Veratridine and other depolarizing agents counteract the inhibitory effect of Mg2+ ions on N-methyl-D-aspartate (NMDA)-induced noradrenaline release in vitro

Abstract

Rat brain cortex slices preincubated with ³H-noradrenaline were superfused with Krebs-Henseleit solution with or without Mg²⁺. In the absence of Mg²⁺ ions, NMDA evoked ³H-noradrenaline overflow above basal efflux; this effect was concentration-dependently inhibited by Mg²⁺ (IC₅₀: 19 μmol/l). Despite the presence of 1.2 mmol/l Mg²⁺, which is known to block cation influx through the ion channel coupled to the NMDA receptor, NMDA evoked ³H-noradrenaline release if the membrane was permanently kept depolarized by 20 or 25 mmol/l K⁺, 1 μmol/l veratridine or 200 μmol/l 3,4-diaminopyridine; the stimulant effect of NMDA was counteracted by 2-amino-5-phosphonovaleric acid (2-APV), a competitive antagonist at the NMDA receptor and by (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyc-lohept-5,10-imine hydrogen maleate (MK 801), an antagonist acting at the cation channel associated with the NMDA receptor. In contrast, no stimulatory effect of NMDA in the presence of 1.2 mmol/l Mg²⁺ was observed when the membrane of the nerve terminals was intermittently depolarized by electrical impulses of 2 ms duration at a frequency of 1–3 Hz. It is concluded that continuous depolarization of the nerve membrane counteracts the blocking effect of Mg²⁺ on cation influx through the NMDA receptor-associated ion channel. Under this condition, noradrenaline release can be stimulated by NMDA receptor activation even in the presence of physiological Mg²⁺ concentrations.