REEVALUATION OF ACEA-1021 AS AN ANTAGONIST AT THE STRYCHNINE-INSENSITIVE GLYCINE SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR

Electrophysiological experiments were performed in vitro and in vivo t o characterize the inhibitory effects of -dichloro-5-nitro-1,4-dihydro -2,3-quinoxalinedione (ACEA 1021; licostinel) on rat brain glutamate r eceptors. In vitro: ACEA 1021 was tested on N-methyl-D-aspartate (NMDA )-induced depolarizations in the neocortical slice preparation and on epileptiform activity in Mg2+-free hippocampal slices, which is known to be NMDA receptor mediated. In both in vitro models, ACEA 1021 exhib ited antagonistic effects on the NMDA receptor-mediated responses. Sel ectivity tests in the neocortical slice preparation, using NMDA, kaina te and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepronic acid (AMPA) sh owed that 10 mu M ACEA 1021 reduced NMDA and kainate responses to 27.9 and 79.9% of the control value, respectively, whereas responses to AM PA were increased by 2.4% above the control value, thus showing that a t this concentration ACEA 1021 acts preferentially at NMDA receptors. However; at 30 mu M, all the NMDA-, AMPA- and kainate-induced response s were reduced. In vivo, ACEA 1021 was tested on NMDA-induced excitati on in the CA1 region. After systemic administration of ACEA 1021, cent ral effects were observed at 10 mg/kg i.v. in the CA1 region. These re sults indicate that ACEA 1021 is centrally active and inhibits NMDA re ceptor-mediated responses. Interestingly, selectivity tests in the CA1 region did not show clear differences in the action of ACEA 1021 on N MDA- and AMPA-induced excitations. Furthermore, ACh-induced excitation s were also reduced. Thus, at low concentrations, ACEA 1021 seems to b e a selective antagonist at the strychnine insensitive glycine site of the NMDA receptor. However, at 30 mu M in vitro and at 10 mg/kg in vi vo, non-NMDA receptor-mediated actions of ACEA 1021 are observed. Our results suggest that these additional effects of ACEA 1021 may contrib ute to its anticonvulsive properties in mice as well as to its neuropr otective properties in animal models of cerebral ischemia. (C) 1998 El sevier Science Ltd. All rights reserved.