Abstract
Associative learning processes have an important role in the initiation and persistence of heroin-seeking. Here we show in a rat self-administration model that reexposure to cues previously associated with heroin results in downregulation of AMPA receptor subunit GluR2 and concomitant upregulation of clathrin-coat assembly protein AP2ml in synaptic membranes of the medial prefrontal cortex (mPFC). Reduced AMPA receptor expression in synaptic membranes was associated with a decreased AMPA/NMDA current ratio and increased rectification index in mPFC pyramidal neurons. Systemic or ventral (but not dorsal) mPFC injections of a peptide inhibiting GluR2 endocytosis attenuated both the rectification index and cue-induced relapse to heroin-seeking, without affecting sucrose-seeking. We conclude that GluR2 receptor endocytosis and the resulting synaptic depression in ventral mPFC are crucial for cue-induced relapse to heroin-seeking. As reexposure to conditioned stimuli is a major cause for heroin relapse, inhibition of GluR2 endocytosis may provide a new target for the treatment of heroin addiction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acoustic Stimulation
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Analysis of Variance
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Animals
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Behavior, Animal / drug effects
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Cues*
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Endocytosis / drug effects
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Endocytosis / physiology
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Excitatory Amino Acid Agonists / pharmacology
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Extinction, Psychological
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology*
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Heroin / administration & dosage*
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Heroin Dependence / psychology*
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In Vitro Techniques
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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N-Methylaspartate / pharmacology
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Narcotics / administration & dosage*
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Neurons / drug effects
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Neurons / physiology
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Patch-Clamp Techniques
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Peptides / pharmacology
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Prefrontal Cortex / cytology
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / physiology*
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Rats
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Rats, Wistar
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Receptors, AMPA / agonists
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Receptors, AMPA / antagonists & inhibitors
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Receptors, AMPA / chemistry
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Receptors, AMPA / metabolism*
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Reinforcement Schedule
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Reinforcement, Psychology
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Self Administration / methods
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Sucrose / administration & dosage
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Tandem Mass Spectrometry / methods
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Excitatory Amino Acid Agonists
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Narcotics
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Peptides
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Receptors, AMPA
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Sucrose
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N-Methylaspartate
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Heroin
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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glutamate receptor ionotropic, AMPA 2