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

Abstract

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.

Methamphetamine abstinence induces changes in μ-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype

“…Although METH withdrawal did not induce memory impairments, or depressive-like behaviors in our mouse model, anxiety-like symptoms were observed, including decreased open-arm entries in the EPM and increased defecation during the FST session, which has been previously associated with measures of anxiety (Walf and Frye, 2007) and emotionality (Craft et al, 2010;Marti and Armario, 1993) respectively. These findings are in line with previous studies showing anxiety-like symptoms following withdrawal from METH self-administration (Nawata et al, 2012) and following a steady-dose injection regimen of METH (Kitanaka et al, 2010) in rodents, and anxiety traits in METH-abstinent individuals (London et al, 2004), highlighting the translational value of our model and a direct link between METH abstinence and the emergence of a negative emotional state.…”

Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency

“…Furthermore, no marked, reproducible changes in behaviour were induced by prior METH treatment, in agreement with several reports that depressive-like behaviours are generally only observable 24-48 h after withdrawal from similar chronic METH doses [10,11] (but see also [12]). Specifically, there were no significant overall differences in saccharin preference between treatment groups and genotypes at each of the three time points studied (3 way ANOVAs for each time point, main effects of treatment, all p [ 0.05; main effects of genotype, all p [ 0.05; treatment 9 genotype, treatment 9 cohort, and genotype 9 cohort interactions, all p [ 0.05).…”

“…Behavioural despair was examined during the critical 48 h withdrawal period as previous reports suggest this measure is perhaps the most sensitive for measuring behavioural changes at this time [10]. However, it would be of interest to test whether Rln3/ Rxfp3 deletion renders mice more or less sensitive to other types of behavioural change (such as anxiety-like behaviour in the elevated plus maze or light/dark box) during this 48 h period [10][11][12].…”

“…Animals were tested in an elevated plus maze on withdrawal day 5, as a previous study detected a significant increase in anxiety-like behaviour in mice using this paradigm after 5 days of drug abstinence [12]. The apparatus consisted of four arms (each 30 cm long 9 6 cm wide) extending from a central square (6 9 6 cm), elevated 39 cm off the ground.…”

“…Following relatively low to moderate chronic METH doses, monoamines can be depleted from presynaptic terminals and this effect is compounded by down-regulation of postsynaptic receptors, resulting in markedly reduced monoamine signalling within limbic and/or hypothalamic brain regions such as the amygdala, hippocampus, septum and paraventricular nucleus [7][8][9]. These decreases have been associated with a range of related behavioural symptoms in animals, including depressive-like behaviours (such as 'behavioural despair' in mice) that are detected within 2 days of withdrawal [10,11], and anxiety-like behaviours, observed after 5 days of drug abstinence [12].…”