ERK activation and the downstream changes in transcription evoked by stimulant drugs and cannabinoids are dependent on the activation of dopamine and NMDA receptors. Dopamine antagonists prevent the increases in ERK phosphorylation that result from cocaine,16 amphetamine,21 methamphetamine,31 or THC administration.32 Dopamine D1 receptor knockout mice fail to display drug-induced increases in p-ERK17,33 or ERK-dependent increases in phosphorylated CREB (p-CREB)33 or c-fos levels.17 Inhibition of NMDA receptors also prevents the ERK phosphorylation that results from treatment with cocaine,33 amphetamine,21 THC,32 or the cannabinoid receptor 1 (CB1) agonist WIN-55212-2.34 The effect of THC on ERK is mediated through Ras. Knockout mice lacking Ras-GRF1 do not show THC-mediated increases in p-ERK in the dorsal striatum or cerebellum.24
