Abstract
To identify the molecular mechanisms underlying psychostimulant-elicited plasticity in the brain reward system, we undertook a phenotype-driven approach using genome-wide microarray profiling of striatal transcripts from three genetic and one pharmacological mouse models of psychostimulant or dopamine supersensitivity. A small set of co-affected genes was identified. One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice. At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case. Finally, targeted deletion of PSD-95 in an independent line of mice enhances LTP, augments the acute locomotor-stimulating effects of cocaine, but leads to no further behavioral plasticity in response to chronic cocaine. Our findings uncover a previously unappreciated role of PSD-95 in psychostimulant action and identify a molecular and cellular mechanism shared between drug-related plasticity and learning.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Brain / cytology
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Brain / drug effects
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Brain / metabolism*
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Cocaine / pharmacology
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Cocaine-Related Disorders / genetics
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Disks Large Homolog 4 Protein
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Dopamine / metabolism*
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Guanylate Kinases
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Long-Term Potentiation / genetics
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Membrane Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / genetics
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Neural Pathways / cytology
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Neural Pathways / drug effects
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Neural Pathways / metabolism*
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Nucleus Accumbens / drug effects
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Nucleus Accumbens / metabolism
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Presynaptic Terminals / drug effects
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Presynaptic Terminals / metabolism*
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Presynaptic Terminals / ultrastructure
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RNA, Messenger / metabolism
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Reward
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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RNA, Messenger
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postsynaptic density proteins
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Guanylate Kinases
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Cocaine
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Dopamine