title: Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving.
abstract: Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc preceded and enabled CP-AMPAR accumulation. Thus, restoring mGluR1 transmission by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results suggest a strategy in which recovering addicts could use a systemically active compound to protect against cue-induced relapse.
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Loweth
authors.affiliation: 1] Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2] Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Scheyer
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Milovanovic
authors.affiliation: Department of Psychology, Arizona State University, Tempe, Arizona, USA.
authors.forename: Amber L
authors.initials: AL
authors.lastname: LaCrosse
authors.affiliation: Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Eden
authors.initials: E
authors.lastname: Flores-Barrera
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Werner
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: 1] Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2] Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Ford
authors.affiliation: Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Tuan
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Psychology, Arizona State University, Tempe, Arizona, USA.
authors.forename: M Foster
authors.initials: MF
authors.lastname: Olive
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California, Santa Barbara, California, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
authors.affiliation: 1] Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2].
authors.forename: Kuei Y
authors.initials: KY
authors.lastname: Tseng
authors.affiliation: 1] Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2].
authors.forename: Marina E
authors.initials: ME
authors.lastname: Wolf
mesh_terms: D000494:Allosteric Regulation; D000704:Analysis of Variance; D000818:Animals; D019921:Biotinylation; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D003463:Cues; D000229:Dependovirus / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D049452:Green Fluorescent Proteins; D000072233:Homer Scaffolding Proteins; D018091:Receptors, AMPA