Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking

Michel C Van den Oever; Natalia A Goriounova; Ka Wan Li; Roel C Van der Schors; Rob Binnekade; Anton N M Schoffelmeer; Huibert D Mansvelder; August B Smit; Sabine Spijker; Taco J De Vries

doi:10.1038/nn.2165

Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking

Nat Neurosci. 2008 Sep;11(9):1053-8. doi: 10.1038/nn.2165.

Authors

Michel C Van den Oever¹, Natalia A Goriounova, Ka Wan Li, Roel C Van der Schors, Rob Binnekade, Anton N M Schoffelmeer, Huibert D Mansvelder, August B Smit, Sabine Spijker, Taco J De Vries

Affiliation

¹ Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.

PMID: 19160503
DOI: 10.1038/nn.2165

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

Research Support, Non-U.S. Gov't

MeSH terms

Acoustic Stimulation
Analysis of Variance
Animals
Behavior, Animal / drug effects
Cues*
Endocytosis / drug effects
Endocytosis / physiology
Excitatory Amino Acid Agonists / pharmacology
Extinction, Psychological
Gene Expression Regulation / drug effects
Gene Expression Regulation / physiology*
Heroin / administration & dosage*
Heroin Dependence / psychology*
In Vitro Techniques
Male
Membrane Potentials / drug effects
Membrane Potentials / physiology
N-Methylaspartate / pharmacology
Narcotics / administration & dosage*
Neuronal Plasticity / drug effects
Neuronal Plasticity / physiology*
Neurons / drug effects
Neurons / physiology
Patch-Clamp Techniques
Peptides / pharmacology
Prefrontal Cortex / cytology
Prefrontal Cortex / drug effects
Prefrontal Cortex / physiology*
Rats
Rats, Wistar
Receptors, AMPA / agonists
Receptors, AMPA / antagonists & inhibitors
Receptors, AMPA / chemistry
Receptors, AMPA / metabolism*
Reinforcement Schedule
Reinforcement, Psychology
Self Administration / methods
Sucrose / administration & dosage
Tandem Mass Spectrometry / methods
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

Excitatory Amino Acid Agonists
Narcotics
Peptides
Receptors, AMPA
Sucrose
N-Methylaspartate
Heroin
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
glutamate receptor ionotropic, AMPA 2