title: Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats.
abstract: Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1-8mg/kg), the benzodiazepine diazepam (1mg/kg), the cannabinoid CB(1) receptor antagonist rimonabant (1mg/kg), or JZL184 (8mg/kg) coadministered with rimonabant (1mg/kg). JZL184 (8mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB(1). Anxiolytic effects of JZL184 were preserved following chronic (8mg/kg per day×6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5mg/kg i.p.) 24 or 72h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.
authors: Department of Psychology, Neuroscience and Behavior Program, University of Georgia, Athens, GA, United States.
authors: Natale R
authors: NR
authors: Sciolino
authors: Wenyi
authors: W
authors: Zhou
authors: Andrea G
authors: AG
authors: Hohmann
references: Annu Rev Biochem. 2005;74:411-32
references: 15952893
references: J Pharmacol Exp Ther. 2009 Sep;330(3):902-10
references: 19502530
references: Pharmacol Biochem Behav. 2001 Sep;70(1):123-31
references: 11566149
references: Chem Biol. 2009 Jul 31;16(7):744-53
references: 19635411
references: Neuroreport. 1997 Jan 20;8(2):491-6
references: 9080435
references: Eur J Neurosci. 2007 Apr;25(8):2445-56
references: 17445240
references: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9371-6
references: 11470906
references: Eur J Neurosci. 2005 Feb;21(4):1057-69
references: 15787710
references: Neuropharmacology. 2008 Jan;54(1):108-16
references: 17675104
references: Endocrinology. 2005 Oct;146(10):4292-301
references: 15994343
references: Neuropsychopharmacology. 2009 Dec;34(13):2733-45
references: 19710634
references: Dev Neurobiol. 2008 Sep 15;68(11):1334-47
references: 18666205
references: Nat Chem Biol. 2009 Jan;5(1):37-44
references: 19029917
references: Eur J Pharmacol. 2008 Sep 28;593(1-3):73-8
references: 18691568
references: CNS Neurol Disord Drug Targets. 2009 Dec;8(6):451-8
references: 19839936
references: Nature. 2005 Jun 23;435(7045):1108-12
references: 15973410
references: Neuropsychopharmacology. 2009 Feb;34(3):593-606
references: 18580871
references: J Pharmacol Exp Ther. 2006 Jul;318(1):304-11
references: 16569753
references: Endocrinology. 2004 Dec;145(12):5431-8
references: 15331569
references: J Pharmacol Exp Ther. 2001 Aug;298(2):753-68
references: 11454940
references: Biol Psychiatry. 2009 Jul 1;66(1):9-16
references: 19103437
references: Neuropsychopharmacology. 2008 Feb;33(3):574-87
references: 17460614
references: Biol Psychiatry. 2005 Feb 1;57(3):261-7
references: 15691527
references: Behav Pharmacol. 2005 Sep;16(5-6):395-404
references: 16148444
references: Eur J Neurosci. 2002 Oct;16(7):1395-8
references: 12405999
references: Neuroscience. 2010 Jun 30;168(2):371-86
references: 20394803
references: Chem Biol. 2007 Dec;14(12):1347-56
references: 18096503
references: Neuropharmacology. 2008 Jan;54(1):141-50
references: 17709120
references: Curr Opin Investig Drugs. 2010 Jan;11(1):51-62
references: 20047159
references: Nature. 1996 Nov 7;384(6604):83-7
references: 8900284
references: J Neurosci. 1996 Oct 15;16(20):6601-11
references: 8815936
references: Cereb Cortex. 2009 Jan;19(1):165-75
references: 18477688
references: Neuropsychopharmacology. 2005 Mar;30(3):508-15
references: 15525997
references: Behav Pharmacol. 2004 Jul;15(4):299-304
references: 15252281
references: Lancet. 2007 Nov 17;370(9600):1706-13
references: 18022033
references: J Neurosci Methods. 1985 Aug;14(3):149-67
references: 2864480
references: Basic Clin Pharmacol Toxicol. 2009 Nov;105(5):333-8
references: 19614892
references: Mol Pharmacol. 2010 Aug;78(2):260-8
references: 20424126
references: Psychopharmacology (Berl). 2009 Jul;205(1):63-72
references: 19343330
references: Hippocampus. 2008;18(2):221-6
references: 18058925
references: Psychopharmacology (Berl). 2008 Jul;198(4):509-20
references: 17882402
references: Mol Pharmacol. 2004 Nov;66(5):1260-4
references: 15272052
references: Neural Plast. 2007;2007:52908
references: 17641734
references: Neuropharmacology. 1991 Jan;30(1):67-71
references: 1646420
references: CNS Drug Rev. 2006 Spring;12(1):21-38
references: 16834756
references: PLoS One. 2010 May 21;5(5):e10752
references: 20505775
references: Neurosci Biobehav Rev. 2008 Aug;32(6):1087-102
references: 18423591
references: Nat Med. 2003 Jan;9(1):76-81
references: 12461523
references: Lancet. 2010 Aug 14;376(9740):517-23
references: 20709233
references: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10819-24
references: 12136125
references: Neurosci Biobehav Rev. 2010 May;34(6):808-20
references: 20171244
references: Psychopharmacology (Berl). 2008 Jul;198(4):449-60
references: 18446329
references: Neural Plast. 2009;2009:625469
references: 19096514
references: Psychopharmacology (Berl). 2002 Jan;159(2):188-95
references: 11862348
references: Br J Pharmacol. 2011 Aug;163(7):1464-78
references: 21198549
references: Psychopharmacology (Berl). 2009 Jul;204(4):607-16
references: 19259645
references: Clin Auton Res. 2009 Dec;19(6):343-6
references: 19756829
references: Nat Neurosci. 2010 Sep;13(9):1113-9
references: 20729846
references: Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):133-44
references: 19285266
references: Neuropharmacology. 2008 Jan;54(1):129-40
references: 17904589
references: Cereb Cortex. 2008 Jun;18(6):1292-301
references: 17921459
references: Br J Pharmacol. 2007 Nov;152(5):765-77
references: 17572696
references: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9406-11
references: 20439721
references: Psychoneuroendocrinology. 2009 Sep;34(8):1257-62
references: 19394765
references: Psychopharmacology (Berl). 2009 Jul;205(1):171-4
references: 19300982
references: Pharmacol Res. 2010 May;61(5):419-29
references: 20044005
references: Pharmacol Biochem Behav. 2011 Mar;98(1):21-7
references: 21145341
references: AAPS J. 2009 Jun;11(2):342-52
references: 19430909
references: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20270-5
references: 19918051
references: BMJ. 2007 Dec 8;335(7631):1194-9
references: 18006966
references: Pharmacol Res. 2010 Sep;62(3):249-58
references: 20416378
references: Eur J Neurosci. 2004 Apr;19(7):1906-12
references: 15078564
references: Psychopharmacology (Berl). 2007 May;192(1):61-70
references: 17279376
references: Behav Pharmacol. 2005 Sep;16(5-6):405-13
references: 16148445
references: Brain Res. 2010 Aug 19;1349:162-73
references: 20599824