Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking.
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.
Van den Oever
Michel C
MC
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics & Cognitive Research, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
Goriounova
Natalia A
NA
Li
Ka Wan
KW
Van der Schors
Roel C
RC
Binnekade
Rob
R
Schoffelmeer
Anton N M
AN
Mansvelder
Huibert D
HD
Smit
August B
AB
Spijker
Sabine
S
De Vries
Taco J
TJ
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003463:Cues; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005108:Extinction, Psychological; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000523:psychology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D013395:Sucrose / Q000008:administration & dosage; D053719:Tandem Mass Spectrometry / Q000379:methods; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D009294:Narcotics; D010455:Peptides; D018091:Receptors, AMPA; D013395:Sucrose; D016202:N-Methylaspartate; D003932:Heroin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C104722:glutamate receptor ionotropic, AMPA 2