NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801

Pharmacol Biochem Behav. 1997 Sep;58(1):261-8. doi: 10.1016/s0091-3057(96)00555-2.


The ion channel of the N-methyl-D-aspartate (NMDA) receptor complex is subject to a voltage-dependent regulation by Mg2+ cations. Under physiological 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 and 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 blocker. 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 test, Mg2+ salts reduce the immobility time in a way similar to imipramine and thus resemble the antidepressant-like activity of MK-801. This activity is masked at high doses of magnesium by a myorelaxant effect that is comparable to MK-801-induced ataxia. Potentiation of yohimbine fatal toxicity is another test commonly used to evaluate putative antidepressant 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 demonstrate that oral administration of magnesium to normal animals can antagonize NMDA-mediated responses and lead to antidepressant-like effects that are comparable to those of MK-801. This important regulatory role of Mg2+ in the central nervous system needs further investigation to evaluate the potential therapeutic advantages of magnesium supplementation in psychiatric disorders.

Publication types

  • Comparative Study

MeSH terms

  • Adrenergic alpha-Agonists / toxicity
  • Animals
  • Body Temperature / drug effects
  • Depression / psychology
  • Dizocilpine Maleate / pharmacology*
  • Dizocilpine Maleate / toxicity
  • Drug Synergism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / toxicity
  • Female
  • Magnesium / blood
  • Magnesium / pharmacology*
  • Magnesium / toxicity
  • Male
  • Mice
  • Mice, Inbred Strains
  • Motor Activity / drug effects
  • Psychomotor Performance / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Reserpine / pharmacology
  • Seizures / physiopathology
  • Sympatholytics / pharmacology
  • Yohimbine / toxicity


  • Adrenergic alpha-Agonists
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Sympatholytics
  • Yohimbine
  • Dizocilpine Maleate
  • Reserpine
  • Magnesium