Previous studies in humans have demonstrated a high co-morbidity between alcoholism and smoking. This co-morbidity between alcohol and nicotine dependence can be attributed, in part, to common genetic factors. In rodents, behavioral and physiological responses to alcohol and nicotine also appear to share common genetic influences. In this report, the genetic correlation between free-choice oral nicotine and oral alcohol consumption was evaluated using an ascending two-bottle choice paradigm in C57BL/6xC3H/HeJ F2 intercross mice. For all concentrations of nicotine (25, 50, and 100 microg/ml) and alcohol (3, 6, and 10%) tested, nicotine consumption was significantly correlated with alcohol consumption. Nicotine consumption at the highest nicotine concentration tested (100 microg/ml) showed low, but significant, correlations with the number of [3H]-cytisine binding sites in the hippocampus (r=0.307) and the number of [125I]-alpha-bungarotoxin binding sites in the cortex (r=-0.328). No significant correlations between alcohol consumption and the number of either [3H]-cytisine or [125I]-alpha-bungarotoxin binding sites was observed. A polymorphism in the nicotinic receptor alpha4 subunit gene, Chrna4, showed a trend with nicotine consumption and a significant association with alcohol consumption in female but not male mice. These results indicate that common genetic factors influence nicotine and alcohol consumption in mice. However, neither individual differences in the expression of [3H]-cytisine or [125I]-alpha-bungarotoxin binding nicotinic receptors nor the polymorphism in Chrna4 likely contribute to the genetic overlap that influences the consumption of both of these drugs of abuse in C57BL/6xC3H/HeJ F2 mice.