title: The Extracellular Matrix Protein Brevican Limits Time-Dependent Enhancement of Cocaine Conditioned Place Preference.
abstract: Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting memories of cocaine reward. During periods of abstinence, responding to cocaine cues can time-dependently intensify a phenomenon referred to as 'incubation of cocaine craving'. Here, we investigated the role of the extracellular matrix protein brevican in recent (1 day after training) and remote (3 weeks after training) expression of cocaine conditioned place preference (CPP). Wild-type and Brevican heterozygous knock-out mice, which express brevican at ~50% of wild-type levels, received three cocaine-context pairings using a relatively low dose of cocaine (5 mg/kg). In a drug-free CPP test, heterozygous mice showed enhanced preference for the cocaine-associated context at the remote time point compared with the recent time point. This progressive increase was not observed in wild-type mice and it did not generalize to contextual-fear memory. Virally mediated overexpression of brevican levels in the hippocampus, but not medial prefrontal cortex, of heterozygous mice prevented the progressive increase in cocaine CPP, but only when overexpression was induced before conditioning. Post-conditioning overexpression of brevican did not affect remote cocaine CPP, suggesting that brevican limited the increase in remote CPP by altering neuro-adaptive mechanisms during cocaine conditioning. We provide causal evidence that hippocampal brevican levels control time-dependent enhancement of cocaine CPP during abstinence, pointing to a novel substrate that regulates incubation of responding to cocaine-associated cues.
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bart R
authors.initials: BR
authors.lastname: Lubbers
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mariana R
authors.initials: MR
authors.lastname: Matos
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Horn
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Visser
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rolinka C
authors.initials: RC
authors.lastname: Van der Loo
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Gouwenberg
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gideon F
authors.initials: GF
authors.lastname: Meerhoff
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Renato
authors.initials: R
authors.lastname: Frischknecht
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Constanze I
authors.initials: CI
authors.lastname: Seidenbecher
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Michel C
authors.identifier: 0000-0001-5523-8612
authors.initials: MC
authors.lastname: van den Oever
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D000818:Animals; D058581:Brevican / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D005239:Fear / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D000779:Anesthetics, Local; C553057:Bcan protein, mouse; D058581:Brevican; D019063:Tenascin; D049452:Green Fluorescent Proteins; C074638:tenascin R; D003042:Cocaine