Résumé : Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2AR) co-localize with metabotropic glutamate 5 receptors (mGlu5R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2AR in mice, we investigated whether A2AR–mGlu5R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2AR, as well as combined administration of sub-threshold doses of the selective A2AR antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5R binding was reduced in the nucleus accumbens core of A2AR knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5R binding in wild-type mice, which was absent in the A2AR KO mice. These data are in support of a critical role of striatal A2AR–mGlu5R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2AR and mGlu5R may represent a novel therapy for methamphetamine addiction.