Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.
Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid-CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety.
Hotchkiss Brain Institute, Mathison Centre for Mental Health Research and Education, Departments of Cell Biology & Anatomy and Psychiatry, and.
J Megan
JM
Gray
Hotchkiss Brain Institute, Mathison Centre for Mental Health Research and Education, Department of Neuroscience, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Haley A
http://orcid.org/0000-0001-6331-6107
HA
Vecchiarelli
Hotchkiss Brain Institute, Mathison Centre for Mental Health Research and Education, Departments of Cell Biology & Anatomy and Psychiatry, and.
Maria
M
Morena
Hotchkiss Brain Institute, Department of Psychology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Tiffany T Y
TT
Lee
Department of Chemistry and.
Daniel J
DJ
Hermanson
Hotchkiss Brain Institute, Department of Neuroscience, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Alexander B
http://orcid.org/0000-0003-3405-9812
AB
Kim
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington 99164, and.
Ryan J
RJ
McLaughlin
Hotchkiss Brain Institute.
Kowther I
KI
Hassan
Department of Stress Neurobiology & Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Claudia
C
Kühne
Department of Stress Neurobiology & Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Carsten T
CT
Wotjak
Department of Stress Neurobiology & Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Jan M
JM
Deussing
Department of Psychiatry & Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37240.
Sachin
S
Patel
Hotchkiss Brain Institute, Mathison Centre for Mental Health Research and Education, Departments of Cell Biology & Anatomy and Psychiatry, and mnhill@ucalgary.ca.
Matthew N
MN
Hill
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000581:Amidohydrolases / Q000378:metabolism; D000679:Amygdala / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000503:physiopathology*; D001095:Arachidonic Acids / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D006868:Hydrolysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism / Q000523:psychology; D000099052:CRF Receptor, Type 1; D000099252:Fatty Acid Amide Hydrolases
D000324:Adrenocorticotropic Hormone; D000581:Amidohydrolases; D001095:Arachidonic Acids; D003346:Corticotropin-Releasing Hormone; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide
HPA axis; anxious behavior; basolateral amygdala; endocannabinoid signaling; stress