NMDA RECEPTOR COMPLEX BLOCKADE BY ORAL-ADMINISTRATION OF MAGNESIUM - COMPARISON WITH MK-801

The ion channel of the N-methyl-D-aspartate (NMDA) receptor complex is subject to a voltage-dependent regulation by Mg2+ cations. Under phys iological conditions, this channel is supposed to be blocked by a high concentration of magnesium in extracellular fluids. A single dose of magnesium organic salts (i.e., aspartate, pyroglutamate, and lactate) given orally to normal mice rapidly increases the plasma Mg2+ level an d reveals a significant dose-dependent antagonist effect of magnesium on the latency of NMDA-induced convulsions; this effect is similar to that seen after administration of the dizocilpine (MK-801) channel blo cker. An anticonvulsant effect of Mg2+ treatment is also observed with strychnine-induced convulsions but not with bicuculline-, picrotoxin- , or pentylenetetrazol-induced convulsions. In the forced swimming tes t, Mg2+ salts reduce the immobility time in a way similar to imipramin e and thus resemble the antidepressant-like activity of MK-801. This a ctivity is masked at high doses of magnesium by a myorelaxant effect t hat is comparable to MK-801-induced ataxia. Potentiation of yohimbine fatal toxicity is another test commonly used to evaluate putative anti depressant drugs. Administration of Mg2+ salts, like administration of imipramine, strongly potentiates yohimbine lethality, in contrast to MK-801, which is only poorly active in this test. Neither Mg2+ nor MK- 801 treatment can prevent reserpine-induced hypothermia. These data de monstrate that oral administration of magnesium to normal animals can antagonize NMDA-mediated responses and lead to antidepressant-like eff ects that are comparable to those of MK-801. This important regulatory role of Mg2+ in the central nervous system needs further investigatio n to evaluate the potential therapeutic advantages of magnesium supple mentation in psychiatric disorders. (C) 1997 Elsevier Science Inc.