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Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects
Author(s) -
Rubino Tiziana,
Forlani Greta,
Viganò Daniela,
Zippel Renata,
Parolaro Daniela
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03101.x
Subject(s) - mapk/erk pathway , cannabinoid , cannabinoid receptor , biology , kinase , chemistry , agonist , endocrinology , receptor , microbiology and biotechnology , pharmacology , medicine , biochemistry
We investigated the role of the Ras/extracellular‐regulated kinase (ERK) pathway in the development of tolerance to Δ 9 ‐tetrahydrocannabinol (THC)‐induced reduction in spontaneous locomotor activity by a genetic (Ras‐specific guanine nucleotide exchange factor (Ras‐GRF1) knock‐out mice) and pharmacological approach. Pre‐treatment of wild‐type mice with SL327 (50 mg/kg i.p.), a specific inhibitor of mitogen‐activated protein kinase kinase (MEK), the upstream kinase of ERK, fully prevented the development of tolerance to THC‐induced hypolocomotion. We investigated the impact of the inhibition of ERK activation on the biological processes involved in cannabinoid tolerance (receptor down‐regulation and desensitization), by autoradiographic cannabinoid CB1 receptor and cannabinoid‐stimulated [ 35 S]GTPγS binding studies in subchronically treated mice (THC, 10 mg/kg s.c., twice a day for 5 days). In the caudate putamen and cerebellum of Ras‐GRF1 knock‐out mice and SL327 pre‐treated wild‐type mice, CB1 receptor down‐regulation and desensitization did not occur, suggesting that ERK activation might account for CB1 receptor plasticity involved in the development of tolerance to THC hypolocomotor effect. In contrast, the hippocampus and prefrontal cortex showed CB1 receptor adaptations regardless of the genetic or pharmacological inhibition of the ERK pathway, suggesting regional variability in the cellular events underlying the altered CB1 receptor function. These findings suggest that at least in the caudate putamen and cerebellum, the Ras/ERK pathway is essential for triggering the alteration in CB1 receptor function responsible for tolerance to THC‐induced hypomotility.