Adaptation of Brain Glutamate Plus Glutamine during Abstinence from Chronic Methamphetamine Use

Abstract

Methamphetamine (METH) is a stimulant drug that is toxic primarily to dopaminergic and serotonergic neurons, and may lead to inflammatory changes in the brain. Additionally, the glutamatergic system is altered following METH exposure. Therefore, concentrations of brain glutamate+glutamine (GLX) were assessed during abstinence from chronic METH abuse. 25 subjects with a history of METH-dependence (age 31.8 ± 7.4 years, 14 females and 11 males) and 28 control subjects without a history of drug abuse (age 32.6 ± 8.8 years, 14 females) were enrolled. Twelve of the METH subjects were followed and rescanned 5-months later. METH users had used the drug 5.9 ± 1.7 times / week, for 109 ± 69 months, and had been abstinent for 2.1 ± 3.0 months. GLX was measured in the basal ganglia and frontal gray and white matter, using proton magnetic resonance spectroscopy. While overall GLX concentrations at baseline were similar between METH and control subjects, METH users with ≤ 1 month of abstinence showed reduced frontal gray matter GLX (p=0.01). Time of abstinence correlated positively with GLX in frontal gray (p<0.0001) and white matter (p=0.03). After 5-months, changes in frontal gray matter GLX showed a trend to correlate inversely with duration of abstinence (p=0.07). Subjects with craving symptoms had lower frontal gray matter GLX than those without craving (−8%, p=0.05). These findings suggest dynamic abnormalities in brain GLX in recently abstinent methamphetamine users, with a depletion of the glutamatergic system in METH users within the first two months of abstinence, and some normalization during prolonged abstinence. Since craving may contribute to relapse, medications that normalize GLX may minimize craving in METH users.

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

“…Our study demonstrated that melatonin protects glial cells against ER stress-induced cell death. Recent studies have demonstrated that METH is a neurotoxic drug that can induce neuronal (Ajjimaporn et al, 2005;Zhu et al, 2006;Deng et al, 2007) and glial cell death by several pathways, including oxidative stress (Riddle et al, 2006;Tocharus et al, 2008), mitochondrial dysfunction (Brown et al, 2005;Jumnongprakhon et al, 2014), excitotoxicity (Staszewski and Yamamoto, 2006;Ernst and Chang, 2008), inflammatory responses (Jumnongprakhon et al, 2015), and ER stress (Shah and Kumar, 2016). We have previously reported that exposure to METH causes an overproduction of ROS (Tocharus et al, 2010) that leads to oxidative stress.…”

Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging

“…Moreover, the NAA/Cr ratio in the ACC is positively correlated with attentional control (Salo et al, 2007) and negatively correlated with years of methamphetamine use (Nordahl et al, 2005) among methamphetamine users, and appears to recover, albeit slowly, with extended abstinence (Nordahl et al, 2005; Salo et al, 2011). Higher levels of choline (Cho) metabolites have been found in frontal regions and the basal ganglia of methamphetamine users than non-users (Ernst et al, 2000; Nordahl et al, 2002; Nordahl et al, 2005; Sekine et al, 2002), and evidence that the level of frontal glutamate is increased (Ernst and Chang, 2008; Sailasuta et al, 2010) implicates glutamate excitotoxicity as a potential contributing factor. Inverse correlations between months of abstinence and Cho/Cr and Cho/NAA ratios in the ACC suggest that some recovery is possible after prolonged abstinence (Nordahl et al, 2005).…”

Structural neuroimaging in polysubstance users

“…We are aware of only one truly longitudinal structural MRI study in psychostimulant users; it involved methamphetamine abusers over 5 months of abstinence [20]. In numerous serial studies of abstinent alcoholics, we and others showed substantial neurobiological, including structural and cognitive recovery with abstinence [4, 5, 21].…”