Impact of nicotine's autonomic effect on nicotine's discriminative stimulus

Purpose: As the leading cause of preventable death, tobacco smoking has inspired years of research into the mechanisms of addiction and pharmacological targets for smoking cessation. Nicotine, an active psychostimulant in tobacco, activates the brain's reward system and drives the addiction to smoking via dopaminergic neurons. Although some studies have suggested that the autonomic effects of psychostimulants may independently serve as cues for the release of dopamine in the brain, it has not been demonstrated behaviorally. A previous locomotor activity study in our lab showed that hexamethonium, a brain-impermeable nicotinic receptor antagonist blocks the locomotor stimulant effects of nicotine in mice. To further assess the impact of the autonomic effects of nicotine on behavior, we conducted a nicotine discrimination study. In this study, we subtracted nicotine’s autonomic effects from the overall subjective effect by using hexamethonium. Method: Using a two-lever drug discrimination operant chamber, six male Sprague-Dawley rats were trained to discriminate 0.1 mg/kg nicotine tartrate from saline by lever pressing. Subcutaneous injections of nicotine or saline for training occurred five minutes prior to the start of the training session. On test days, rats received hexamethonium (1, 2.5, 5, 10, 25, or 50 mg/kg) intraperitoneally 25 minutes prior to subcutaneous administration of nicotine at the training dose (0.1 mg/kg). Percentage of drug lever responses and response rate were recorded to measure antagonism and analyzed using repeated measures ANOVA. Results: Within the dose range of 10-50 mg/kg, hexamethonium partially antagonized nicotine’s discriminative stimulus effect by reducing the percentage nicotine-lever response to 42% of nicotine’s maximum discriminative stimulus effect. Conclusion: Although full antagonism was not observed, the partial antagonism of nicotine’s discriminative stimulus by a solely peripherally-acting antagonist shows that the autonomic effects of nicotine are a component of the overall subjective effect of nicotine that influences behavior and can be explored as a target for smoking cessation. More direct assays of reward, such as the self-administration assay will be required to affirm the autonomic contributions to the neurobiology of nicotine addiction.