title: Endogenous cannabinoid signaling is essential for stress adaptation.
abstract: Secretion of glucocorticoid hormones during stress produces an array of physiological changes that are adaptive and beneficial in the short term. In the face of repeated stress exposure, however, habituation of the glucocorticoid response is essential as prolonged glucocorticoid secretion can produce deleterious effects on metabolic, immune, cardiovascular, and neurobiological function. Endocannabinoid signaling responds to and regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis that governs the secretion of glucocorticoids; however, the role this system plays in adaptation of the neuroendocrine response to repeated stress is not well characterized. Herein, we demonstrate a divergent regulation of the two endocannabinoid ligands, N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), following repeated stress such that AEA content is persistently decreased throughout the corticolimbic stress circuit, whereas 2-AG is exclusively elevated within the amygdala in a stress-dependent manner. Pharmacological studies demonstrate that this divergent regulation of AEA and 2-AG contribute to distinct forms of HPA axis habituation. Inhibition of AEA hydrolysis prevented the development of basal hypersecretion of corticosterone following repeated stress. In contrast, systemic or intra-amygdalar administration of a CB(1) receptor antagonist before the final stress exposure prevented the repeated stress-induced decline in corticosterone responses. The present findings demonstrate an important role for endocannabinoid signaling in the process of stress HPA habituation, and suggest that AEA and 2-AG modulate different components of the adrenocortical response to repeated stressor exposure.
authors.affiliation: Departments of Psychology and Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Hill
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: McLaughlin
authors.forename: Brenda
authors.initials: B
authors.lastname: Bingham
authors.forename: Lalita
authors.initials: L
authors.lastname: Shrestha
authors.forename: Tiffany T Y
authors.initials: TT
authors.lastname: Lee
authors.forename: J Megan
authors.initials: JM
authors.lastname: Gray
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
authors.forename: Boris B
authors.initials: BB
authors.lastname: Gorzalka
authors.forename: Victor
authors.initials: V
authors.lastname: Viau
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D063388:Endocannabinoids; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C078814:anandamide; D003345:Corticosterone; C107594:N-(4-hydroxyphenyl)arachidonylamide