Influence of kinetics of nicotine administration on tolerance development and receptor levels

Nicotine was administered intravenously to DBA mice through cannulae implanted in the jugular veins. Five groups of animals were treated: a control group which received saline and four nicotine treatment groups. All of the nicotine treatment groups received a dose of 4.0 mg/kg/hr. The first group received continuous infusion, the second group received 1 mg/kg pulses four times an hour, the third group received 2 mg/kg pulses twice an hour, and the fourth group received 4 mg/kg pulses once an hour. After a 10-day treatment period, the animals were tested for tolerance to an acute intraperitoneal administration of nicotine. Tolerance was measured using a test battery composed of the following tests: respiratory rate, acoustic startle response, Y-maze crosses and rears, heart rate, and body temperature. Mice from each of the four nicotine treatment groups were tolerant to the acute effect of nicotine, but the extent of tolerance varied among the groups as follows: continuous infusion less than 1 mg/kg pulses four times/hr less than 2 mg/kg pulses twice/hr less than 4 mg/kg pulse once/hr. Chronic nicotine infusion resulted in significant increases in the binding of L-[3H]nicotine in all six brain regions assayed and in significant increases in the binding of alpha-[125I]bungarotoxin binding in cerebral cortex and hippocampus. All increases in binding resulted from increases in Bmax for these ligands. In contrast to the effects observed for tolerance development, the increases in [3H]nicotine binding were not significantly affected by the kinetics of nicotine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)