title: Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D1 receptor agonist sensitization.
abstract: Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia, and other developmental disorders of frontostriatal circuit dysfunction. In these animals a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the postpubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo.
authors.affiliation: Graduate Program in Neurobiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Sophia T
authors.initials: ST
authors.lastname: Papadeas
authors.forename: Christopher
authors.initials: C
authors.lastname: Halloran
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McCown
authors.forename: George R
authors.initials: GR
authors.lastname: Breese
authors.forename: Bonita L
authors.initials: BL
authors.lastname: Blake
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000378:metabolism*; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D003712:Dendrites / Q000648:ultrastructure*; D018491:Dopamine Agonists / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000033:anatomy & histology* / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D013565:Sympatholytics / Q000633:toxicity
chemical_list: D018491:Dopamine Agonists; D005419:Flavonoids; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D011480:Protease Inhibitors; D017447:Receptors, Dopamine D1; C424127:SL 327; D013565:Sympatholytics; D000607:Aminoacetonitrile; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
references.citation: J Neurosci. 2000 Jun 15;20(12):4606-14
references.pmid: 10844030
references.citation: Anal Biochem. 1989 Sep;181(2):259-66
references.pmid: 2573292
references.citation: Curr Opin Neurobiol. 2003 Jun;13(3):391-8
references.pmid: 12850225
references.citation: Brain Res Brain Res Rev. 2005 Feb;48(1):57-73
references.pmid: 15708628
references.citation: Brain Res. 2005 Nov 16;1062(1-2):166-70
references.pmid: 16257395
references.citation: Brain Res. 1994 May 9;645(1-2):49-60
references.pmid: 8062100
references.citation: Curr Opin Neurobiol. 2004 Jun;14(3):311-7
references.pmid: 15194111
references.citation: Cereb Cortex. 1996 May-Jun;6(3):431-45
references.pmid: 8670669
references.citation: Biotechniques. 2000 Feb;28(2):216-8
references.pmid: 10683726
references.citation: J Pharmacol Exp Ther. 1992 Aug;262(2):855-65
references.pmid: 1354257
references.citation: J Neurochem. 1994 Dec;63(6):2336-41
references.pmid: 7525876
references.citation: J Neurosci. 1989 Jan;9(1):125-33
references.pmid: 2521511
references.citation: J Neurochem. 2003 Jul;86(2):351-62
references.pmid: 12871576
references.citation: Dev Cell. 2003 Apr;4(4):521-33
references.pmid: 12689591
references.citation: Exp Neurol. 2002 Jul;176(1):66-74
references.pmid: 12093083
references.citation: Neurochem Res. 2007 Apr-May;32(4-5):707-15
references.pmid: 17024568
references.citation: J Comp Neurol. 1985 Nov 15;241(3):253-67
references.pmid: 2418068
references.citation: Nature. 1996 Jul 25;382(6589):363-6
references.pmid: 8684467
references.citation: Endocr Rev. 2001 Apr;22(2):153-83
references.pmid: 11294822
references.citation: J Neurosci Res. 1999 Oct 1;58(1):42-61
references.pmid: 10491571
references.citation: J Comp Neurol. 2005 Jul 4;487(3):270-82
references.pmid: 15892099
references.citation: Curr Opin Neurobiol. 2000 Jun;10(3):381-91
references.pmid: 10851172
references.citation: Int J Dev Neurosci. 2004 Nov;22(7):507-14
references.pmid: 15465280
references.citation: J Comp Neurol. 2003 Dec 1;467(1):119-33
references.pmid: 14574684
references.citation: J Biol Chem. 1998 Jul 17;273(29):18623-32
references.pmid: 9660836
references.citation: Ann N Y Acad Sci. 1986;466:145-66
references.pmid: 3089105
references.citation: J Neurosci. 2004 Jun 30;24(26):5863-76
references.pmid: 15229233
references.citation: Neuron. 2002 Jun 13;34(6):985-98
references.pmid: 12086645
references.citation: J Biol Chem. 1995 Nov 17;270(46):27489-94
