The discriminative stimulus and reinforcing effects of nicotine in humans following nicotine pretreatment

Smokers often report that the first cigarette of the day is the most reward ing, and subsequent smoking is less rewarding. Reduction in smoking enjoyme nt later in the day may be related to acute tolerance to the discriminative stimulus effects of nicotine. We examined changes in nicotine discriminati on behaviour in humans as a function of acute nicotine pretreatment, Male a nd female dependent smokers (n = 15) were initially trained to discriminate 20 mug/kg nicotine by nasal spray from placebo (0 mug/kg) without nicotine pretreatment. They then were tested on generalization of discrimination ac ross a range of spray doses from 0-20 mug/kg following pretreatment with pl acebo, moderate dose (14-21 mg) or high dose (28-42 mg) transdermal nicotin e. Generalization testing involved both two- and three-response ('novel' op tion) quantitative procedures. Subjects also engaged in a self-administrati on phase at the end of each session, involving choices between nicotine (20 mug/kg) and placebo spray. Nicotine pretreatment significantly attenuated nicotine-appropriate responding at higher nicotine spray doses, suggesting acute tolerance, but only in women, Similar results were seen for subjectiv e 'head rush', suggesting this effect may be related to discrimination beha viour in women. However, nicotine pretreatment also increased novel-appropr iate responding, especially in men, following intermediate generalization d oses, suggesting qualitatively different stimulus effects. Although differe nces were not significant, nicotine self-administration tended to be invers ely associated with nicotine pretreatment dose in men but not in women. The se results only modestly support the notion of acute tolerance to the discr iminative stimulus effects of nicotine, and even then only in women and not in men. (C) 2001 Lippincott Williams & Wilkins.