CHARACTERIZATION AND MODULATION OF ACUTE TOLERANCE TO NICOTINE IN MICE

Acute tolerance to the effects of nicotine is believed to play an impo rtant role in the development and maintenance of dependence to this dr ug. The objective of this study was to investigate and characterize th e development of acute tolerance to nicotine after systemic and intrat hecal administrations. Acute tolerance developed to several centrally mediated pharmacological effects of nicotine after systemic (motor coo rdination, body temperature, antinociception) and intrathecal (antinoc iception) injection of the drug. The appearance and the magnitude of a cute tolerance varied depending on the response measured. Development of acute tolerance to nicotine-induced hypothermia and motor impairmen t was blocked after intraperitoneal pretreatment with nimodipine. Simi larly, an intrathecal injection of nimodipine blocked the development of acute tolerance to nicotine-induced antinociception. On the other h and, intrathecal administration of calcium and thapsigargin enhanced t he acute tolerance to nicotine-induced antinociception. Characterizati on of the acute tolerance to nicotine in several animal models reveale d time and dose dependencies that are consistent with receptor-mediate d events. More importantly, acute tolerance was modulated by agents th at influence cellular calcium homeostasis.