title: Inhibition of Protein kinase Mzeta (PKMζ) in the mesolimbic system alters cocaine sensitization in rats.
abstract: Chronic cocaine use produces long-lasting changes in reward circuits that may underlie the transition from casual to compulsive patterns of drug use. Although strong neuroadaptations within the mesocorticolimbic system are known to occur, the specific role of these drug-induced plasticities on sensitization remains to be elucidated. Here we investigate whether PKMζ, a protein involved in maintaining long-term potentiation (LTP), plays a role in these cocaine-induced changes in synaptic strengthening. We performed whole-cell voltage clamp recordings of putative ventral tegmental area (VTA) dopamine (DA) cells 24 hours after five days of 15 mg/kg i.p. cocaine or isovolumetric saline injections. We observed that superfusion of 5µM ZIP (PKMζ inhibitory peptide) decreased AMPA currents and AMPA/NMDA ratios only in cocaine sensitized rats. In vivo ZIP microinfusions (10 nmol) into the VTA after cocaine sensitization decreased locomotor activity on a subsequent cocaine challenge only if given ZIP is given before the withdrawal period. On the other hand, ZIP microinfusions into the nucleus accumbens (NAc) core after a seven days withdrawal period disrupt the expression of locomotor sensitization. The present data provide a potentially relevant region, and time-specific PKMζ-dependent brain mechanism that enables sensitization. Our results support the vision that addiction involves a pathological learning process. They imply that if this synaptic strengthening is reversed, changes in the behavioral response may also be overturned.
authors.affiliation: Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: María E
authors.initials: ME
authors.lastname: Vélez-Hernández
authors.affiliation: Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Vázquez-Torres
authors.affiliation: Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Velasquez-Martinez
authors.affiliation: Section of Neurological Surgery, Department of Neurosurgery, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Lincoln
authors.initials: L
authors.lastname: Jiménez
authors.affiliation: Section of Neurological Surgery, Department of Neurosurgery, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Frankie
authors.initials: F
authors.lastname: Báez
authors.affiliation: Departments of Physiology, Pharmacology and Neurology, SUNY Downstate Medical Center, New York.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Sacktor
authors.affiliation: Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Jiménez-Rivera
keywords: AMPA/NMDA ratio; LTP; Protein kinase Mzeta; VTA; cocaine sensitization; dopamine
references.citation: Nat Rev Neurosci. 2004 Dec;5(12):963-70
references.pmid: 15550951
references.citation: Learn Mem. 2011 Jul 22;18(8):529-33
references.pmid: 21784922
references.citation: Behav Neurosci. 2009 Aug;123(4):844-50
references.pmid: 19634944
references.citation: Neuron. 2000 Mar;25(3):515-32
references.pmid: 10774721
references.citation: Nat Neurosci. 2008 Mar;11(3):344-53
references.pmid: 18278040
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:241-9
references.pmid: 14684450
references.citation: PLoS One. 2012;7(2):e30502
references.pmid: 22348011
references.citation: Nat Neurosci. 2009 Aug;12(8):1036-41
references.pmid: 19597494
references.citation: Neurosci Lett. 2009 Sep 18;461(2):159-62
references.pmid: 19524640
references.citation: PLoS One. 2010 Dec 31;5(12):e15870
references.pmid: 21209835
references.citation: Biol Psychiatry. 2012 Apr 15;71(8):706-13
references.pmid: 22153887
references.citation: Drug Alcohol Depend. 1995 Feb;37(2):95-100
references.pmid: 7758408
references.citation: Curr Psychiatry Rep. 2004 Oct;6(5):347-51
references.pmid: 15355757
references.citation: Science. 2011 Mar 4;331(6021):1207-10
references.pmid: 21385716
references.citation: Nat Neurosci. 2001 Dec;4(12):1217-23
references.pmid: 11694884
references.citation: J Neurosci. 2007 Jul 25;27(30):7921-8
references.pmid: 17652583
references.citation: J Neurosci. 1996 Apr 15;16(8):2444-51
references.pmid: 8786421
references.citation: PLoS One. 2010 Jun 15;5(6):e11125
references.pmid: 20559553
references.citation: Neuropharmacology. 2004;47 Suppl 1:242-55
references.pmid: 15464141
references.citation: J Neurosci. 2001 Apr 1;21(7):2526-35
references.pmid: 11264326
references.citation: Science. 2010 Aug 6;329(5992):649-56
references.pmid: 20689011
references.citation: Neuron. 2003 Feb 20;37(4):577-82
references.pmid: 12597856
references.citation: Brain Res. 1986 Jun;396(2):157-98
references.pmid: 3527341
references.citation: J Neurosci. 2005 Feb 23;25(8):1979-84
references.pmid: 15728837
references.citation: Chang Gung Med J. 2009 Mar-Apr;32(2):148-54
references.pmid: 19403004
references.citation: J Biol Chem. 2003 Oct 10;278(41):40305-16
references.pmid: 12857744
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8342-6
references.pmid: 8378304
references.citation: PLoS One. 2010 Apr 29;5(4):e10400
references.pmid: 20454458
references.citation: Hippocampus. 2006;16(5):443-52
references.pmid: 16463388
