title: CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory.
abstract: Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Jimok
authors.initials: J
authors.lastname: Kim
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D005239:Fear / Q000502:physiology; D057567:Memory, Long-Term / Q000502:physiology*; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory / Q000502:physiology*
chemical_list: D043885:Receptor, Cannabinoid, CB2
references.citation: Br J Pharmacol. 2008 Jan;153(2):309-18
references.pmid: 17965741
references.citation: Psychiatry Res. 2013 Nov 30;210(1):1-7
references.pmid: 23932838
references.citation: Hippocampus. 2010 Oct;20(10):1126-38
references.pmid: 19830813
references.citation: Behav Neurosci. 1992 Apr;106(2):274-85
references.pmid: 1590953
references.citation: Br J Pharmacol. 2010 Jun;160(3):467-79
references.pmid: 20590558
references.citation: Invest Ophthalmol Vis Sci. 2013 Dec;54(13):8079-90
references.pmid: 24255040
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17501-6
references.pmid: 17088541
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3984-9
references.pmid: 8633002
references.citation: Neurosci Biobehav Rev. 2005 May;29(3):385-97
references.pmid: 15820545
references.citation: Ann N Y Acad Sci. 2006 Aug;1074:514-36
references.pmid: 17105950
references.citation: Nature. 1993 Sep 2;365(6441):61-5
references.pmid: 7689702
references.citation: Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S91-6
references.pmid: 18291574
references.citation: J Pharmacol Exp Ther. 2002 Jun;301(3):915-24
references.pmid: 12023519
references.citation: Br J Pharmacol. 2012 Feb;165(4):951-64
references.pmid: 21838753
references.citation: Neuropharmacology. 2005 Apr;48(5):658-72
references.pmid: 15814101
references.citation: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5780-5
references.pmid: 10318961
references.citation: Behav Pharmacol. 2006 May;17(3):223-30
references.pmid: 16572000
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jun;29(5):840-5
references.pmid: 15925435
references.citation: Eur Neuropsychopharmacol. 2000 Sep;10(5):389-95
references.pmid: 10974611
references.citation: Brain Struct Funct. 2015 Sep;220(5):2721-38
references.pmid: 24972960
references.citation: Hippocampus. 2012 Mar;22(3):643-4
references.pmid: 21538668
references.citation: Mol Pharmacol. 1988 Nov;34(5):605-13
references.pmid: 2848184
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2014 Feb;387(2):175-84
references.pmid: 24185999
references.citation: Psychopharmacology (Berl). 2001 Sep;157(2):142-50
references.pmid: 11594438
references.citation: Pharmacol Biochem Behav. 2008 Nov;91(1):91-6
references.pmid: 18639576
references.citation: Nature. 2002 Aug 1;418(6897):530-4
references.pmid: 12152079
references.citation: Biochem Pharmacol. 1995 Jun 29;50(1):83-90
references.pmid: 7605349
references.citation: J Affect Disord. 2011 Nov;134(1-3):427-30
references.pmid: 21658778
references.citation: J Biol Chem. 2012 Jan 6;287(2):1198-209
references.pmid: 22102284
references.citation: J Physiol. 2015 Feb 15;593(4):871-86
references.pmid: 25504573
references.citation: PLoS One. 2008;3(2):e1640
references.pmid: 18286196
references.citation: Neurobiol Learn Mem. 2012 Jul;98(1):47-55
references.pmid: 22579951
references.citation: Neurochem Int. 2012 Jan;60(2):145-52
references.pmid: 22133429
references.citation: Br J Pharmacol. 2011 Oct;164(4):1162-94
references.pmid: 21449915
