptor subunit combinations can add another layer of selectivity to the acute actions of ethanol. In looking for genetic determinants of differential ethanol sensitivity and predisposition to alcoholism, one may, therefore, be confronted with a search that leads to subtle differences in receptor structure or posttranslational modification, rather than to gross differences in the primary structure of an individual protein. The adaptive changes induced by ethanol in the GABAA receptor system may have a more significant relationship to the development of ethanol tolerance, while the changes in the NMDA receptor system seem to mirror the expression of signs of physical dependence (withdrawal signs). A dissociation in the development of ethanol tolerance and physical dependence has also been demonstrated in prior studies (reviewed byTabakoff et al. 1996xHandbook Exp. Tabakoff, B, Hellevuo, K, and Hoffman, P.L. Pharmacol. 1996; 118: 373–458See all ReferencesTabakoff et al. 1996). The NMDA and GABAA receptor systems may also be involved in the control of particular aspects of ethanol intake, the NMDA receptor by mediating actions of glutamate on dopaminergic neurons, which influence reinforcement, and GABA through actions downstream of these neurons, on processes that control termination of ethanol intake. It is enticing to think that the witnessed adaptive changes in GABAA and NMDA receptor systems would not only underlie the phenomena of tolerance and physical dependence on ethanol, but would also contribute to difficulties that alcohol-dependent individuals experience in controlling their drinking and their compulsion to drink alcohol.