Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice

Limbic endocannabinoid signaling is known to be sensitive to chronic stress; however, studies investigating the impact of prolonged exposure to glucocorticoid hormones have been limited by the concurrent exposure to the stress of daily injections. The present study was designed to examine the effects of a noninvasive approach to alter plasma corticosterone (CORT) on the endocannabinoid system. More precisely, we explored the effects of a 4-week exposure to CORT dissolved in the drinking water of mice (100 μg/ml) and measured cannabinoid CB ₁ receptor binding, endocannabinoid content, activity of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH), and mRNA expression of both the CB ₁ receptor and FAAH in both the hippocampus and amygdala. Our data demonstrate that CORT decreases CB ₁ receptor binding site density in both the hippocampus and amygdala and also reduced anandamide (AEA) content and increased FAAH activity within both structures. These changes in both CB ₁ receptor binding and FAAH activity were not accompanied by changes in mRNA expression of either the CB ₁ receptor or FAAH in either brain region. Interestingly, our CORT delivery regimen significantly increased 2-AG concentrations within the hippocampus, but not the amygdala. Collectively, these data demonstrate that the confounder of injection stress is sufficient to conceal the ability of protracted exposure to glucocorticoids to reduce CB ₁ receptor density and augment AEA metabolism within limbic structures. This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.