Long-Lasting Impairment of mGluR 5 -Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue International Journal of Neuropsychopharmacology Année : 2017

Long-Lasting Impairment of mGluR 5 -Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration

Résumé

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 with drawal 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 with drawal. 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.
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hal-02149071 , version 1 (11-06-2021)

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Paternité - Pas d'utilisation commerciale

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Hanne Mette Hoffmann, Nadine Crouzin, Estefanía Moreno, Noora Raivio, Silvia Fuentes, et al.. Long-Lasting Impairment of mGluR 5 -Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration. International Journal of Neuropsychopharmacology, 2017, pyw086. ⟨10.1093/ijnp/pyw086⟩. ⟨hal-02149071⟩
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