Role of corticosterone in altered neurobehavioral responses to acute stress in a model of compromised hypothalamic-pituitary-adrenal axis function.

An organism's capacity to cope with stressful experiences is dependent on its ability to appropriately engage central and peripheral systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, to adapt to changing environmental demands. The HPA axis is a primary neuroendocrine mediator of neural and behavioral responses to stress, and dysfunction of this system is linked to increased risk for developing mental health disorders such as depression, anxiety, and post-traumatic stress disorder. However, the mechanisms by which dysregulated HPA function results in abnormal behavioral responses to stress are poorly understood. Here, we tested how corticosterone (CORT)-induced HPA axis disruption affects behavioral responses to stress in male C57BL/6 N mice, and probed correlates of these behaviors in the brain. We show that chronic HPA disruption blunts acute stress-induced grooming and rearing behaviors in the open field test, effects which were accompanied by decreased FOS immunoreactivity in the paraventricular nucleus of the hypothalamus (PVH) and paraventricular nucleus of the thalamus (PVT). Blockade of CORT secretion with metyrapone injection prior to acute stress did not recapitulate the effects of chronic HPA disruption on open field behavior, and acute CORT replacement did not rescue normal behavioral stress responses following chronic HPA disruption. This suggests that under acute conditions, CORT is not necessary for these responses normally, nor sufficient to rescue the deficits of chronic HPA dysregulation. Together, these findings support the hypothesis that chronic HPA dysregulation causes adaptation in stress-related brain circuits and demonstrate that these changes can influence an organism's behavioral response to stress exposure.

Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo.

Functional interactions between glucocorticoids and the endocannabinoid system have been repeatedly documented; yet, to date, no studies have demonstrated in vivo that glucocorticoid hormones regulate endocannabinoid signaling. We demonstrate that systemic administration of the glucocorticoid corticosterone (3 and 10 mg/kg) resulted in an increase in the tissue content of the endocannabinoid N-arachidonylethanolamine (AEA) within several limbic structures (amygdala, hippocampus, hypothalamus), but not the prefrontal cortex, of male rats. Tissue AEA content was increased at 10min and returned to control 1h post-corticosterone administration. The other primary endocannabinoid, 2-arachidonoylglycerol, was found to be elevated by corticosterone exclusively within the hypothalamus. The rapidity of the change suggests that glucocorticoids act through a non-genomic pathway. Tissue contents of two other N-acylethanolamines, palmitoylethanolamide and oleolyethanolamide, were not affected by corticosterone treatment, suggesting that the mechanism of regulation is neither fatty acid amide nor N-acylphosphatidylethanolamine phospholipase D. These data provide in vivo support for non-genomic steroid effects in mammals and suggest that AEA is a mediator of these effects.