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
✍ Scribed by David Moranta; Susana Esteban; Jesús A. García-Sevilla
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 462 KB
- Volume
- 85
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
The cannabinoids (CB) modulate the extracellular signal‐regulated 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 CB~1~ 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 CB~1~ receptors in the frontal cortex results in the sequential phosphorylation of Raf‐MEK‐ERK 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. © 2006 Wiley‐Liss, Inc.