The purpose of this study was to characterize behavioral interactions between glutamatergic and serotonergic 5-HT2 receptors. Both competitive (AP-5 [D-2-amino-5-phosphovalerate] and D-CPP [3-(2carboxypiperazine-4yl)-propylphosphonate]) and noncompetitive (MK-801 [dizocilpine], ketamine, dextrorphan and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists markedly enhanced a selective serotonergic behavior, the head twitch response (HTR), in mice. In contrast, NMDA itself inhibited 5-hydroxytryptamine (5-HT)-induced HTR in mice. These results suggest that glutamatergic neurotransmission may modulate serotonergic function at the 5-HT2 receptor.