Tolerance to nicotine in mice lacking alpha7 nicotinic receptors

Abstract

Rationale: Previous studies have suggested that a knockout of the gene coding for alpha7 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 alpha7-/- and alpha7+/+ 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 alpha7 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 approximately 2.5-fold shifts to the right of the dose-response curves.

Conclusions: Nicotinic receptors containing the alpha7 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 in sensitivity to nicotine in nicotinic receptor beta2-/- mice.