Tolerance to nicotine in mice lacking α7 nicotinic receptors

Rationale: Previous studies have suggested that a knockout of the gene coding for alpha 7 nicotinic receptor subunits influences the behaviour of undrugged mice but not the acute effect of nicotine on locomotor activity. Objectives: The present studies extend these observations to nicotine tolerance assessed by means of schedule-controlled behaviour. Methods: Groups of alpha 7(-/-) and alpha 7(+/+) mice were trained to press levers under an FR20 schedule of food reinforcement. The acute response rate-depressant effects of nicotine were determined in both genotypes and the mice were then subdivided into groups treated daily with nicotine ( 1.2 mg/kg/day) or saline. After 39 days of exposure to this regimen, the dose-response curves were re-determined. Results: Knockout of the alpha 7 gene had no consistent effect on the lever-pressing behaviour of undrugged mice and did not influence the acute, dose-related, response rate-depressant effect of nicotine ( 0.2-1.2 mg/kg). When dose-response curves for nicotine ( 0.4-2.0 mg/kg) were re-determined after daily dosing with the drug, both wild-type and knockout mice developed similar tolerance to nicotine, as shown by similar to 2.5-fold shifts to the right of the dose-response curves. Conclusions: Nicotinic receptors containing the alpha 7 subunit do not play a significant role in the regulation of the lever-pressing behaviour studied or in the acute behavioural depressant effect of nicotine and the development of tolerance to that effect. Such results contrast with previous reports suggesting profound impairments mice.