ALTERED BEHAVIORAL SENSITIVITY OF CA2-MODULATING DRUGS AFTER CHRONIC NICOTINE ADMINISTRATION IN MICE()

Numerous studies have demonstrated that tolerance develops to the phys iological and behavioral effects of nicotine in animals after chronic administration of the drug. However, the mechanisms underlying toleran ce to nicotine are not well known. There are several lines of evidence which support a role for Ca2+ in nicotine's acute pharmacological eff ects. 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 Ca2+ modulating drugs after systemic ( BAY K 8644: l-5-nitro-4-[2-(trifluromethyl)-phenyl]-3-pyridine carboxy lic acid methyl ester) and intrathecal administration (BAY K 8644, Ca2 + and thapsigargin) in nicotine-tolerant mice. The ability of BAY K 86 44 to induce motor impairment and hypomotility after i.p. injection wa s decreased in nicotine-tolerant mice. Ln addition, tolerance to Ca2thapsigargin, and BAY K 8644-induced antinociception after i.t. inject ion also developed in nicotine-tolerant mice. ED(50) values for BAY K 8644 and thapsigargin increased from 3.7 to 12 mu g/mouse and 0.83 to 19.7 mu g/mouse, respectively. The greatest tolerance developed to the effects of thapsigargin with an ED(50) value that increased from 0.83 to 20 mu g Furthermore, chronic nicotine injections did not alter [H- 3]nitrendipine binding in the brain. These results suggest the involve ment of Ca2+-dependent mechanisms in nicotine tolerance in mice. (C) 1 997 Elsevier Science B.V.