references.pmid: 7499206
references.citation: J Biol Chem. 2000 Apr 21;275(16):12200-6
references.pmid: 10766856
references.citation: J Neurosci. 2000 Dec 1;20(23):8701-9
references.pmid: 11102476
references.citation: Neuron. 1996 Feb;16(2):357-68
references.pmid: 8789950
references.citation: Mol Ther. 2006 Jul;14(1):63-8
references.pmid: 16730475
references.citation: Brain Res. 1990 Apr 2;512(2):284-90
references.pmid: 2162235
references.citation: J Pharmacol Exp Ther. 1985 Aug;234(2):447-55
references.pmid: 3926987
references.citation: J Neurosci. 1999 Jun 15;19(12):4907-20
references.pmid: 10366625
references.citation: Int J Neuropsychopharmacol. 2004 Mar;7 Suppl 1:S7-S13
references.pmid: 14972079
references.citation: J Neurosci. 1999 May 1;19(9):3535-44
references.pmid: 10212313
references.citation: Prog Neurobiol. 2000 Jun;61(2):133-68
references.pmid: 10704996
references.citation: J Pharmacol Exp Ther. 1984 Nov;231(2):343-54
references.pmid: 6149306
references.citation: Neuron. 2002 Jun 13;34(6):999-1010
references.pmid: 12086646
references.citation: J Neurosci. 2002 Oct 1;22(19):8597-606
references.pmid: 12351733
references.citation: Nat Rev Neurosci. 2004 Jan;5(1):45-54
references.pmid: 14708003
references.citation: Mol Biol Cell. 1996 Jun;7(6):893-905
references.pmid: 8816996
references.citation: Nat Neurosci. 1998 Nov;1(7):602-9
references.pmid: 10196568
references.citation: Cell Mol Life Sci. 2005 Sep;62(17):1913-24
references.pmid: 15990959
references.citation: J Neurosci. 2003 Dec 10;23(36):11420-6
references.pmid: 14673006
references.citation: Neuropharmacology. 2004;47 Suppl 1:33-46
references.pmid: 15464124
references.citation: Neurobiol Dis. 2005 Nov;20(2):479-90
references.pmid: 15908225
references.citation: Biochem J. 2000 Oct 1;351(Pt 1):95-105
references.pmid: 10998351
references.citation: J Neurobiol. 2005 Feb 5;62(2):278-88
references.pmid: 15514998
references.citation: Brain Res. 2001 May 18;901(1-2):79-84
references.pmid: 11368953
references.citation: J Neurosci. 1996 Dec 1;16(23):7627-37
references.pmid: 8922419
references.citation: Nat Neurosci. 2001 Feb;4(2):151-8
references.pmid: 11175875
references.citation: J Comp Neurol. 2006 Jun 1;496(4):529-43
references.pmid: 16572431
references.citation: Neuroscientist. 2006 Feb;12(1):16-28
references.pmid: 16394190
references.citation: Eur J Biochem. 2004 Jun;271(11):2060-6
references.pmid: 15153095
references.citation: N Engl J Med. 1996 Jun 13;334(24):1568-72
references.pmid: 8628337
references.citation: Trends Neurosci. 1997 Jun;20(6):269-74
references.pmid: 9185309
references.citation: Neuroscience. 2001;106(1):5-14
references.pmid: 11564412
references.citation: J Neurosci. 1997 Dec 15;17(24):9596-604
references.pmid: 9391014
references.citation: Exp Brain Res. 2004 Oct;158(3):265-77
references.pmid: 15365664
references.citation: Brain Res Brain Res Rev. 2000 Apr;32(2-3):449-75
references.pmid: 10760551
references.citation: Brain Res. 1998 Nov 9;810(1-2):181-99
references.pmid: 9813316
references.citation: Neuroscience. 1993 Jul;55(2):463-72
references.pmid: 8377938
references.citation: Exp Brain Res. 1997 May;114(3):433-41
references.pmid: 9187279
references.citation: J Neurobiol. 2005 Jul;64(1):4-10
references.pmid: 15884010
references.citation: Neuroscience. 2001;105(4):1041-54
references.pmid: 11530241
references.citation: J Neurophysiol. 2001 Feb;85(2):926-37
references.pmid: 11160523
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8881-5
references.pmid: 7568036
references.citation: Brain Res. 1996 Aug 19;730(1-2):75-86
references.pmid: 8883891
references.citation: Neuroscience. 2005;133(2):463-70
references.pmid: 15878241
references.citation: Trends Neurosci. 2000 Feb;23(2):59
references.pmid: 10652545
references.citation: J Neurosci. 2007 Oct 24;27(43):11473-82
references.pmid: 17959790
references.citation: Brain Res. 1989 Jan 23;478(1):127-37
references.pmid: 2538199