Abstract
Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca(2+)/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca(2+) channels and CaMKII. Cocaine reinstatement is associated with D1-like dopamine receptor-dependent increases in accumbens shell CaMKII phosphorylated on Thr286 and glutamate receptor 1 (GluR1) phosphorylated on Ser831 (a known CaMKII phosphorylation site), in addition to increases in cell-surface expression of GluR1-containing AMPA receptors in the shell. Consistent with these findings, cocaine reinstatement is attenuated by intra-shell administration of AAV10-GluR1-C99, a vector that impairs the transport of GluR1-containing AMPA receptors. Thus, CaMKII may be an essential link between accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine craving and relapse.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites / drug effects
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Calcium Channel Blockers / pharmacology
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Calcium Channels, L-Type / drug effects
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Calcium Channels, L-Type / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / drug effects*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Cocaine / pharmacology
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Cocaine-Related Disorders / metabolism*
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Cocaine-Related Disorders / physiopathology
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Diltiazem / pharmacology
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Dopamine / metabolism*
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Dopamine Agonists / pharmacology
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Dopamine Uptake Inhibitors / pharmacology
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Glutamic Acid / metabolism*
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Male
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Nucleus Accumbens / drug effects*
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Nucleus Accumbens / metabolism
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Nucleus Accumbens / physiopathology
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Phosphorylation / drug effects
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Protein Transport / genetics
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Rats
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Rats, Sprague-Dawley
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Receptors, AMPA / drug effects
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Receptors, AMPA / metabolism
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Receptors, Dopamine D1 / drug effects
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Receptors, Dopamine D1 / metabolism
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Synaptic Transmission / drug effects*
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Synaptic Transmission / physiology
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Threonine / metabolism
Substances
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Calcium Channel Blockers
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Calcium Channels, L-Type
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Dopamine Agonists
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Dopamine Uptake Inhibitors
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Receptors, AMPA
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Receptors, Dopamine D1
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Threonine
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Glutamic Acid
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Diltiazem
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Cocaine
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glutamate receptor ionotropic, AMPA 1
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Dopamine