Abstract In male C57BL/6, BALB/c, and SHR (bred from Swiss) mice, pretreatment with (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, attenuated the hyperlocomotion induced by β-phenylethylamine (PEA). This effect of CPP was blocked by intracerebroventricularly (ICV) administered NMDA (0.2 nM). CPP did not alter the hyperlocomotion induced by d-amphetamine. PEA rarely inhibited spontaneous motor activity in those strains. Two other competitive antagonists of NMDA, 2-amino-5-phosphonopentanoic acid (AP-5) and 2-amino-7-phosphonoheptanoic acid (AP-7), ICV at doses of 0.01 – 0.1 μg, were ineffective. The noncompetitive antagonists of NMDA, dizocilpine (MK-801) and phencyclidine, at subthreshold doses of 0.1 – 0.5 mg/kg, potentiated the stimulant effect of PEA. In earlier studies we also observed antagonism between CPP and PEA in NIH-Swiss mice, a strain in which PEA inhibits locomotion. Relationships between the stimulant and the anxiogenic effects of PEA are discussed.