references.citation: Behav Pharmacol. 1993;4(4):315-334
references.pmid: 11224200
references.citation: J Neurosci. 2011 Apr 13;31(15):5737-43
references.pmid: 21490215
references.citation: Neuron. 2009 Feb 12;61(3):340-50
references.pmid: 19217372
references.citation: J Neurochem. 2009 Jul;110(1):363-77
references.pmid: 19457111
references.citation: Learn Mem. 2012 Jun 20;19(7):307-14
references.pmid: 22723053
references.citation: J Neurosci. 2009 May 27;29(21):6955-63
references.pmid: 19474322
references.citation: Brain Res Brain Res Rev. 1991 Sep-Dec;16(3):223-44
references.pmid: 1665095
references.citation: J Neurosci. 2000 Aug 1;20(15):5581-6
references.pmid: 10908594
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: Science. 2001 Jun 22;292(5525):2266-7
references.pmid: 11423644
references.citation: Trends Neurosci. 2010 Jun;33(6):267-76
references.pmid: 20207024
references.citation: Am J Addict. 2001 Summer;10(3):201-17
references.pmid: 11579619
references.citation: J Neurosci. 2011 Apr 6;31(14):5436-46
references.pmid: 21471379
references.citation: Annu Rev Physiol. 2004;66:447-75
references.pmid: 14977410
references.citation: J Neurosci. 2007 Sep 26;27(39):10621-35
references.pmid: 17898233
references.citation: Br J Pharmacol. 2008 May;154(2):327-42
references.pmid: 18345022
references.citation: J Neurosci. 2005 Oct 5;25(40):9144-51
references.pmid: 16207873
references.citation: Nat Rev Neurosci. 2009 Aug;10(8):561-72
references.pmid: 19571793
references.citation: Eur J Neurosci. 2007 Aug;26(3):749-56
references.pmid: 17686047
references.citation: J Neurochem. 1994 Oct;63(4):1361-70
references.pmid: 7931287
references.citation: J Neurosci. 2004 Aug 25;24(34):7482-90
references.pmid: 15329395
references.citation: Nat Neurosci. 2002 Apr;5(4):295-6
references.pmid: 11914719
references.citation: Mol Interv. 2002 Jun;2(3):146-57
references.pmid: 14993375
references.citation: Int J Neuropsychopharmacol. 2010 Mar;13(2):133-41
references.pmid: 19545477
references.citation: Nat Neurosci. 2010 May;13(5):630-4
references.pmid: 20383136
references.citation: J Physiol. 2006 Dec 15;577(Pt 3):907-24
references.pmid: 16959856
references.citation: Neuropsychopharmacology. 2010 Feb;35(3):818-33
references.pmid: 19924109
references.citation: J Mol Neurosci. 2012 Jul;47(3):546-53
references.pmid: 22127928
references.citation: Neuropharmacology. 2004;47 Suppl 1:190-201
references.pmid: 15464137
references.citation: Nat Rev Neurosci. 2001 Oct;2(10):695-703
references.pmid: 11584307
references.citation: J Neurosci. 2007 Mar 28;27(13):3535-9
references.pmid: 17392469
references.citation: Learn Mem. 2009 Jan 29;16(2):122-8
references.pmid: 19181618
references.citation: J Neurosci. 1993 Jan;13(1):266-75
references.pmid: 8423473
references.citation: Science. 2006 Aug 25;313(5790):1141-4
references.pmid: 16931766
references.citation: Hippocampus. 2010 Jun;20(6):691-5
references.pmid: 19806657
references.citation: Neuropsychopharmacology. 2005 Aug;30(8):1464-74
references.pmid: 15856078
references.citation: Nature. 2008 Jul 3;454(7200):118-21
references.pmid: 18500330
references.citation: Neuropsychopharmacology. 2011 Sep;36(10):1972-81
references.pmid: 21633338
references.citation: J Neurosci. 2008 Sep 10;28(37):9092-100
references.pmid: 18784289
references.citation: Nat Neurosci. 2006 May;9(5):636-41
references.pmid: 16582902
references.citation: Eur J Neurosci. 2009 Sep;30(6):1117-27
references.pmid: 19735286
references.citation: Science. 2007 Aug 17;317(5840):951-3
references.pmid: 17702943
references.citation: Psychopharmacology (Berl). 2000 Aug;151(2-3):99-120
references.pmid: 10972458
references.citation: J Neurosci. 2010 Jun 9;30(23):7900-9
references.pmid: 20534838
references.citation: Neurosci Biobehav Rev. 2010 Nov;35(2):185-211
references.pmid: 20109488
references.citation: J Neurosci. 2008 Jul 30;28(31):7820-7
references.pmid: 18667614
references.citation: Lancet. 1996 Jan 27;347(8996):237-40
references.pmid: 8551886
references.citation: Nat Rev Neurosci. 2007 Nov;8(11):844-58
references.pmid: 17948030
references.citation: Neuroscience. 2009 Mar 3;159(1):414-26
references.pmid: 19105975
references.citation: Neuron. 2010 Jul 15;67(1):11-24
references.pmid: 20624588
references.citation: PLoS Biol. 2008 Dec 23;6(12):2698-706
references.pmid: 19108606
references.citation: Neurobiol Learn Mem. 2012 Sep;98(2):148-53
references.pmid: 22659643
references.citation: Trends Neurosci. 2008 Nov;31(11):552-8
references.pmid: 18786735
references.citation: Nature. 2001 May 31;411(6837):583-7
references.pmid: 11385572
references.citation: Ann N Y Acad Sci. 2006 Aug;1074:390-402
references.pmid: 17105937
references.citation: Science. 1975 Oct 31;190(4213):475-7
references.pmid: 1166317
references.citation: Ann N Y Acad Sci. 2010 Feb;1187:35-75
references.pmid: 20201846
references.citation: Prog Neurobiol. 1998 Apr;54(6):679-720
references.pmid: 9560846
references.citation: Science. 1997 Oct 3;278(5335):45-7
references.pmid: 9311924
references.citation: Neuroreport. 1999 Feb 5;10(2):221-6
references.pmid: 10203312
references.citation: J Neurochem. 1998 Jan;70(1):198-209
references.pmid: 9422363