Elsevier

Psychoneuroendocrinology

Volume 35, Issue 9, October 2010, Pages 1333-1338
Psychoneuroendocrinology

Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo

https://doi.org/10.1016/j.psyneuen.2010.03.005Get rights and content

Summary

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 10 min and returned to control 1 h 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.

Introduction

Glucocorticoid hormones are produced by the adrenal cortex and secreted into the general circulation following exposure to stressful or aversive stimuli; the glucocorticoid hormones promote adaptive physiological responses to the stressor and restoration of homeostasis. The effects of glucocorticoids occur in several phases, although they are typically categorized as those that occur rapidly (seconds to minutes) and those that develop more slowly (minutes to hours (McEwen, 1994)). Within the brain, as well as throughout other systems in the body, glucocorticoids exert effects through activation of cytosolic receptors, which dimerize, enter the nucleus and modify gene transcription through binding to specific response elements in the promoter regions of target genes. However, several studies have demonstrated physiological and behavioral effects of glucocorticoids that occur too rapidly to be mediated by alterations in gene transcription or are unaffected by protein synthesis inhibitors (Haller et al., 2008). Accumulating data indicate that these non-genomic effects of glucocorticoids occur through the activation of either G-protein coupled receptors or membrane-associated cytosolic steroid receptors (Karst et al., 2005, Tasker et al., 2006). These mechanisms produce rapid effects on behavior and physiology contributing to adaptive responses to stress as well as the immediate normalization of homeostasis following stress (Tasker et al., 2006). To date, few in vivo studies have elucidated the biochemical changes that underlie the rapid, non-genomic neurobehavioral effects of the glucocorticoids.

Endocannabinoids, acting through the CB1 cannabinoid receptor, subserve a retrograde signaling system that is widely distributed throughout the brain and functions to modulate axonal release of excitatory and inhibitory neurotransmitters (Freund et al., 2003). There are several lines of evidence which indicate that endocannabinoid signaling is regulated by glucocorticoid hormones. First, exposure of isolated hypothalamic slices to glucocorticoids rapidly induces endocannabinoid mobilization through activation of a G-protein coupled receptor (Di et al., 2003). Second, rapid behavioral responses to glucocorticoid administration in vivo are blocked by administration of CB1 receptor antagonists (Campolongo et al., 2009, Coddington et al., 2007), suggesting that glucocorticoids rapidly recruit endocannabinoid signaling. These data have lead to the hypothesis that endocannabinoids are the synaptic “workhorse” of glucocorticoids (Hill and McEwen, 2009). The purpose of this study was to extend these observations and measure the effects of exogenous glucocorticoid administration on corticolimbic tissue endocannabinoid contents. Our prediction that glucocorticoid administration would rapidly increase endocannabinoid contents was confirmed, lending further support to both the importance of rapid glucocorticoid signaling and the role of endocannabinoids in this mechanism.

Section snippets

Subjects

Seventy-day-old male Sprague–Dawley rats (250–325 g; Charles River, Kingston, NY), pair housed in standard maternity bins lined with contact bedding, were used in this study. Colony rooms were maintained at 21 °C, and on a 12 h light/dark cycle, with lights on at 0900 h. All rats were given ad libitum access to Purina Rat Chow and tap water. All protocols were approved by the Institutional Animal Care and Use Committee of Rockefeller University.

Procedure

Rats were administered a subcutaneous injection of

Results

Within the amygdala, AEA content was found to be elevated 10 min following corticosterone administration [F (2, 16) = 11.39, p < 0.005; Fig. 1]. Post hoc analysis demonstrated that AEA content was increased in response to both the 3 mg/kg (p < 0.05) and the 10 mg/kg (p < 0.005) doses of corticosterone compared to vehicle treated controls. At 1 h following corticosterone administration, AEA content within the amygdala was also increased [F (2, 16) = 4.43, p < 0.05; Fig. 1]; however, at this time point, AEA

Discussion

In the present study, we demonstrated that systemic administration of corticosterone resulted in a rapid, transient increase in AEA contents in the amygdala, hippocampus and hypothalamus, but not the PFC. Specifically, tissue AEA concentrations were increased at 10 min following corticosterone administration, but had largely returned to baseline concentrations within 1 h, despite the fact that plasma corticosterone remained elevated. These data suggest that AEA-mediated signaling is a transient

Conflict of interest

Dr. Hill reports no biomedical financial interests or potential conflicts of interest. Dr. Karatsoreos reports no biomedical financial interests or potential conflicts of interest. Dr. Hillard reports no biomedical financial interests or potential conflicts of interest. Dr. McEwen reports no biomedical financial interests or potential conflicts of interest.

Role of funding source

This research was supported by National Institute of Health (NIH) grants MH-41256 to BSM and DA022439 and DA09155 to CJH. MNH and INK are supported by postdoctoral fellowships from the Canadian Institute of Health Research (CIHR); the CIHR and NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Acknowledgement

The authors would like to thank Kara Stuhr for her technical assistance with the execution of these experiments.

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