Chronic nicotine treatment will produce an upregulation of brain nicotinic receptors, and rats treated for 5 months with ethanol had increased [ 3 H]nicotine binding in two of the three brain regions that were studied. However, several studies using short-term treatment did not detect an effect of ethanol on mouse brain nicotinic receptor numbers. Therefore, LS and SS mice were force-fed ethanol (15%, v/v) in the drinking water for 6 months. The LS mice developed tolerance to ethanol as measured by Y-maze crossing and rearing activity, body temperature, and sleep time. No evidence for tolerance to ethanol was seen in the SS mice. However, the SS mice showed increases in [ 3 H]nicotine binding in thalamus and an increase in [ 1 2 5 I]α-bungarotoxin binding in the cereellum and superior colliculus. LS mice had reduced levels of hippocampal [ 1 2 5 I]α-bungarotoxin binding. Thus, long-term ethanol treatment may affect brain nicotinic receptor binding but the effect is limited to only a few brain regions and may be influenced by genetic factors.