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

Summary Introduction We recently showed that a single high dose of methamphetamine (METH) induces a persistent frontal cortical monoamine depletion that is accompanied by helpless‐like behavior in mice. However, brain metabolic alterations underlying both neurochemical and mood alterations remain unknown. Aims Herein, we aimed at characterizing frontal cortical metabolic alterations associated with early negative mood behavior triggered by METH. Adult C57BL/6 mice were injected with METH (30 mg/kg, i.p.), and their frontal cortical metabolic status was characterized after probing their mood and anxiety‐related phenotypes 3 days postinjection. Results Methamphetamine induced depressive‐like behavior, as indicated by the decreased grooming time in the splash test and by a transient decrease in sucrose preference. At this time, METH did not alter anxiety‐like behavior or motor functions. Depolarization‐induced glucose uptake was reduced in frontocortical slices from METH‐treated mice compared to controls. Consistently, astrocytic glucose transporter (GluT1) density was lower in the METH group. A proton high rotation magic angle spinning (HRMAS) spectroscopic approach revealed that METH induced a significant decrease in N‐acetyl aspartate (NAA) and glutamate levels, suggesting that METH decreased neuronal glutamatergic function in frontal cortex. Conclusions We report, for the first time, that a single METH injection triggers early self‐care and hedonic deficits and impairs frontal cortical energetics in mice.