Tsukamoto T, Iyo M, Tani K, Sekine Y, Hashimoto K, Ohashi Y, Suzuki K, Iwata Y, Mori N
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 20-1 Handayama 1-chome, Hamamatsu, Shizuoka 431-3192, Japan.
Psychopharmacology (Berl). 2001 Nov;158(2):107-13. doi: 10.1007/s002130100870.
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.
We investigated the effects of FK506 on MAP-induced behavioral changes and the development of sensitization in rats.
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.
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.
These results suggest that calcineurin plays an important role in MAP-induced behavioral changes and sensitization, especially the latter.
FK506可抑制钙调神经磷酸酶的活性，从而抑制依赖钙的细胞内过程。最近的研究表明，细胞内钙可能参与甲基苯丙胺（MAP）诱导的运动活性和刻板行为，以及对MAP的敏化作用的发展。
我们研究了FK506对MAP诱导的大鼠行为变化和敏化作用发展的影响。
在实验1中，给动物腹腔注射2mg/kg FK506或赋形剂，10分钟后再腹腔注射MAP（1、2、4和8mg/kg）。另一组动物先给予FK506（0.1、2、5和10mg/kg），然后给予2mg/kg MAP。评估运动活性和刻板行为。在实验2中，动物连续5天接受腹腔注射2mg/kg FK506或赋形剂预处理后再注射2mg/kg MAP。一周后，用1mg/kg MAP对大鼠进行激发试验。
用2mg/kg FK506预处理导致1-8mg/kg MAP诱导的运动活性倒U形反应曲线向右移动。相同的预处理显著减弱了MAP诱导的刻板行为的增强。0.1-10mg/kg剂量的FK506剂量依赖性地抑制2mg/kg MAP诱导的行为反应。连续5天同时给予2mg/kg FK506和2mg/kg MAP可显著抑制对1mg/kg MAP激发试验的行为反应。
这些结果表明，钙调神经磷酸酶在MAP诱导的行为变化和敏化作用中起重要作用，尤其是在后者中。
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