Glutamatergic Neurometabolites during Early Abstinence from Chronic Methamphetamine Abuse

Abstract

Background:The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon.Methods:We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment.Results:In the methamphetamine group, small but significant (5–15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex.Conclusions:Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery.

Methamphetamine Induces Anhedonic‐Like Behavior and Impairs Frontal Cortical Energetics in Mice

“…In our studies, we only observed significant changes in glutamate and NAA levels, suggesting that our model causes less severe metabolic alterations. Glutamate homeostasis was also proven dysregulated in cortex in rats following METH self‐administration , and in humans during early abstinence from chronic METH abuse . Our metabolic data in mice are consistent with previous data reporting energy metabolism dysfunction in frontal cortices from rats using different METH paradigms .…”

Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity

“…Similar results were observed for Glx levels in the PCC, precuneus, and right inferior frontal cortex (O’Neill et al, 2015), but not glutamate levels in the occipital cortex (Sailasuta et al, 2010). Moreover, lower PCC Glx levels were correlated with more years of methamphetamine abuse (O’Neill et al, 2015).…”

“…Similar results were observed for Glx levels in the PCC, precuneus, and right inferior frontal cortex (O’Neill et al, 2015), but not glutamate levels in the occipital cortex (Sailasuta et al, 2010). Moreover, lower PCC Glx levels were correlated with more years of methamphetamine abuse (O’Neill et al, 2015). Glx concentrations in the frontal cortex were also reduced in addicted individuals with ≤ 1 month of abstinence (but not after longer abstinence), and reduced Glx levels were correlated with fewer days of abstinence and higher craving (Ernst and Chang, 2008).…”

“…A notable exception to this pattern was seen in some studies that showed positive correlation of glutamate levels with years of use. These findings suggest that the extent of dysregulation may vary with length of abuse (O’Neill et al, 2015). Interestingly, acute withdrawal (and possibly the number of withdrawals) instead tended to correlate with higher brain glutamate associated with the use of some substances (especially alcohol and opiates, which perhaps not coincidentally produce the most severe withdrawal syndromes).…”

Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment

“…Studies in autopsied human brains determined that three DAergic markers (DA, DAT, and TH, but not 3,4-dihydroxyphenylalanine decarboxylase and VMAT2) are decreased in the caudate, putamen, and nucleus accumbens in METH users compared with matched controls; DA deficit was more pronounced in the cognition-mediating caudate than in the motor activity-mediating putamen (Wilson et al, 1996;Moszczynska et al, 2004;Kitamura et al, 2007). In vivo imaging techniques [positron emission tomography (PET) and magnetic resonance imaging] revealed reduced density of DAT (McCann et al, 1998;Volkow et al, 2001cVolkow et al, ,d, 2015Sekine et al, 2003), dopamine D 2 receptor (Volkow et al, 2001a), VMAT2 (Johanson et al, 2006;Kitamura et al, 2007) [see Boileau et al (2008Boileau et al ( , 2016], SERT (Sekine et al, 2006;Kish et al, 2009), and GLU1glutamine (Ernst and Chang, 2008;O'Neill et al, 2014) in abstinent (weeks to months) human abusers of METH. The DAT was decreased in the orbitofrontal cortex, dorsolateral prefrontal cortex, dorsal striatum, nucleus accumbens, and amygdala, whereas the SERT was decreased in the orbitofrontal and occipital cortices, midbrain, thalamus, dorsal striatum, and cerebellum.…”