Behavioral and morphological responses to cocaine require kalirin7.
BACKGROUND
Long-lasting increases in dendritic spine density and gene expression in the nucleus accumbens and in the ambulatory response to cocaine occur following chronic cocaine treatment. Despite numerous reports of these findings, the molecular mechanisms leading to these morphological, biochemical, and behavioral changes remain unclear.


METHODS
We used mice genetically lacking Kalirin7 (Kal7(KO)), a Rho guanine nucleotide exchange factor that regulates dendritic spine formation and function. Both wild-type (Wt) and Kal7(KO) mice were given high-dose cocaine (20 mg/kg) for 4 or 8 consecutive days. Locomotor sensitization and conditioned place preference elicited by cocaine were evaluated. The nucleus accumbens core was diolistically labeled and spine density and morphology were quantified using confocal microscopy.


RESULTS
Cocaine increased Kalirin7 messenger RNA and protein expression in the nucleus accumbens of Wt mice. The Kal7(KO) animals showed greater locomotor sensitization to cocaine than Wt mice. In contrast, Kal7(KO) mice exhibited decreased place preference for cocaine, despite displaying a normal place preference for food. While Wt mice showed a robust increase in dendritic spine density after 4 and 8 days of cocaine treatment, dendritic spine density failed to increase in cocaine-exposed Kal7(KO) mice. Wild-type mice treated with cocaine for 8 days exhibited larger dendritic spines than cocaine-treated Kal7(KO) mice.


CONCLUSIONS
Kalirin7 is an essential determinant of dendritic spine formation following cocaine treatment. The absence of this single isoform of one of the many Rho guanine nucleotide exchange factors expressed in the nucleus accumbens results in enhanced locomotor sensitization and diminished place preference in response to cocaine.
Kiraly
Drew D
DD
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut, USA.
Ma
Xin-Ming
XM
Mazzone
Christopher M
CM
Xin
Xiaonan
X
Mains
Richard E
RE
Eipper
Betty A
BA
D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
D002492:Central Nervous System Depressants; D020662:Guanine Nucleotide Exchange Factors; C548820:KALRN protein, mouse; D012333:RNA, Messenger; D003042:Cocaine
Nat Neurosci. 2009 May;12(5):602-10
19349975
Neuron. 2001 Jan;29(1):229-42
11182094
J Biol Chem. 2000 Jun 23;275(25):19324-33
10777487
Curr Opin Neurobiol. 2007 Jun;17(3):381-6
17498943
Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10523-8
12939407
Annu Rev Neurosci. 2008;31:47-67
18284372
J Cell Sci. 2008 Aug 1;121(Pt 15):2601-11
18628310
Nature. 2008 Jul 3;454(7200):118-21
18500330
Exp Neurol. 2006 Aug;200(2):343-55
16631172
Nature. 2007 Aug 23;448(7156):894-900
17713528
J Neurosci. 2008 Aug 13;28(33):8178-88
18701680
Ann N Y Acad Sci. 2004 Oct;1025:335-44
15542734
Eur J Neurosci. 1999 Mar;11(3):1114-8
10103106
Eur J Neurosci. 2004 Sep;20(6):1647-54
15355332
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2915-20
19202072
J Neurosci. 2006 Feb 1;26(5):1579-87
16452681
Nat Neurosci. 2000 Nov;3 Suppl:1178-83
11127835
Eur J Neurosci. 1999 May;11(5):1598-604
10215912
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3399-404
16492766
Annu Rev Neurosci. 2006;29:565-98
16776597
Nat Rev Neurosci. 2009 Sep;10(9):647-58
19693029
Pharmacopsychiatry. 2009 May;42 Suppl 1:S69-78
19434558
Nature. 1999 Sep 16;401(6750):272-6
10499584
Neuron. 2008 Aug 28;59(4):621-33
18760698
Neuron. 2005 Mar 3;45(5):647-50
15748840
J Neurosci. 2007 Nov 21;27(47):12967-76
18032670
Nat Rev Neurosci. 2000 Dec;1(3):173-80
11257905
Synapse. 2001 Mar 1;39(3):257-66
11169774
J Neurosci. 2007 Nov 28;27(48):13140-50
18045908
Psychopharmacology (Berl). 2005 Apr;179(1):164-71
15619119
Nat Neurosci. 2007 Jul;10(7):880-886
17529984
Methods Enzymol. 2008;439:285-302
18374172
Nature. 2008 Oct 9;455(7214):743-4
18843354
Neuron. 2004 Aug 5;43(3):401-13
15294147
J Neurosci Methods. 2007 May 15;162(1-2):237-43
17346799
J Neurosci. 2008 Nov 19;28(47):12368-82
19020030
Trends Neurosci. 2005 Apr;28(4):182-7
15808352
J Neurosci. 2008 Jun 11;28(24):6079-91
18550750
Nat Rev Neurosci. 2005 Jun;6(6):423-34
15928715
Nat Protoc. 2006;1(3):1517-21
17406443
Neuropharmacology. 2004;47 Suppl 1:33-46
15464124
J Neurosci. 2008 Jan 16;28(3):711-24
18199770
Brain Res. 1995 Oct 30;697(1-2):76-82
8593597
Psychopharmacology (Berl). 2000 Aug;151(2-3):99-120
10972458
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1639-44
11818568
Biol Psychiatry. 2004 Sep 15;56(6):381-5
15364034
J Neurosci. 2009 Mar 18;29(11):3529-37
19295158
Nat Rev Neurosci. 2007 Nov;8(11):844-58
17948030
Nature. 2001 Mar 15;410(6826):376-80
11268215
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4147-52
17360491
ACS Chem Neurosci. 2010 May 19;1(5):348-365
20543890
Neuroscience. 2003;116(1):19-22
12535933
J Neurosci. 2009 Mar 4;29(9):2876-84
19261883