Glial Dysfunction in Abstinent Methamphetamine Abusers

Abstract

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized 13 C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects (P > 0.1). However, glial 13 C-bicarbonate production rate from [1-13 C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamineaddicted women (methamphetamine 0.04 lmol/g per min (N = 5) versus controls 0.11 lmol/g per min (N = 5), P = 0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous 13 C MRS methods may determine 'cause and effect' between glial failure and neuronal injury.

Swift Acetate Glial Assay (SAGA): An accelerated human 13C MRS brain exam for clinical diagnostic use

“…This proportion of glial metabolism as a fraction of the total cerebral metabolic rate is comparable to that previously established for [1- 13 C] acetate by Bluml [5] or more recently from this Laboratory [19] and for [2- 13 C] acetate by Lebon [20]. In a recently completed study [19], we demonstrate that both the higher value for human glial metabolic rate and the lower value can be generated in the same subjects depending on the method of analysis employed [19, p.6].…”

Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways

“…This microgliosis persisted in the brains of METH addicts even after two years of abstinence (Sekine et al 2008), suggesting that microgliosis may participate in long-term neurological effects of the drug (Cadet and Bisagno 2014), including parkinsonism (Callaghan et al 2012) that involves neuroinflammatory processes (Long-Smith et al 2009). Further evidence for the participation of glial cells in the pathological substrate of METH addiction was provided by a recent imaging study showing that METH-dependent women exhibited severe reductions in glial tricarboxylic acid cycle rate (Sailasuta et al 2010). …”

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

“…In an earlier report the analog of “ecstasy,” 3,4-methylenedioxyethamphetamine (MDE) and methamphetamine were shown to induce cortical hypometabolism and cerebellar hypermetabolism (Gouzoulis-Mayfrank et al, 1999). More recently, Sailasuta and colleagues measured glial metabolic flux rate in frontal brain structures and observed a 50% reduction in the oxidative rate in recovering brain (at least seven days abstinent) following methamphetamine abuse (Sailasuta et al, 2010). Methamphetamine exposure also significantly inhibits glucose uptake by neurons and astrocytes, and neurons appear to be more sensitive to methamphetamine's effects on glucose uptake than astrocytes.…”