references.citation: PLoS One. 2013;8(10):e76907
references.pmid: 24130809
references.citation: J Pharmacol Exp Ther. 1996 Sep;278(3):989-99
references.pmid: 8819477
references.citation: Neuropharmacology. 2009 Sep;57(4):356-68
references.pmid: 19616018
references.citation: Science. 2005 Oct 14;310(5746):329-32
references.pmid: 16224028
references.citation: Handb Exp Pharmacol. 2005;(168):117-45
references.pmid: 16596773
references.citation: Brain Behav Immun. 2011 Feb;25(2):181-213
references.pmid: 20970492
references.citation: PLoS One. 2013;8(8):e70849
references.pmid: 23951024
references.citation: J Biol Chem. 2000 Jan 7;275(1):605-12
references.pmid: 10617657
references.citation: Mol Cell Neurosci. 2008 Jul;38(3):374-80
references.pmid: 18499473
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3534-9
references.pmid: 22331871
references.citation: Eur J Pharmacol. 2000 May 19;396(2-3):141-9
references.pmid: 10822068
references.citation: Neuropsychopharmacology. 2011 Jun;36(7):1489-504
references.pmid: 21430651
references.citation: Mol Cell Neurosci. 2008 Aug;38(4):526-36
references.pmid: 18562209
references.citation: Behav Brain Res. 2000 Jun 1;110(1-2):73-81
references.pmid: 10802305
references.citation: J Neurosci. 1999 Nov 1;19(21):9570-8
references.pmid: 10531459
references.citation: Brain Res Rev. 2007 Apr;54(1):92-112
references.pmid: 17306884
references.citation: J Neurosci Methods. 2013 Jun 15;216(2):87-95
references.pmid: 23583232
references.citation: FASEB J. 2006 Nov;20(13):2405-7
references.pmid: 17015409
references.citation: Nat Rev Neurosci. 2013 Jun;14(6):417-28
references.pmid: 23635870
references.citation: Science. 1999 Jan 15;283(5400):401-4
references.pmid: 9888857
references.citation: Br J Pharmacol. 2012 Jan;165(1):260-73
references.pmid: 21671903
references.citation: Psychopharmacology (Berl). 2005 Jun;179(4):863-72
references.pmid: 15619104
references.citation: Nature. 1990 Aug 9;346(6284):561-4
references.pmid: 2165569
references.citation: Neurosci Biobehav Rev. 2004 Sep;28(5):497-505
references.pmid: 15465137
references.citation: J Psychopharmacol. 2011 Jan;25(1):97-104
references.pmid: 20488834
references.citation: Biol Psychiatry. 2010 May 15;67(10):974-82
references.pmid: 19931854
references.citation: Neuropharmacology. 2013 Oct;73:388-96
references.pmid: 23796670
references.citation: Eur J Immunol. 2012 Jan;42(1):45-7
references.pmid: 22213045
references.citation: Nat Neurosci. 2011 Sep;14(9):1160-6
references.pmid: 21785434
references.citation: Neurosci Lett. 2006 Apr 10-17;397(1-2):88-92
references.pmid: 16406322
references.citation: Brain Res Rev. 2009 Apr;60(1):255-66
references.pmid: 19150370
references.citation: Eur J Neurosci. 2004 Aug;20(4):1059-64
references.pmid: 15305874
references.citation: J Histochem Cytochem. 2014 Mar 26;62(6):395-404
references.pmid: 24670796
references.citation: Schizophr Bull. 2010 Mar;36(2):289-300
references.pmid: 20026558
references.citation: Psychiatry Res. 2007 Mar 30;150(2):111-21
references.pmid: 17292970
references.citation: Trends Neurosci. 2006 Sep;29(9):496-505
references.pmid: 16872686
references.citation: Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):E5007-15
references.pmid: 25368177
references.citation: J Mol Neurosci. 2013 Oct;51(2):454-60
references.pmid: 23846977
references.citation: Neuropsychopharmacology. 2015 Mar;40(4):1037-51
references.pmid: 25374096
references.citation: Pharmacol Biochem Behav. 1999 Nov;64(3):555-61
references.pmid: 10548271