title: Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse.
abstract: Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration.
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, Peoples' Republic of China, and Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Hao-wei
authors.initials: HW
authors.lastname: Shen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Scofield
authors.forename: Heather
authors.initials: H
authors.lastname: Boger
authors.forename: Megan
authors.initials: M
authors.lastname: Hensley
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D003932:Heroin / Q000008:administration & dosage* / Q000009:adverse effects; D006556:Heroin Dependence / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D060172:Morpholinos / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055502:Secondary Prevention; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D060172:Morpholinos; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D003932:Heroin; D002443:Ceftriaxone; D011188:Potassium
keywords: extrasynaptic glutamate receptor; glutamate spillover; glutamate uptake; heroin self-administration; nucleus accumbens; relapse
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