The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the alpha-amino-3-hydroxy-5-methylisoxazole- 4-propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here.