Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol

Ethanol shares with all major dependence producing drugs the ability to act ivate brain mesocorticolimbic dopamine neurons, an important part of the br ain reward systems. This dopamine activation may be involved in mediating t he positive reinforcing effects of ethanol. The mechanisms of action of eth anol in its activation of this dopamine system remain, however, to be eluci dated. A selective pharmacological interference with these mechanisms may o ffer a possibility to reduce the reinforcing properties of ethanol without simultaneously interfering with the reinforcing properties of natural rewar ds. Ethanol has been shown to directly influence the function of various li gand-gated ion-channels. Several of these are located on or nearby mesocort icolimbic dopamine neurons. One such receptor is the nicotinic acetylcholin e receptor (nAChR). The present article reviews a series of investigations aimed at investigating whether nAChRs are involved in the dopamine activati ng and reinforcing properties of ethanol. To this end acute and chronic beh avioral acid neurochemical experiments were performed in mice and rats. The results obtained indicate that central nAChRs in the ventral tegmental are a are involved in mediating the mesolimbic dopamine activating and reinforc ing effects of ethanol. Furthermore, the ethanol-induced activation of thes e receptors is probably indirect, subsequent to a primary interference of e thanol in the nucleus accumbens. Moreover, subchronic nicotine treatment en hances the reinforcing and dopamine activating properties of ethanol. This long-term effect may, however, derive from autonomic adaptations in respons e to intermittent blockade of peripheral nAChRs (rather than from intermitt ent stimulation of central receptors), and appears to be associated with de velopment of a disinhibitory behavior that could involve also other neurotr ansmittors, e.g. serotonin. Taken together, these findings could provide a neurobiological explanation to the often observed co-abuse of nicotine and ethanol in man. Furthermore, since the behavioral models applied previously have predicted therapeutic drug effects in the clinic, the results suggest that selective blockade of the ventral tegmental nAChRs that are involved in the above effects may provide a new pharmacological alternative in the t reatment of alcoholism. (C) 2000 Elsevier Science B.V. All rights reserved.