Acute tolerance to the effects of nicotine is believed to play an important role in the development and maintenance of dependence to this drug. The objective of this study was to investigate and characterize the development of acute tolerance to nicotine after systemic and intrathecal administrations. Acute tolerance developed to several centrally mediated pharmacological effects of nicotine after systemic (motor coordination, body temperature, antinociception) and intrathecal (antinociception) injection of the drug. The appearance and the magnitude of acute tolerance varied depending on the response measured. Development of acute tolerance to nicotine-induced hypothermia and motor impairment was blocked after intraperitoneal pretreatment with nimodipine. Similarly, an intrathecal injection of nimodipine blocked the development of acute tolerance to nicotine-induced antinociception. On the other hand, intrathecal administration of calcium and thapsigargin enhanced the acute tolerance to nicotine-induced antinociception. Characterization of the acute tolerance to nicotine in several animal models revealed time and dose dependencies that are consistent with receptor-mediated events. More importantly, acute tolerance was modulated by agents that influence cellular calcium homeostasis.