Numerous studies have demonstrated that tolerance develops to the physiological and behavioral effects of nicotine in animals after chronic administration of the drug. However, the mechanisms underlying tolerance to nicotine are not well known. There are several lines of evidence which support a role for Ca2+ in nicotine's acute pharmacological effects. The objective of the study was to determine whether Ca2+ plays a role in the development of tolerance to nicotine by investigating the behavioral activity of several Ca(2+)-modulating drugs after systemic (BAY K 8644: (+/-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluromethyl)-pheny l] -3-pyridine carboxylic acid methylester) and intrathecal administration (BAY K 8644, Ca2+ and thapsigargin) in nicotine-tolerant mice. The ability of BAY K 8644 to induce motor impairment and hypomotility after i.p. injection was decreased in nicotine-tolerant mice. In addition, tolerance to Ca2+, thapsigargin, and BAY K 8644-induced antinociception after i.t. injection also developed in nicotine-tolerant mice. ED50 values for BAY K 8644 and thapsigargin increased from 3.7 to 12 micrograms/mouse and 0.83 to 19.7 micrograms/mouse, respectively. The greatest tolerance developed to the effects of thapsigargin with an ED50 value that increased from 0.83 to 20 micrograms. Furthermore, chronic nicotine injections did not alter [3H]nitrendipine binding in the brain. These results suggest the involvement of Ca(2+)-dependent mechanisms in nicotine tolerance in mice.