Long-lasting impairment of mGluR<inf>5</inf>-activated intracellular pathways in the striatum after withdrawal of cocaine self-administration

Hanne Mette Hoffmann, Nadine Crouzin, Estefanía Moreno, Noora Raivio, Silvia Fuentes, Peter J. McCormick, Jordi Ortiz, Michel Vignes

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

© The Author 2016. Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Original languageEnglish
Pages (from-to)72-82
JournalInternational Journal of Neuropsychopharmacology
Volume20
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • cAMP response element binding protein
  • Cocaine self-administration withdrawal
  • Extracellular signal-regulated protein kinase1 and 2
  • Long term depression
  • Striatum

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