title: Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety.
abstract: Systemic activation of cannabinoid receptors often induces biphasic effects on emotional memory and anxiety depending on the levels of emotional arousal associated to the experimental context. The basolateral nucleus of the amygdala (BLA) represents a crucial structure for the ability of endocannabinoid (eCB) signaling to modulate emotional behaviour, and receives dense projections from brainstem arousal system nuclei. We examined whether changes in emotional arousal state would influence the ability of acute eCB manipulations within the BLA to modulate anxiety. Rats were tested in an elevated plus maze (EPM) under low or high arousal conditions. The low emotional arousal group was extensively handled and habituated to the experimental room and tested under red light condition, the high emotional arousal group was not handled or habituated and tested under high light condition. We examined amygdalar eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels immediately after the EPM and the effects of intra-BLA administration of the AEA hydrolysis inhibitor URB597 or the 2-AG hydrolysis inhibitor KML29 on anxiety behaviour. The modulation of anxiety-like behaviour by eCBs in the BLA was strictly dependent on the environmental-associated emotional arousal. Pharmacologically-induced elevations of AEA or 2-AG in the BLA decreased anxiety under conditions of low emotional arousal. Conversely, when the level of emotional arousal increased, local eCB manipulation was ineffective in the modulation of the emotional arousal-induced anxiety response. These findings suggest that, depending on the emotional arousal state, eCB system is differentially activated to regulate the anxiety response in the amygdala and help to understand the state-dependency of many interventions on anxiety.
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, T2N 4N1 Calgary, AB, Canada; Mathison Centre for Mental Health Research and Education, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Cell Biology & Anatomy, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Psychiatry, University of Calgary, T2N 4N1 Calgary, AB, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Morena
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, T2N 4N1 Calgary, AB, Canada; Mathison Centre for Mental Health Research and Education, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Cell Biology & Anatomy, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Psychiatry, University of Calgary, T2N 4N1 Calgary, AB, Canada.
authors.forename: Kira D
authors.initials: KD
authors.lastname: Leitl
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, T2N 4N1 Calgary, AB, Canada; Mathison Centre for Mental Health Research and Education, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Cell Biology & Anatomy, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Psychiatry, University of Calgary, T2N 4N1 Calgary, AB, Canada.
authors.forename: Haley A
authors.initials: HA
authors.lastname: Vecchiarelli
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, T2N 4N1 Calgary, AB, Canada; Mathison Centre for Mental Health Research and Education, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Cell Biology & Anatomy, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Psychiatry, University of Calgary, T2N 4N1 Calgary, AB, Canada.
authors.forename: J Megan
authors.initials: JM
authors.lastname: Gray
authors.affiliation: Dept. of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Campolongo
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, T2N 4N1 Calgary, AB, Canada; Mathison Centre for Mental Health Research and Education, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Cell Biology & Anatomy, University of Calgary, T2N 4N1 Calgary, AB, Canada; Dept. of Psychiatry, University of Calgary, T2N 4N1 Calgary, AB, Canada. Electronic address: mnhill@ucalgary.ca.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Hill
mesh_terms: D000818:Animals; D001007:Anxiety / Q000097:blood / Q000503:physiopathology*; D001095:Arachidonic Acids / Q000008:administration & dosage*; D001143:Arousal / Q000187:drug effects; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001549:Benzamides / Q000008:administration & dosage; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage*; D002219:Carbamates / Q000008:administration & dosage; D003345:Corticosterone / Q000097:blood; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids / Q000008:administration & dosage*; D004837:Epinephrine / Q000097:blood; D005989:Glycerides / Q000008:administration & dosage*; D008297:Male; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D015398:Signal Transduction
chemical_list: D001095:Arachidonic Acids; D001549:Benzamides; D063386:Cannabinoid Receptor Agonists; D002219:Carbamates; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094503:glyceryl 2-arachidonate; C078814:anandamide; D003345:Corticosterone; D004837:Epinephrine
keywords: Anxiety; Basolateral amygdala; Corticosterone; Emotional arousal; Endocannabinoid; FAAH