title: An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors.
abstract: Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: R N
authors: RN
authors: Arey
authors: 1] Department of Biology, Austin College, Sherman, TX, USA [2] Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: J F
authors: JF
authors: Enwright
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: S M
authors: SM
authors: Spencer
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: E
authors: E
authors: Falcon
authors: 1] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: A R
authors: AR
authors: Ozburn
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: S
authors: S
authors: Ghose
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: C
authors: C
authors: Tamminga
authors: 1] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: C A
authors: CA
authors: McClung
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology*; D056926:CLOCK Proteins / Q000235:genetics / Q000502:physiology*; D002766:Cholecystokinin / Q000096:biosynthesis / Q000502:physiology*; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D051788:Myeloid-Lymphoid Leukemia Protein; D002766:Cholecystokinin; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D018021:Lithium Chloride
references: Genes Brain Behav. 2006 Mar;5(2):150-7
references: 16507006
references: Annu Rev Clin Psychol. 2011;7:297-319
references: 21166537
references: Peptides. 2001 Aug;22(8):1213-21
references: 11457513
references: Cell. 2006 May 5;125(3):497-508
references: 16678094
references: Nat Neurosci. 2006 Apr;9(4):519-25
references: 16501568
references: Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141B(3):234-41
references: 16528748
references: Science. 1994 Apr 29;264(5159):719-25
references: 8171325
references: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6406-11
references: 17379666
references: Biol Psychiatry. 2010 Sep 15;68(6):503-11
references: 20591414
references: Neurosci Lett. 2004 Mar 18;358(1):17-20
references: 15016424
references: Brain Res. 1984 Mar 26;296(1):189-93
references: 6324955
references: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R271-7
references: 16987893
references: Proc Natl Acad Sci U S A. 2011 May 10;108(19):7814-9
references: 21518915
references: Nature. 1980 Jun 12;285(5765):476-8
references: 6105617
references: Peptides. 2001 Aug;22(8):1201-11
references: 11457512
references: Ann N Y Acad Sci. 2011 Dec;1242:1-25
references: 22191553
references: Behav Pharmacol. 2011 Dec;22(8):766-72
references: 21989497
references: Pharmacol Ther. 2007 May;114(2):222-32
references: 17395264
references: Neuropeptides. 1991 Mar;18(3):115-9
references: 2067597
references: Brain Res. 2006 Dec 6;1123(1):1-11
references: 17045977
references: Neuropsychopharmacology. 2010 May;35(6):1279-89
references: 20072116
references: J Circadian Rhythms. 2009 Jan 23;7:2
references: 19166596
references: Peptides. 1998;19(5):859-68
references: 9663451
references: PLoS Genet. 2011 Mar;7(3):e1001354
references: 21483810
references: PLoS One. 2010 Sep 09;5(9):e12632
references: 20856823
references: Nat Struct Mol Biol. 2010 Dec;17(12):1414-21
references: 21113167
references: CNS Drugs. 2009;23(3):225-40
references: 19320531
references: Chronobiol Int. 1995 Apr;12(2):87-99
references: 8653803
references: Neuropsychopharmacology. 2011 Jun;36(7):1478-88
references: 21430648
references: Brain Res. 2010 May 6;1329:10-20
references: 20226774
references: Dialogues Clin Neurosci. 2007;9(3):333-42
references: 17969870
references: Bipolar Disord. 2009 Nov;11(7):701-10
references: 19839995
references: Am J Med Genet B Neuropsychiatr Genet. 2007 Jul 5;144B(5):631-5
references: 17221848
references: J Biol Chem. 2007 Feb 16;282(7):4408-4416
references: 17166833
references: Am J Med Genet B Neuropsychiatr Genet. 2003 Aug 15;121B(1):35-8
references: 12898572
references: Isr J Psychiatry Relat Sci. 2010;47(1):27-35
references: 20686197
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9377-81
references: 15967985
references: Peptides. 2010 Apr;31(4):736-56
references: 20026211
references: Nat Cell Biol. 2007 Mar;9(3):268-75
references: 17310242
references: J Neurosci. 2004 Jun 16;24(24):5603-10
references: 15201333
references: Aust N Z J Psychiatry. 2009 Dec;43(12):1096-104
references: 20001408
references: Int J Neurosci. 2008 Nov;118(11):1609-27
references: 18853337
references: Eur J Pharmacol. 1994 Aug 22;261(3):257-63
references: 7813546
references: Genetics. 1997 Jul;146(3):1049-60
references: 9215907
references: Nat Rev Mol Cell Biol. 2005 Nov;6(11):838-49
references: 16261189
references: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728-32
references: 1975695