IBOGAINE BLOCK OF THE NMDA RECEPTOR - IN-VITRO AND IN-VIVO STUDIES

Ibogaine is an hallucinogenic indole alkaloid claimed to have anti-add ictive properties. Although its mechanism of action is unknown, bindin g studies have indicated that the drug may interact with N-methyl-D-as partate (NMDA) receptors. We further investigated the nature of the in teraction between ibogaine and NMDA receptors in voltage clamp and bin ding studies, and sought to confirm that the drug has NMDA receptor bl ocking activity in vivo. In whole-cell recordings from cultured rat hi ppocampal neurons, ibogaine caused a slow, concentration-dependent blo ck of NMDA-induced currents (IC50, 3.1 mu M at -60 mV). In contrast, i bogaine failed to affect either kainate- or gamma-aminobutyric acid-ev oked currents. The blockade of NMDA currents was use- and voltage-depe ndent, and the long lasting ibogaine block could be occluded by co-app lication of Mg2+. Ibogaine also inhibited equilibrium [H-3]dizocilpine binding to NMDA receptors in rat forebrain membranes (IC50, 3.2 mu M) . We conclude that ibogaine is an open channel NMDA receptor antagonis t. Administration of ibogaine to mice resulted in complete protection in the maximal electroshock test (ED(50), 31 mg/kg, i.p.) and partial protection against NMDA-induced lethality, confirming that ibogaine ca n block NMDA receptors in vivo. Published by Elsevier Science Ltd 1996 .