Chronic nicotine and locomotor activity: influences of exposure dose and test dose

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Abstract
Repeated exposure to nicotine increases both the number of central nicotinic receptors and the behavioral stimulant effect of nicotine. In the present experiments, the behavioral response to nicotine was examined in photocell activity cages. Groups of rats were tested using doses from 0.1 to 1.6 mg/kg both before and after all rats were exposed for 5 days to a common dose of 0.2 mg/kg/day. Prior to the 5-day exposure, there was a dose-related stimulant response to nicotine, with a maximum response seen at 0.4 mg/kg. After the 5-day exposure, the dose-effect curve was shifted upward, so that greater stimulation was produced at each test dose of nicotine. Other groups of rats were exposed for 5 days to doses of nicotine ranging from 0.01 to 0.30 mg/kg/day. On the 6th day all rats received a common test dose of 0.2 mg/kg and their response was measured in the activity cages. In animals exposed to 0.01 mg/kg/day, the test day response was not different from saline controls, but the groups exposed to higher doses showed increased stimulation in response to the common test dose. Measurements of nicotinic receptor binding using [3H]-acetylcholine found increased binding in groups receiving 0.03 mg/kg/day or more, but not in the group that received 0.01 mg/kg/day. The correspondence between the doses that increase behavioral stimulant reactions to nicotine and the doses that increase nicotinic binding suggest that increased receptor numbers may be responsible for the increased behavioral stimulation. However, rats given high doses (1.6 mg/kg, twice per day) did not show increased behavioral stimulation to a test dose of 0.2 mg/kg. In those rats, receptor binding was increased even more than in rats exposed to lower chronic doses. Several hypotheses are offered for this apparent discrepancy.