dc.contributor.author |
Moranta Mesquida, David
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dc.contributor.author |
Esteban Valdés, Susana Cristina
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dc.contributor.author |
Garcia-Sevilla, Jesús Andrés
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dc.date.accessioned |
2018-09-18T08:08:27Z |
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dc.identifier.uri |
http://hdl.handle.net/11201/147487 |
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dc.description.abstract |
[eng] The cannabinoids (CB) modulate the extracellular signalregulated kinase (ERK), leading to various forms of plasticity in the brain. Little is known, however, on the in vivo short- and long-term activation and regulation of the components of mitogen-activated protein kinase (MAPK)/ERK signaling by CB. The CB agonist WIN55212-2 (8 mg/kg) increased the immunodensities of phosphorylated c-Raf-1 (42%), MEK1/2 (63%), ERK1 (24%), and ERK2 (28%) in the rat cerebral frontal cortex. These effects were antagonized by SR141716A (rimonabant, 10 mg/kg), a selective CB1 receptor antagonist. Repeated WIN55212-2 treatment (2-8 mg/kg for 5 days) resulted in tachyphylaxis to the acute activation of Raf-MEK-ERK signaling. Acute WIN55212-2 also induced a hypothermic effect in rats, which was reduced after repeated administration (tolerance). Treatment with SR141716A after chronic WIN55212-2 resulted in the expected cannabinoid withdrawal syndrome, without concomitant alterations in the phosphorylation state of c-Raf-1, MEK1/2, or ERK1/2. Pretreatment with SL327 (20 mg/kg, a MEK1/2 inhibitor) increased the basal phosphorylation of c-Raf-1 (40%) and MEK1/2 (74%; feedback regulation) and fully prevented the up-regulation of ERK1/2 (23-31%) induced by WIN55212-2. Pretreatment with MK801 (1 mg/kg, a NMDA receptor antagonist) effectively blocked the up-regulation c-Raf-1 (41%), MEK1/2 (57%) and ERK1/2 (25-30%) induced by the CB agonist. The main findings demonstrate that the acute stimulation of CB1 receptors in the frontal cortex results in the sequential phosphorylation of Raf-MEKERK cascade, in which c-Raf-1 activation (rate-limiting process) plays a crucial role. Moreover, the in vivo stimulating effect of WIN55212-2 on Raf-MEK-ERK signaling is under the extrinsic regulation of an excitatory glutamatergic mechanism. |
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dc.format |
application/pdf |
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dc.relation.isformatof |
Versió postprint del document publicat a: |
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dc.relation.ispartof |
Journal of Neuroscience Research, 2007, vol. 85, num. 3, p. 656-667 |
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dc.subject.classification |
612 - Fisiologia |
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dc.subject.classification |
615 - Farmacologia. Terapèutica. Toxicologia. Radiologia |
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dc.subject.other |
612 - Physiology. Human and comparative physiology |
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dc.subject.other |
615 - Pharmacology. Therapeutics. Toxicology |
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dc.title |
Acute, chronic and withdrawal effects of the cannabinoid receptor agonist WIN55212-2 on the sequential activation of MAPK/Raf-MEK-ERK signaling in the rat cerebral frontal cortex: short-term regulation by intrinsic and extrinsic pathways. |
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dc.type |
info:eu-repo/semantics/article |
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dc.type |
info:eu-repo/semantics/acceptedVersion |
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dc.date.updated |
2018-09-18T08:08:27Z |
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dc.date.embargoEndDate |
info:eu-repo/date/embargoEnd/2075-01-01 |
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dc.embargo |
2075-01-01 |
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dc.subject.keywords |
cerebro |
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dc.subject.keywords |
Rata |
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dc.subject.keywords |
cannabis |
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dc.subject.keywords |
MAPK |
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dc.subject.keywords |
síndrome de abstinència |
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dc.rights.accessRights |
info:eu-repo/semantics/embargoedAccess |
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