Nicotine tolerance: an analysis of the time course of its development and loss in the rat.
The time course of the development and loss of tolerance to nicotine was measured in female rats that were injected subcutaneously (SC), twice daily with 1.6 mg/kg nicotine. Tolerance to nicotine-induced decreases in locomotor activity and body temperature were observed. Tolerance to the effects of nicotine on both of these measures developed rapidly, with maximal changes occurring within 2-4 days after initiation of treatment. The binding of L-[3H]-nicotine was measured in six brain regions. Chronic nicotine treatment resulted in increases in binding in most brain regions. The increase in binding correlated significantly with the development of tolerance. Rats that had been injected chronically with nicotine did not lose their tolerance throughout a 7-day post-treatment test period. Control levels of binding were regained in all of the brain regions except cortex by 7 days after nicotine treatment was stopped. These findings indicate that changes in receptor binding may relate to the development of tolerance but the retention of tolerance is clearly not related to the number of brain nicotinic receptors, unless nicotine-induced decreases in body temperature and locomotor activity are controlled by cortical [3H]-nicotine binding sites.