Long‐Term Ethanol and Nicotine Treatment Elicit Tolerance to Ethanol

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Abstract
Several previous studies have shown that 1 to 2 weeks of treatment with ethanol elicits tolerance to several effects produced by ethanol and cross‐tolerance to nicotine‐induced hypothermia. Similarly, short‐term, high‐dose nicotine treatment produces tolerance to nicotine and cross‐tolerance to ethanol‐induced hypothermia. In the studies reported here, C57BL/6 mice were force‐fed ethanol, nicotine, or an ethanol/nicotine combination in the drinking water for 6 months. All of the chronic drug‐treated mice developed tolerance to ethanol as measured by open‐field activity, body temperature, and sleep‐time tests. Ethanol tolerance is due, in part, to enhanced metabolism and reduced CNS sensitivity in the two ethanol‐treated groups but only to reduced CNS sensitivity in the nicotine‐treated group. Similar levels of tolerance to nicotine developed in those two groups that were nicotine‐treated, but no tolerance to nicotine was seen in those animals treated with ethanol alone. The tolerance to nicotine may be related to an upregulation of brain (cortex, hippocampus, and hypothalamus) [3H]‐nicotine binding, but ethanol tolerance is not readily explained by changes in the number of the brain high affinity nicotine binding sites.