CHRONIC AND ACUTE TOLERANCE TO SUBJECTIVE, BEHAVIORAL AND CARDIOVASCULAR EFFECTS OF NICOTINE IN HUMANS

Understanding tolerance to effects of nicotine in humans may elucidate processes involved in the onset and maintenance of tobacco dependence . Subjective, behavioral and cardiovascular responses to nicotine were examined as a function of past history of nicotine exposure (i.e., sm okers vs. nonsmokers, chronic tolerance) and of immediately preceding nicotine exposure (acute tolerance). Dose-effect relationships between nicotine (0-20 mu g/kg via measured-dose nasal spray) and each respon se were determined in male and female smokers (n = 17) and nonsmokers (n = 18), with different doses presented on different days. Each day, subjects also received a challenge dose of 20 mu g/kg 30 min after the previous dosing to assess acute tolerance. Plasma nicotine concentrat ions were 30% lower in nonsmokers compared with smokers and analyses w ere adjusted to control for this difference. Results showed significan t changes in nearly all responses as a function of nicotine dose. Dose -effect curves were shifted to the right or dampened in smokers relati ve to nonsmokers for most subjective and some behavioral responses, co nsistent with chronic tolerance, but there was less evidence of chroni c tolerance to other behavioral effects or to cardiovascular responses . A pattern of acute tolerance generally similar to that of chronic to lerance was observed across response domains (i.e., clear acute tolera nce to subjective measures but less to behavioral or cardiovascular ef fects). These results support the notions that regular use of nicotine is associated with chronic functional tolerance and that repeated nic otine exposure during a single episode produces acute tolerance. A sim ilar pattern of chronic vs. acute tolerance suggests similarity of mec hanisms responsible for both ''types'' of tolerance. However, variabil ity in tolerance magnitude across subjective, behavioral and cardiovas cular response domains indicates that different mechanisms may be resp onsible for these different effects of nicotine.