Long-lasting impairment of mGluR5-activated intracellular pathways in the striatum after withdrawal of cocaine self-administration
Hoffmann, Hanne Mette (University of California San Diego. Department of Reproductive Medicine)
Crouzin, Nadine (Oxidative Stress and Neuroprotection. IBMM. CNRS UMR-5247. University of Montpellier II)
Moreno, Estefanía (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Raivio, Noora (Universitat Autònoma de Barcelona. Institut de Neurociències)
Fuentes Garcia, Silvia (Universitat Autònoma de Barcelona. Departament de Psicobiologia i de Metodologia de Ciències de la Salut)
McCormick, Peter J. (University of East Anglia. School of Pharmacy)
Ortiz de Pablo, Jordi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Vignes, Michel (Oxidative Stress and Neuroprotection. IBMM. CNRS UMR-5247. University of Montpellier II)

Data:	2017
Resum:	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 mGluR 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.
Ajuts:	Ministerio de Educación y Ciencia SAF2006-08240 Ministerio de Ciencia e Innovación SAF2009-12510 Ministerio de Economía y Competitividad SAF2014-58396 Ministerio de Sanidad y Consumo RD06/0001/0015 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR-1236
Nota:	ANECA
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Extracellular signal-regulated protein kinase1 and 2 ; Camp response element binding protein ; Cocaine self-administration withdrawal ; Striatum ; Long term depression
Publicat a:	International journal of neuropsychopharmacology, Vol. 20 Núm. 1 (2017) , p. 72-82, ISSN 1469-5111

DOI: 10.1093/ijnp/pyw086
PMID: 27744406

11 p, 1.7 MB

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