Modulation of extracellular signal-regulated kinases cascade by chronic Δ9-tetrahydrocannabinol treatment

ERK-Dependent Modulation of Cerebellar Synaptic Plasticity after Chronic Δ9-Tetrahydrocannabinol Exposure

“…In vivo, the pharmacological block of the ERK pathway suppresses behavioral responses and CB1R-mediated plasticity in the cerebellum and basal ganglia, thereby suggesting a role for the Ras/ERK pathway in cannabinoid tolerance to the THC-induced hypolocomotor effects (Rubino et al, 2005). Similar results have been reported in RasGRF1 null mice (Rubino et al, 2004(Rubino et al, , 2005. RasGRF1 is a neuron-specific Ras guanine nucleotide exchange factor (Zippel et al, 1997) that acts on the Ras/ERK pathway and is activated in response to G-protein-coupled and ionotropic receptors (Feig, 1994;Zippel et al, 1996;Tian et al, 2004).…”

“…RasGRF ϩ/ϩ and Ϫ/Ϫ mice originating from the leading strain described by Brambilla et al (1997) on a C57BL/6 background were housed in a controlled environment at constant temperature and humidity, on a 12-h light/dark cycle, with free access to food and water. They were chronically treated with THC or its vehicle, subcutaneously administered at the dose of 10 mg/kg twice per day for 4.5 d. This is a well known chronic treatment protocol inducing tolerance in mice (Bass and Martin, 2000;Rubino et al, 2004). Bradykinesia and/or catalepsy were routinely observed during the initial THC exposure.…”

“…⌬ 9 -Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, impairs motor function in humans and laboratory animals (Adams and Martin, 1996) through the activation CB1R located in control motor regions, such as the basal ganglia and cerebellum (Chaperon and Thiebot, 1999;Patel and Hillard, 2001). Behavioral tolerance to the cannabinoid-induced locomotor effects (hypolocomotion, ataxia, and catalepsy) develops after chronic THC exposure, in parallel with CB1R downregulation and desensitization occurring in several brain areas, including the cerebellum Rubino et al, 2004Rubino et al, , 2005. Additionally, the THC withdrawal syndrome is associated with compensatory changes in the cAMP pathway occurring selectively in the cerebellum, indicating this area as a major neurobiological substrate for the chronic effects of THC (Tzavara et al, 2000).…”

“…Administration of THC in rodents activates the monomeric GTP-binding protein Ras/extracellular signal regulated kinase (ERK) cascade (Valjent et al, 2001(Valjent et al, , 2004Derkinderen et al, 2003;Rubino et al, 2004). In vivo, the pharmacological block of the ERK pathway suppresses behavioral responses and CB1R-mediated plasticity in the cerebellum and basal ganglia, thereby suggesting a role for the Ras/ERK pathway in cannabinoid tolerance to the THC-induced hypolocomotor effects (Rubino et al, 2005).…”

“…RasGRF1 is a neuron-specific Ras guanine nucleotide exchange factor (Zippel et al, 1997) that acts on the Ras/ERK pathway and is activated in response to G-protein-coupled and ionotropic receptors (Feig, 1994;Zippel et al, 1996;Tian et al, 2004). Mice lacking RasGRF1 (Ϫ/Ϫ) do not develop behavioral tolerance after chronic treatment with THC (Rubino et al, 2004), thereby representing a useful genetic model to investigate the role of the Ras/ERK pathway in cannabinoid dependence.…”