Purpose: Inhibition of the NMDA receptor likely contributes to ketamine's neurodepressive properties. Magnesium also inhibits the NMDA receptor by binding to a site associated with the ketamine-binding domain. Electrophysiological studies suggest that magnesium prevents ketamine from binding to the NMDA receptor and thereby prevents ketamine inhibition. We undertook an in vivo study to determine if magnesium deficiency was associated with an increased sensitivity to ketamine.
Methods: Weanling rats were maintained on a Mg(2+)-deficient or control diet for 14 days. In Study I, rats were anaesthetized then sacrificed and the Mg2+ concentrations in the brain and plasma were measured. In a second prospective study, experimental animals were rendered hypomagnesaemic and the potency of 125 mg.kg-1 ip ketamine was evaluated. Animals were then were fed a Mg(2+)-containing diet and ketamine sensitivity was re-examined 14 days later.
Results: The Mg(2+)-deficient diets rendered the rats hypomagnesaemic as indicated by the brain and plasma concentration of Mg2+. In Study 2, the time to loss of righting reflex was shorter; 1.9 +/- 0.3 min (n = 12) and 2.6 +/- 0.2 min (n = 16, P < 0.05), whereas the latency to toe pinch was prolonged: 25.0 +/- 5.8 min (n = 12) vs 3.1 +/- 2.1 min (n = 16, P < 0.05) in the Mg(2+)-deficient compared with age-matched control animals, respectively. The hypomagnesaemic animals had a higher death rate following ketamine injection. The increased sensitivity to ketamine was no longer apparent when the animals were re-tested following replenishment of Mg2+.
Conclusion: Hypomagnesaemia is associated with an increased sensitivity to ketamine.