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Gαq/11 protein transduces signals from neurotransmitter receptors and has been implicated in several functions of the central nervous system. In this study, the role of Gαq/11 protein in methamphetamine (METH)-induced behavioral sensitization was investigated using neurochemical and behavioral approaches. Repeated treatment with METH (2 mg/kg, intraperitoneally) significantly increased behavioral sensitization as well as Gαq/11 protein expression and Gα protein activity in the striata of mice, while a single treatment of METH at the same dose did not affect these parameters. Repeated intrastriatal injections of a Gαq/11 inhibitor, [D-Trp7,9,10]-substance P, significantly reduced behavioral sensitization and striatal dopamine (DA) level in response to METH, with no effect on striatal tyrosine hydroxylase expression. These results suggest that Gαq/11 protein facilitates METH-induced behavioral sensitization by modulating DA release in the mouse striatum.