Hypothalamic-pituitary-adrenal axis responsiveness to methamphetamine is modulated by gonadectomy in males

Sex differences in patterns of methamphetamine (MA) abuse have been reported with females (humans and rodents) showing an elevated addiction phenotype. Previous findings indicate MA-induced hypothalamic-pituitary-adrenal (HPA) axis activation is also sexually dimorphic with females exhibiting an elevated glucocorticoid release and differential neural activation patterns within HPA axis-associated brain regions. These effects may contribute to sex differences in abuse. To determine the role of gonadal hormones in mediating sex differences in MA-induced glucocorticoids, male and female C57BL/6J mice were gonadectomized or sham-operated, and following recovery, injected with MA (5mg/kg) and sacrificed 60min or 120min later. Blood was collected for corticosterone radioimmunoassay, and brains were used to assess c-Fos, and c-Fos co-localization with glucocorticoid receptor (GR). At 120min after MA injection, corticosterone levels were elevated in females compared to males and gonadectomy in males increased corticosterone to female levels. C-Fos was greater in females than males in the medial preoptic area, bed nucleus of the stria terminalis, basolateral amygdala, and central amygdala. Female gonadectomy had little effect on either corticosterone or c-Fos, while male gonadectomy elevated c-Fos in the central amygdala. Relative to sham males, gonadectomized males also showed decreased c-Fos/GR cell number in the CA3 hippocampal area compared to sham males, indicating a central site for attenuated negative feedback. Together, these findings indicate that androgens regulate MA-induced activation of the HPA axis, potentially by enhancing negative feedback. These sex and gonadal hormone effects on the HPA axis may contribute to sex differences in MA abuse patterns.