title: Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response.
abstract: The mechanisms subserving the ability of glucocorticoid signaling within the medial prefrontal cortex (mPFC) to terminate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis are not well understood. We report that antagonism of the cannabinoid CB(1) receptor locally within the mPFC prolonged corticosterone secretion following cessation of stress in rats. Mice lacking the CB(1) receptor exhibited a similar prolonged response to stress. Exposure of rats to stress produced an elevation in the endocannabinoid 2-arachidonoylglycerol within the mPFC that was reversed by pretreatment with the glucocorticoid receptor antagonist RU-486 (20 mg/kg). Electron microscopic and electrophysiological data demonstrated the presence of CB(1) receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the prelimbic region of the mPFC. Bath application of corticosterone (100 nm) to prefrontal cortical slices suppressed GABA release onto principal neurons in layer V of the prelimbic region, when examined 1 h later, which was prevented by application of a CB(1) receptor antagonist. Collectively, these data demonstrate that the ability of stress-induced glucocorticoid signaling within mPFC to terminate HPA axis activity is mediated by a local recruitment of endocannabinoid signaling. Endocannabinoid activation of CB(1) receptors decreases GABA release within the mPFC, likely increasing the outflow of the principal neurons of the prelimbic region to contribute to termination of the stress response. These data support a model in which endocannabinoid signaling links glucocorticoid receptor engagement to activation of corticolimbic relays that inhibit corticosterone secretion.
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Hill
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: McLaughlin
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.forename: Megan L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Roberts
authors.forename: Tiffany T-Y
authors.initials: TT
authors.lastname: Lee
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Karatsoreos
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Victor
authors.initials: V
authors.lastname: Viau
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
authors.forename: Qing-song
authors.initials: QS
authors.lastname: Liu
authors.forename: Boris B
authors.initials: BB
authors.lastname: Gorzalka
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D005989:Glycerides / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D015735:Mifepristone / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D006727:Hormone Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D015735:Mifepristone; C103505:AM 251; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003345:Corticosterone