The effects of FK506, a specific calcineurin inhibitor, on methamphetamine-induced behavioral change and its sensitization in rats

Rationale: FK506 inhibits calcineurin activity, resulting in the inhibition of calcium-dependent intracellular processes. Recent studies have suggeste d that intracellular calcium is likely to be involved in methamphetamine (M AP)-induced locomotor activity and stereotyped behavior, and in the develop ment of sensitization to MAP. Objectives: We investigated the effects of FK 506 on MAP-induced behavioral changes and the development of sensitization in rats. Methods: In experiment 1, animals were administered IP 2 mg/kg FK5 06 or vehicle followed 10 min later by MAP (1, 2, 4 and 8 mg/kg, IP). Anoth er set of animals were administered FK506 (0.1, 2, 5 and 10 mg/kg) followed by 2 mg/kg MAP Locomotor activity and stereotyped behavior were assessed. In experiment 2, animals received repeated IP injections of 2 mg/kg MAP pre treated with 2 mg/kg FK506 or vehicle for 5 consecutive days. One week late r, rats were challenged with 1 mg/kg MAP. Results: Pretreatment with 2 mg/k g FK506 caused a rightward shift of the inverted U-shaped response curve of the locomotor activity induced by 1-8 mg/kg MAP The same pretreatment sign ificantly attenuated augmentation of the MAP-induced stereotyped behavior. FK506 at doses of 0.1-10 mg/kg dose-dependently inhibited the behavioral re sponse induced by 2 mg/kg MAP. Coadministration of 2 mg/kg FK506 with 2 mg/ kg MAP for 5 consecutive days resulted in significant suppression of the be havioral response to challenge with 1 mg/kg MAP. Conclusions: These results suggest that calcineurin plays an important role in MAP-induced behavioral changes and sensitization, especially the latter.