Chronic Methamphetamine Exposure Attenuates Neural Activation in Hypothalamic-Pituitary-Adrenal Axis-Associated Brain Regions in a Sex-specific Manner

Sex differences in methamphetamine (MA) abuse and consequences of MA have been reported with females showing an increased addiction phenotype and withdrawal symptoms. One mechanism through which these effects might occur is via sex-specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis and its associated brain regions. In this study, mice were administered MA (5 mg/kg) or saline for 10 consecutive days. During early withdrawal, anxiety-like behaviors were assessed in the open field, light/dark box, and elevated plus maze. At ten days of withdrawal, mice were injected with a final dose of MA (5 mg/kg) or saline. Chronic MA did not alter anxiety-like behaviors or corticosterone responses to a final dose of MA, although females showed elevated corticosterone responses compared to males. Chronic MA attenuated final MA-induced c-Fos in both sexes in the paraventricular hypothalamus (PVH), bed nucleus of the stria terminalis (BNST), cingulate cortex, central and basolateral amygdala. In CA1 and CA3 hippocampal areas, c-Fos attenuation by chronic MA occurred only in females. Within the PVH, final MA injection increased c-Fos to a greater extent in females compared to males regardless of prior MA exposure. Dual-labeling of c-Fos with glucocorticoid receptor revealed a specific attenuation of neural activation within this cell type in the PVH, central and basolateral amygdala, and BNST. Together these findings demonstrate that chronic MA can suppress subsequent activation of HPA axis-associated brain regions and cell phenotypes. Further, in select regions this reduction is sex-specific. These changes may contribute to reported sex differences in MA abuse patterns.