Intracerebroventricular (i.c.v.) administration of N-methyl-D-aspartate (NMDA) caused a biphasic rise of brain temperature, namely, a rapid, early rise and a larger, late rise, in urethane-anesthetized rats. I.c.v. pretreatment with a noncompetitive NMDA receptor antagonist, MK-801, attenuated the late rise of the brain temperature, but had no effect on the early rise, whereas i.c.v. pretreatment with a competitive NMDA receptor antagonist, (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), attenuated both rises. AP-5 per se caused a rise in brain temperature without any rise of rectal temperature, whereas MK-801 per se caused no significant change of the brain or rectal temperature. This rise by AP-5 was suppressed by MK-801, suggesting an agonistic effect of AP-5 on NMDA receptors in rat brain in vivo.