Withdrawal from Fixed-Dose Injection of Methamphetamine Decreases Cerebral Levels of 3-Methoxy-4-hydroxyphenylglycol and Induces the Expression of Anxiety-Related Behavior in Mice
Withdrawal from Fixed-Dose Injection of Methamphetamine Decreases Cerebral Levels of 3-Methoxy-4-hydroxyphenylglycol and Induces the Expression of Anxiety-Related Behavior in Mice
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DOI：
10.1007/s11064-010-0132-4
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Takemura, Motohiko
中科院分区：
文献类型：
--
作者：
Kitanaka, Nobue;Kitanaka, Junichi;Takemura, Motohiko
已经提出了各种药物治疗方案来模拟大鼠甲基苯丙胺（METH）戒断期间观察到的烦躁状态，但在使用小鼠的实验中几乎没有建立。在雄性ICR小鼠中，使用固定剂量的METH注射方案（1.0或2.5mg/kg，i. p.，每天两次，连续10天）诱导在药物戒断5天后在高架十字迷宫中在开放臂中花费的时间显著减少。在递增剂量注射方案（0.2-2.0 mg/kg，i. p.，每日3次，共4天，总量：15 mg/kg/动物）或用渗透微型泵连续皮下给药（15或76 mg/kg METH，共2周），与对照动物相比，在药物戒断5天后未观察到显著的行为变化。在固定剂量注射和微型泵治疗方案中，在METH重复治疗期间观察到体重增加减少，但在递增剂量注射方案中未观察到。HPLC分析显示大脑3-甲氧基-4-羟基苯乙二醇（一种去甲肾上腺素代谢物）和去甲肾上腺素周转率水平显著降低，这可能归因于高架十字迷宫中焦虑相关行为的表达。这些观察结果表明，用固定剂量的METH处理的小鼠可以模拟在人类中由METH戒断诱导的烦躁状态中观察到的焦虑相关行为。
A variety of drug treatment regimens have been proposed to model the dysphoric state observed during methamphetamine (METH) withdrawal in rats, but little has been established in experiments using mice. In male ICR mice, a fixed-dose injection regimen of METH (1.0 or 2.5 mg/kg, i.p., twice daily for 10 consecutive days) induced a significant decrease in the time spent in open arms in an elevated plus maze after 5 days of drug abstinence. Under an escalating-dose injection regimen (0.2-2.0 mg/kg, i.p., 3 times daily for 4 days, total: 15 mg/kg/animal) or continuous subcutaneous administration with osmotic mini-pumps (15 or 76 mg/kg of METH for 2 weeks), no significant behavioral change was observed after 5 days of drug abstinence, compared with control animals. Reduced gains in body weight were observed during repeated treatment with METH in the fixed-dose injection and mini-pump treatment regimens, but not the escalating-dose injection regimen. HPLC analysis revealed significant decreases in the level of cerebral 3-methoxy-4-hydroxyphenylglycol, a norepinephrine metabolite, and norepinephrine turnover, which may be attributed to the expression of anxiety-related behavior in the elevated plus maze. These observations suggest that the mice treated with a fixed-dose of METH may model the anxiety-related behavior observed in the dysphoric state induced by METH withdrawal in humans.