Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions

Rationale: Chronic methamphetamine (MA) abuse leads to dependence and symptoms of withdrawal after use has ceased. Negative mood states associated with withdrawal, as well as drug reinstatement, have been linked to drug-induced disruption of the hypothalamic-pituitary-adrenal (HPA) axis. However, effects of chronic MA exposure or acute MA exposure following withdrawal on neural activation patterns within brain regions that regulate the HPA axis are unknown. Objectives: In this study, neural activation patterns were assessed by quantification of c-Fos protein in mice exposed to different regimens of MA administration. Methods: (Experiment 1) Adult male mice were treated with MA (5 mg/kg) or saline once or once daily for 10 days. (Experiment 2) Mice were treated with MA or saline once daily for 10 days and following a 10-day withdrawal period were re-administered a final dose of MA or saline. c-Fos was quantified in brains after the final injection. Results: (Experiment 1) Compared to exposure to a single dose of MA (5 mg/kg), chronic MA exposure decreased the number of c-Fos expressing cells in the paraventricular hypothalamus, dorsomedial hypothalamus, central amygdala, basolateral amygdala, bed nucleus of the stria terminalis (BNST), and CA3 hippocampal region. (Experiment 2) Compared to mice receiving their first dose of MA, mice chronically treated with MA, withdrawn, and re-administered MA, showed decreased c-Fos expressing cells within the central and basolateral amygdala, BNST, and CA3. Conclusions: HPA axis-associated amygdala, extended amygdala, and hippocampal regions endure lasting effects following chronic MA exposure and therefore may be linked to stress-related withdrawal symptoms.