Exposure to opiates induces locomotor sensitization in rodents,which may be related to developing compulsive drug-seeking behavior.Although increased striatal dopamine transmission is widely accepted to be critical for expressing locomotor sensitization,numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner.The underlying mechanisms for these observations are unclear.Here we propose the modulation of μOR function by D1R through physical association with μOR as a potential mechanism.In support of this hypothesis,we showed that D1R antagonist SCH23390 significantly inhibited μOR-mediated G-protein activation,adenylyl cyclese inhibition,ERK1/2 phosphorylation and c-fos expression in cotransfected HEK-293 cells in which dopamine transmission is absent.Some of these effects were also demonstrated in rodent striatal membranes or in primarily cultured striatal neurons in which dopamine release is absent because mesocorticolimbic dopamine transmission has been cut off.In vivo we demonstrated that,under the conditions of dopamine release absence (e.g.destruction of the dopaminergic projection from the ventral tegmental area to the striatum or direct microinjection of DAMGO into the striatum),SCH23390 significantly inhibited morphine-or DAMGO-induced locomotor sensitization in rats.Moreover,we showed that interacting complexes containing μOR and D1R existed in live cells and rodent striatal membranes.The functional correlation between interacting complexes and locomotor sensitization was supported by the findings that μOR and D1R mutant mice,which are unable to form μOR-D1R complexes,fail to express locomotor sensitization to morphine.Together,these results support that D1R modulates μOR function through direct receptor-receptor interactions via physical association.