Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala.
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.
Patel
Sachin
S
Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, USA. sachin.patel@vanderbilt.edu
Kingsley
Philip J
PJ
Mackie
Ken
K
Marnett
Lawrence J
LJ
Winder
Danny G
DG
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
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
J Am Acad Child Adolesc Psychiatry. 2004 Aug;43(8):994-1002
15266194
Cereb Cortex. 2007 Sep;17 Suppl 1:i16-26
17725998
Neuron. 1993 Aug;11(2):371-86
8352945
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5875-8
18752948
Chem Biol. 2007 Dec;14(12):1347-56
18096503
Pharmacol Biochem Behav. 2005 Jun;81(2):331-42
15927244
J Neurosci. 2007 Apr 4;27(14):3663-76
17409230
J Neurosci. 2001 Oct 15;21(20):RC174
11588204
Ann N Y Acad Sci. 2003 Apr;985:263-72
12724164
J Neurosci. 2008 Jul 16;28(29):7284-92
18632932
Nat Neurosci. 2004 Jun;7(6):585-6
15146190
Neuropsychopharmacology. 2008 Jan;33(1):88-109
17851537
Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8142-7
18523004
Annu Rev Clin Psychol. 2005;1:293-319
17716090
Mol Pharmacol. 2007 Sep;72(3):612-21
17584991
Eur J Neurosci. 2005 Feb;21(4):1057-69
15787710
Neuropharmacology. 2008 Jan;54(1):108-16
17675104
Nat Chem Biol. 2009 Jan;5(1):37-44
19029917
Learn Mem. 2003 Mar-Apr;10(2):116-28
12663750
Neuropsychopharmacology. 2005 Mar;30(3):497-507
15280883
J Neurosci. 2004 Nov 3;24(44):9953-61
15525780
Science. 2003 Jul 18;301(5631):386-9
12869766
Physiol Rev. 2003 Jul;83(3):803-34
12843409
Addict Biol. 2008 Jun;13(2):196-212
18422832
Behav Pharmacol. 2005 Sep;16(5-6):333-52
16148438
Physiol Rev. 2009 Jan;89(1):309-80
19126760
Brain Res. 2003 Feb 14;963(1-2):15-25
12560108
Nat Rev Neurosci. 2003 Nov;4(11):873-84
14595399
Nature. 2001 Mar 29;410(6828):588-92
11279497
Psychol Med. 2007 Aug;37(8):1119-29
17407618
J Neurosci. 2005 Jun 29;25(26):6199-207
15987949
Neuropsychopharmacology. 2009 Jul;34(8):2019-27
19242408
J Neurosci. 2007 Jan 31;27(5):1211-9
17267577
Curr Opin Neurobiol. 2007 Jun;17(3):360-5
17419048
Nature. 2002 Aug 1;418(6897):530-4
12152079
Chem Rev. 2008 May;108(5):1687-707
18429637
Eur J Neurosci. 2008 Jun;27(11):2821-9
18588527
J Neurosci. 2006 May 24;26(21):5628-37
16723519
J Neurosci. 2006 Jun 21;26(25):6677-86
16793875
Mol Pharmacol. 2005 Nov;68(5):1196-202
16051747
J Neurosci. 2001 Dec 1;21(23):9506-18
11717385