title: Long-Lasting Impairment of mGluR5-Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration.
abstract: Cocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors, with allosteric modulators showing particular promise.
  
  
  
  We evaluated the capacity of group I metabotropic glutamate receptors to induce functional responses in ex vivo striatal slices from rats with (1) acute cocaine self-administration, (2) chronic cocaine self-administration, and (3) 60 days cocaine self-administration withdrawal by Western blot and extracellular recordings of synaptic transmission.
  
  
  
  We found that striatal group I metabotropic glutamate receptors are the principal mediator of the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine-induced cAMP responsive-element binding protein phosphorylation. Both acute and chronic cocaine self-administration blunted group I metabotropic glutamate receptor effects on cAMP responsive-element binding protein phosphorylation in the striatum, which correlated with the capacity to induce long-term depression, an effect that was maintained 60 days after chronic cocaine self-administration withdrawal. In the nucleus accumbens, the principal brain region mediating the rewarding effects of drugs, chronic cocaine self-administration blunted group I metabotropic glutamate receptor stimulation of extracellular signal-regulated protein kinases 1/2 and cAMP responsive-element binding protein. Interestingly, the group I metabotropic glutamate receptor antagonist/inverse-agonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride, led to a specific increase in cAMP responsive-element binding protein phosphorylation after chronic cocaine self-administration, specifically in the nucleus accumbens, but not in the striatum.
  
  
  
  Prolonged cocaine self-administration, through withdrawal, leads to a blunting of group I metabotropic glutamate receptor responses in the striatum. In addition, specifically in the accumbens, group I metabotropic glutamate receptor signaling to cAMP responsive-element binding protein shifts from an agonist-induced to an antagonist-induced cAMP responsive-element binding protein phosphorylation.
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Variabilité de réponse aux psychotropes, Inserm, Université Paris Descartes, Faculté de pharmacie, Université Paris Diderot, UMR-S 1144, Paris,France.
authors.forename: Hanne Mette
authors.initials: HM
authors.lastname: Hoffmann
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Variabilité de réponse aux psychotropes, Inserm, Université Paris Descartes, Faculté de pharmacie, Université Paris Diderot, UMR-S 1144, Paris,France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Crouzin
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Variabilité de réponse aux psychotropes, Inserm, Université Paris Descartes, Faculté de pharmacie, Université Paris Diderot, UMR-S 1144, Paris,France.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Variabilité de réponse aux psychotropes, Inserm, Université Paris Descartes, Faculté de pharmacie, Université Paris Diderot, UMR-S 1144, Paris,France.
authors.forename: Noora
authors.initials: N
authors.lastname: Raivio
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Variabilité de réponse aux psychotropes, Inserm, Université Paris Descartes, Faculté de pharmacie, Université Paris Diderot, UMR-S 1144, Paris,France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fuentes
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Variabilité de réponse aux psychotropes, Inserm, Université Paris Descartes, Faculté de pharmacie, Université Paris Diderot, UMR-S 1144, Paris,France.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.affiliation: Department of Reproductive Medicine, 349 Leichtag Biomedical Research Building, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0674.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ortiz
authors.forename: Michel
authors.initials: M
authors.lastname: Vignes
mesh_terms: D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: D018765:Dopamine Uptake Inhibitors; D018683:Excitatory Amino Acid Agents; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D003042:Cocaine
keywords: cAMP response element binding protein; cocaine self-administration withdrawal; extracellular signal-regulated protein kinase1 and 2; long term depression; striatum