The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function

Forepaw treading induced in rats by the 5HT(1A) agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT(2A) receptor against DOI, a nd by the 5HT precursor (-)5HTP, were significantly increased by pretreatme nt with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilp ine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor a ntagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modif y locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by th e 5HT(2) agonist ketanserin, but was not modified by the selective dopamine D-1 and D-2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine rec eptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to a ll the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the ex pression of serotonergic stimulation, and suggest that a glutamate deficien cy could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity. (C) 1999 Lippin cott Williams & Wilkins.