MODULATION OF NMDA EFFECTS ON AGONIST-STIMULATED PHOSPHOINOSITIDE TURNOVER BY MEMANTINE IN NEONATAL RAT CEREBRAL-CORTEX

1 The ability of memantine (1-amino-3,5-dimethyladamantane) to antagonize the modulatory effects of N-methyl-D-aspartate (NMDA) on phosphoinositide turnover stimulated by muscarinic cholinoceptor- and metabotropic glutamate receptor-agonists has been examined in neonatal rat cerebral cortex slices. 2 Memantine antagonized the inhibitory effect of NMDA (100 mu M) on both total [H-3]-inositol phosphate ([H-3]-InsP(x)) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P-3) mass accumulations stimulated by carbachol (1 mM) with EC(50) values of 21 and 16 mu M respectively. 3 Memantine concentration-dependently antagonized (IC50 24 mu M) the ability of NMDA (10 mu M) to potentiate [H-3]-InsP(x) accumulation in response to a sub-maximal concentration of the metabotropic glutamate receptor agonist, 1S,3R-ACPD (10 mu M). 4 The small (approx. 3 fold), concentration-dependent increase in [H-3]-InsP(x) accumulation stimulated by NMDA was completely antagonized by the prototypic NDMA receptor-channel blocker, MK-801 (1 mu M) at all concentrations of NDMA studied (1-1000 mu M). In contrast, antagonism by memantine (100 mu M) was observed only at low concentrations of NMDA (1-10 mu M), Whilst [H-3]-InsP(x) accumulation stimulated by high concentrations of NMDA (300-1000 mu M) was markedly enhanced by memantine. 5 Assessment of the incorporation of [H-3]-inositol into inositol phospholipids revealed that memantine (100 mu M) caused an approximate 2 fold increase in the labelling of phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. 6 H.p.l.c, separation of (H-3)-inositol (poly)phosphates demonstrated that whilst memantine (100 mu M) alone had no significant effect on the accumulation of any isomer, it substantially altered the profile of accumulation stimulated by NMDA (1 mM), greatly facilitating accumulation of Ins(1,4,5)P-3 and inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P-4). 7 These data provide evidence that memantine can antagonize the actions of NMDA in neonatal rat cerebral cortex dices in a manner consistent with this agent acting as a NMDA receptor-channel blocker. In addition, at least two further actions of memantine can be proposed. Memantine increases the rate of [H-3]-inositol incorporation into the cellular inositol phospholipid fraction, without significantly stimulating phosphoinositide turnover. Furthermore, memantine can substantially alter patterns of inositol (poly)phosphates stimulated by NMDA, promoting the accumulation of the established and putative second messengers Ins(1,4,5)P-3 and Ins(1,3,4,5)P-4 which are not increased by NMDA in the absence of memantine. It is unknown whether these latter loci of memantine action contribute to known therapeutic actions of this agent.