Contrasting dose-dependent effects of acute intravenous methamphetamine on lateral hypothalamic extracellular glucose dynamics in male and female rats

Glucose is the brain's primary energetic resource. The brain's use of glucose is dynamic, balancing delivery from the neurovas-culature with local metabolism. Although glucose metabolism is known to differ in humans with and without methamphetamine use disorder (MUD), it is unknown how central glucose regulation changes with acute methamphetamine experience. Here, we determined how intravenous methamphetamine regulates extracellular glucose levels in a brain region implicated in MUD -like behavior, the lateral hypothalamus (LH). We measured extracellular LH glucose in awake adult male and female drug-naive Wistar rats using enzyme-linked amperometric glucose biosensors. Changes in LH glucose were monitored during a single ses-sion after: 1) natural nondrug stimuli (novel object presentation and a tail-touch), 2) increasing cumulative doses of intravenous methamphetamine (0.025, 0.05, 0.1, and 0.2 mg/kg), and 3) an injection of 60 mg of glucose. We found second-scale fluctua-tions in LH glucose in response to natural stimuli that differed by both stimulus type and sex. Although rapid, second-scale changes in LH glucose during methamphetamine injections were variable, slow, minute-scale changes following most injections were robust and resulted in a reduction in LH glucose levels. Dose and sex differences at this timescale indicated that female rats may be more sensitive to the impact of methamphetamine on central glucose regulation. These findings suggest that the effects of MUD on healthy brain function may be linked to how methamphetamine alters extracellular glucose regulation in the LH and point to possible mechanisms by which methamphetamine influences central glucose metabolism more broadly.NEW & NOTEWORTHY Enzyme-linked glucose biosensors were used to monitor lateral hypothalamic (LH) extracellular fluctua-tions during nondrug stimuli and intravenous methamphetamine injections in drug-naive awake male and female rats. Second -scale glucose changes occurred after nondrug stimuli, differing by modality and sex. Robust minute-scale decreases followed most methamphetamine injections. Sex differences at the minute-scale indicate female central glucose regulation is more sensi-tive to methamphetamine effects. We discuss likely mechanisms underlying these fluctuations, and their implications in metham-phetamine use disorder.