title: Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala.
abstract: Psychosocial stress is a risk factor for development and exacerbation of neuropsychiatric illness. Repeated stress causes biochemical adaptations in endocannabinoid (eCB) signaling that contribute to stress-response habituation, however, the synaptic correlates of these adaptations have not been examined. Here, we show that the synthetic enzyme for the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol (DAG) lipase alpha, is heterogeneously expressed in the amygdala, and that levels of 2-AG and precursor DAGs are increased in the basolateral amygdala (BLA) after 10 days, but not 1 day, of restraint stress. In contrast, arachidonic acid was decreased after both 1 and 10 days of restraint stress. To examine the synaptic correlates of these alterations in 2-AG metabolism, we used whole-cell electrophysiology to determine the effects of restraint stress on depolarization-induced suppression of inhibition (DSI) in the BLA. A single restraint stress exposure did not alter DSI compared with control mice. However, after 10 days of restraint stress, DSI duration, but not magnitude, was significantly prolonged. Inhibition of 2-AG degradation with MAFP also prolonged DSI duration; the effects of repeated restraint stress and MAFP were mutually occlusive. These data indicate that exposure to repeated, but not acute, stress produces neuroadaptations that confer BLA neurons with an enhanced capacity to elevate 2-AG content and engage in 2-AG-mediated short-term retrograde synaptic signaling. We suggest stress-induced enhancement of eCB-mediated suppression of inhibitory transmission in the BLA could contribute to affective dysregulation associated with chronic stress.
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, USA. sachin.patel@vanderbilt.edu
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
mesh_terms: D000679:Amygdala / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D063065:Organophosphonates / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D012149:Restraint, Physical; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D004075:Diglycerides; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D009281:Naphthalenes; D063065:Organophosphonates; D043884:Receptor, Cannabinoid, CB1; C104810:methyl arachidonylfluorophosphonate; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase
references.citation: J Am Acad Child Adolesc Psychiatry. 2004 Aug;43(8):994-1002
references.pmid: 15266194
references.citation: Cereb Cortex. 2007 Sep;17 Suppl 1:i16-26
references.pmid: 17725998
references.citation: Neuron. 1993 Aug;11(2):371-86
references.pmid: 8352945
references.citation: Bioorg Med Chem Lett. 2008 Nov 15;18(22):5875-8
references.pmid: 18752948
references.citation: Chem Biol. 2007 Dec;14(12):1347-56
references.pmid: 18096503
references.citation: Pharmacol Biochem Behav. 2005 Jun;81(2):331-42
references.pmid: 15927244
references.citation: J Neurosci. 2007 Apr 4;27(14):3663-76
references.pmid: 17409230
references.citation: J Neurosci. 2001 Oct 15;21(20):RC174
references.pmid: 11588204
references.citation: Ann N Y Acad Sci. 2003 Apr;985:263-72
references.pmid: 12724164
references.citation: J Neurosci. 2008 Jul 16;28(29):7284-92
references.pmid: 18632932
references.citation: Nat Neurosci. 2004 Jun;7(6):585-6
references.pmid: 15146190
references.citation: Neuropsychopharmacology. 2008 Jan;33(1):88-109
references.pmid: 17851537
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8142-7
references.pmid: 18523004
references.citation: Annu Rev Clin Psychol. 2005;1:293-319
references.pmid: 17716090
references.citation: Mol Pharmacol. 2007 Sep;72(3):612-21
references.pmid: 17584991
references.citation: Eur J Neurosci. 2005 Feb;21(4):1057-69
references.pmid: 15787710
references.citation: Neuropharmacology. 2008 Jan;54(1):108-16
references.pmid: 17675104
references.citation: Nat Chem Biol. 2009 Jan;5(1):37-44
references.pmid: 19029917
references.citation: Learn Mem. 2003 Mar-Apr;10(2):116-28
references.pmid: 12663750
references.citation: Neuropsychopharmacology. 2005 Mar;30(3):497-507
references.pmid: 15280883
references.citation: J Neurosci. 2004 Nov 3;24(44):9953-61
references.pmid: 15525780
references.citation: Science. 2003 Jul 18;301(5631):386-9
references.pmid: 12869766
references.citation: Physiol Rev. 2003 Jul;83(3):803-34
references.pmid: 12843409
references.citation: Addict Biol. 2008 Jun;13(2):196-212
references.pmid: 18422832
references.citation: Behav Pharmacol. 2005 Sep;16(5-6):333-52
references.pmid: 16148438
references.citation: Physiol Rev. 2009 Jan;89(1):309-80
references.pmid: 19126760
references.citation: Brain Res. 2003 Feb 14;963(1-2):15-25
references.pmid: 12560108
references.citation: Nat Rev Neurosci. 2003 Nov;4(11):873-84
references.pmid: 14595399
references.citation: Nature. 2001 Mar 29;410(6828):588-92
references.pmid: 11279497
references.citation: Psychol Med. 2007 Aug;37(8):1119-29
references.pmid: 17407618
references.citation: J Neurosci. 2005 Jun 29;25(26):6199-207
references.pmid: 15987949
references.citation: Neuropsychopharmacology. 2009 Jul;34(8):2019-27
references.pmid: 19242408
references.citation: J Neurosci. 2007 Jan 31;27(5):1211-9
references.pmid: 17267577
references.citation: Curr Opin Neurobiol. 2007 Jun;17(3):360-5
references.pmid: 17419048
references.citation: Nature. 2002 Aug 1;418(6897):530-4
references.pmid: 12152079
references.citation: Chem Rev. 2008 May;108(5):1687-707
references.pmid: 18429637
references.citation: Eur J Neurosci. 2008 Jun;27(11):2821-9
references.pmid: 18588527
references.citation: J Neurosci. 2006 May 24;26(21):5628-37
references.pmid: 16723519
references.citation: J Neurosci. 2006 Jun 21;26(25):6677-86
references.pmid: 16793875
references.citation: Mol Pharmacol. 2005 Nov;68(5):1196-202
references.pmid: 16051747
references.citation: J Neurosci. 2001 Dec 1;21(23):9506-18
references.pmid: 11717385