The effects of FK506, a specific calcineurin inhibitor, on methamphetamine-induced behavioral change and its sensitization in rats.
BACKGROUND
FK506 inhibits calcineurin activity, resulting in the inhibition of calcium-dependent intracellular processes. Recent studies have suggested that intracellular calcium is likely to be involved in methamphetamine (MAP)-induced locomotor activity and stereotyped behavior, and in the development of sensitization to MAP.


OBJECTIVE
We investigated the effects of FK506 on MAP-induced behavioral changes and the development of sensitization in rats.


METHODS
In experiment 1, animals were administered IP 2 mg/kg FK506 or vehicle followed 10 min later by MAP (1, 2, 4 and 8 mg/kg, IP). Another 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 pretreated with 2 mg/kg FK506 or vehicle for 5 consecutive days. One week later, rats were challenged with 1 mg/kg MAP.


RESULTS
Pretreatment with 2 mg/kg 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 significantly attenuated augmentation of the MAP-induced stereotyped behavior. FK506 at doses of 0.1-10 mg/kg dose-dependently inhibited the behavioral response 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 behavioral 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.
Tsukamoto
T
T
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 20-1 Handayama 1-chome, Hamamatsu, Shizuoka 431-3192, Japan.
Iyo
M
M
Tani
K
K
Sekine
Y
Y
Hashimoto
K
K
Ohashi
Y
Y
Suzuki
K
K
Iwata
Y
Y
Mori
N
N
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D000697:Central Nervous System Stimulants; D007166:Immunosuppressive Agents; D008694:Methamphetamine; D019703:Calcineurin; D016559:Tacrolimus