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 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.
Decollogne
S
S
Institut de Recherche Preclinique (IRPC), Le Plessis-Robinson, France.
Tomas
A
A
Lecerf
C
C
Adamowicz
E
E
Seman
M
M
D000316:Adrenergic alpha-Agonists / Q000633:toxicity; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003863:Depression / Q000523:psychology; D016291:Dizocilpine Maleate / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D008274:Magnesium / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012110:Reserpine / Q000494:pharmacology; D012640:Seizures / Q000503:physiopathology; D013565:Sympatholytics / Q000494:pharmacology; D015016:Yohimbine / Q000633:toxicity
D000316:Adrenergic alpha-Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D013565:Sympatholytics; D015016:Yohimbine; D016291:Dizocilpine Maleate; D012110:Reserpine; D008274:Magnesium