The effect of the desglycinyl metabolite of remacemide hydrochloride (FPL 12495AA) and dizocilpine (MK‐801) on endogenous amino acid release from mouse cortex

Abstract

1 In this study the effect of FPL 12495AA, the desglycinyl metabolite of remacemide hydrochloride and dizocilpine (MK-801), on potassium-and veratridine-stimulated release of neurotransmitter amino acids from mouse cortical slices was investigated.2 Veratridine (20 gM) and potassium (60 mM) produced a preferential release of glutamate and aspartate. Potassium-stimulated release was calcium-dependent, while veratridine-stimulated release was only partially affected by removal of calcium from the medium. 3 FPL 12495AA significantly inhibited veratridine-and potassium-stimulated release of glutamate and aspartate. Lower concentrations of FPL 12495AA were needed to inhibit veratridine-stimulated release of glutamate (12.5 gM) than potassium-stimulated release (100 gM).4 Dizocilpine significantly inhibited veratridine-and potassium-stimulated release of glutamate and aspartate at concentrations of 100 gM and above. 5 FPL 12495AA and dizocilpine both have an affinity for the ion channel subsite of the N-methyl-Daspartate (NMDA) receptor. The reduction of potassium-stimulated release of glutamate and aspartate by FPL 12495AA and dizocilpine is probably due to NMDA receptor blockade. 6 FPL 12495AA inhibited veratridine-stimulated release at a concentration of 12.5 uM while dizocilpine was effective only at a concentration of 100 gM. This difference in efficacy is probably due to the higher affinity of FPL 12495AA compared to dizocilpine at the veratridine-binding site on the sodium channel.

The effect of losigamone (AO‐33) on electrical activity and excitatory amino acid release in mouse cortical slices

“…In addition, this study showed that losigamone reduced veratridine-induced release of glutamate at concentrations of 100 mM and above, and potassium-induced release of glutamate and potassium-and veratridine-induced release of aspartate at concentrations of 200 mM. As previously shown, potassium-stimulated release is calcium-dependent while veratridine-stimulated release is only partially a ected by removal of calcium from the medium (Srinivasan et al, 1995).…”

“…However, the e ect of losigamone in reducing potassium-stimulated release of glutamate and aspartate, is not a sodium channel e ect as TTX does not reduce release. The action of losigamone probably involves NMDA receptor antagonism as we have previously shown that dizocilpine (MK-801) reduced potassium-stimulated release of glutamate (Srinivasan et al, 1995).…”

“…The di erences in concentration of losigamone between that required to reduce potassium-stimulated release of glutamate and that which reduced NMDA-induced depolarizations is probably due to the nature of the stimulation. We have previously found (Hu & Davies, 1995) that exogenous application of NMDA was reduced by remacemide at lower concentrations than was potassium-stimulated glutamate release (Srinivasan et al, 1995), which, by nature of the methodology, is through endogenous mechanisms.…”

“…The technique adopted here has been previously described (Srinivasan et al, 1995). Brie¯y, adult BALB/c mice weighing 25 ± 30 g were killed by cervical dislocation.…”

Hyperactivity of Endoplasmic Reticulum Associated Exocytosis Mechanism Contributes to Acute Phencyclidine Intoxication

“…The cerebral cortex contains a large number of glutamatergic neurons and the dendrites in these neurons also possess NMDA receptors (32). If activation of these receptors is blocked, as is probably the case by NMDA antagonist, then augmentation of glutamate release by NMDAreceptor facilitation will not occur (33). Thus, PCP prevents both inhibitory GABAergic and excitatory glutamatergic regulations directly in pFC.…”