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 (Kal7KO), a Rho guanine nucleotide exchange factor that regulates dendritic spine formation
and function. Both wild-type (Wt) and Kal7KO 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 Kal7KO animals showed greater locomotor sensitization to cocaine than Wt mice. In contrast,
Kal7KO 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 Kal7KO mice. Wild-type mice treated with cocaine for 8 days exhibited larger dendritic spines
than cocaine-treated Kal7KO 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.
Key Words
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References
- Neural mechanisms of addiction.Annu Rev Neurosci. 2006; 29: 565-598
- Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine.Nature. 1999; 401: 272-276
- Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.Nature. 2008; 454: 118-121
- Structural plasticity associated with exposure to drugs of abuse.Neuropharmacology. 2004; 47: 33-46
- Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens.Proc Natl Acad Sci U S A. 2003; 100: 10523-10528
- Altered dendritic spine plasticity in cocaine-withdrawn rats.J Neurosci. 2009; 29: 2876-2884
- Role of Rho GTPases in the morphogenesis and motility of dendritic spines.Methods Enzymol. 2008; 439: 285-302
- Rho GTPases in neuronal morphogenesis.Nat Rev Neurosci. 2000; 1: 173-180
- Synaptic plasticity.ACS Chem Neurosci. 2010; ([published online ahead of print March 18]) (doi:10.1021/cn100012x)
- Kalirin-7 is an essential component of both shaft and spine excitatory synapses in hippocampal interneurons.J Neurosci. 2008; 28: 711-724
- Coordination of synaptic adhesion with dendritic spine remodeling by AF-6 and kalirin-7.J Neurosci. 2008; 28: 6079-6091
- Kalirin-7 is required for synaptic structure and function.J Neurosci. 2008; 28: 12368-12382
- Flanking gene and genetic background problems in genetically manipulated mice.Biol Psychiatry. 2004; 56: 381-385
- Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice.Eur J Neurosci. 1999; 11: 1114-1118
- Homer proteins regulate sensitivity to cocaine.Neuron. 2004; 43: 401-413
- Diolistic labeling of neuronal cultures and intact tissue using a hand-held gene gun.Nat Protoc. 2006; 1: 1517-1521
- Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens.Proc Natl Acad Sci U S A. 2006; 103: 3399-3404
- Labeling of dendritic spines with the carbocyanine dye DiI for confocal microscopic imaging in lightly fixed cortical slices.J Neurosci Methods. 2007; 162: 237-243
- Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens.Proc Natl Acad Sci U S A. 2009; 106: 2915-2920
- Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice.Nature. 2007; 448: 894-900
- Constitutively active Rap2 transgenic mice display fewer dendritic spines, reduced extracellular signal-regulated kinase signaling, enhanced long-term depression, and impaired spatial learning and fear extinction.J Neurosci. 2008; 28: 8178-8188
- Molecular mechanisms of psychostimulant-induced structural plasticity.Pharmacopsychiatry. 2009; 42: S69-S78
- The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens.Eur J Neurosci. 2004; 20: 1647-1654
- Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine.Eur J Neurosci. 1999; 11: 1598-1604
- Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5.Neuroscience. 2003; 116: 19-22
- Cocaine regulates MEF2 to control synaptic and behavioral plasticity.Neuron. 2008; 59: 621-633
- Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward.J Neurosci. 2009; 29: 3529-3537
- Do thin spines learn to be mushroom spines that remember?.Curr Opin Neurobiol. 2007; 17: 381-386
- Spine architecture and synaptic plasticity.Trends Neurosci. 2005; 28: 182-187
- Integration of biochemical signalling in spines.Nat Rev Neurosci. 2005; 6: 423-434
- Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons.Proc Natl Acad Sci U S A. 2002; 99: 1639-1644
- Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability.J Neurosci. 2007; 27: 12967-12976
- Effects of deletion of gria1 or gria2 genes encoding glutamatergic AMPA-receptor subunits on place preference conditioning in mice.Psychopharmacology (Berl). 2005; 179: 164-171
- Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice.J Neurosci. 2007; 27: 13140-13150
- The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis.Neuron. 2001; 29: 229-242
- Regulation of kalirin by Cdk5.J Cell Sci. 2008; 121: 2601-2611
- Experience-dependent structural synaptic plasticity in the mammalian brain.Nat Rev Neurosci. 2009; 10: 647-658
- Balancing structure and function at hippocampal dendritic spines.Annu Rev Neurosci. 2008; 31: 47-67
- Cocaine increases actin cycling.J Neurosci. 2006; 26: 1579-1587
- Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5.Nature. 2001; 410: 376-380
- Inhibition of Cdk5 in the nucleus accumbens enhances the locomotor-activating and incentive-motivational effects of cocaine.Proc Natl Acad Sci U S A. 2007; 104: 4147-4152
- Unmanageable motivation in addiction.Neuron. 2005; 45: 647-650
- Synaptic plasticity.Nat Neurosci. 2000; 3: 1178-1183
- Neuroscience.Nature. 2008; 455: 743-744
- Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization.Psychopharmacology (Berl). 2000; 151: 99-120
- DNQX in the nucleus accumbens inhibits cocaine-induced conditioned place preference.Brain Res. 1995; 697: 76-82
- Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex.Synapse. 2001; 39: 257-266
- Synaptic plasticity and addiction.Nat Rev Neurosci. 2007; 8: 844-858
- Role of Cdk5 in drug abuse and plasticity.Ann N Y Acad Sci. 2004; 1025: 335-344
- Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation.Nat Neurosci. 2007; 10: 880-886
- Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.Nat Neurosci. 2009; 12: 602-610
- The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats.Exp Neurol. 2006; 200: 343-355
- Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site.J Biol Chem. 2000; 275: 19324-19333
Article info
Publication history
Published online: May 11, 2010
Accepted:
March 23,
2010
Received in revised form:
March 19,
2010
Received:
August 13,
2009
Footnotes
Authors DDK and X-MM contributed equally to this work.
Identification
Copyright
© 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
