Ethanol-nicotine interactions at alpha-bungarotoxin-insensitive nicotinic acetylcholine receptors in rat cortical neurons

Numerous studies have indicated a correlation between ethanol intake and ci garette smoking in heavy drinkers. We have studied the underlying pharmacol ogical basis of this relationship using cultured rat cortical neurons. Thes e neurons express nicotinic receptors having characteristics similar to tho se described for the alpha 4 beta 2 subunit combination. In the presence of cr-bungarotoxin both acetylcholine (ACh) and nicotine evoked currents with respective EC50 values of 4.3 and 3.4 mu M. The maximal nicotine-activated response, however, was only 56% that of the maximal ACh current. It was pr eviously shown that 10 to 100 mM of ethanol potentiated ACh-mediated curren ts in these neurons. We demonstrate that 100 mM ethanol similarly potentiat es currents evoked by 300 nM (40%) end 1 mu M nicotine (61%). This suggests that an ethanol-induced potentiation of nicotinic currents may enhance the acute positive reinforcement associated with nicotine and could increase t obacco use during heavy ethanol intake. However, further experimentation in dicated that the continuous perfusion of 30, 100, or 300 nM nicotine desens itizes ACh-evoked currents by 38, 54, and 62%, respectively, with little di rect receptor-channel activation. The residual ACh currents of nicotine-des ensitized receptor channels were potentiated by 100 mM ethanol to nearly th e extent as were the undesensitized control responses. We propose that the opposing effect of ethanol on nicotine-induced desensitization could also e xplain the increased tobacco use observed with excessive drinking. Thus, et hanol has a dual effect regarding nicotine. It enhances acute nicotine-medi ated receptor activation, although opposing the net effect of nicotine-indu ced receptor channel desensitization.