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

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.