Ibogaine block of the NMDA receptor: in vitro and in vivo studies.

Ibogaine, a hallucinogenic alkaloid claimed to reduce addiction, blocks NMDA receptors in the brain. In cultured rat hippocampal neurons, ibogaine slowly and reversibly blocked NMDA-induced currents with an IC50 of 3.1 µM at −60 mV, while not affecting kainate or GABA currents. The block was use- and voltage-dependent and could be occluded by magnesium. Ibogaine also inhibited dizocilpine binding to NMDA receptors in rat forebrain membranes (IC50, 3.2 µM). In mice, ibogaine fully protected against maximal electroshock seizures (ED50, 31 mg/kg, i.p.) and partially protected against NMDA-induced lethality, confirming in vivo NMDA receptor blockade.

Study at a glance

Abstract

Ibogaine is an hallucinogenic indole alkaloid claimed to have anti-addictive properties. Although its mechanism of action is unknown, binding studies have indicated that the drug may interact with N-methyl-D-aspartate (NMDA) receptors. We further investigated the nature of the interaction between ibogaine and NMDA receptors in voltage clamp and binding studies, and sought to confirm that the drug has NMDA receptor blocking activity in vivo. In whole-cell recordings from cultured rat hippocampal neurons, ibogaine caused a slow, concentration-dependent block of NMDA-induced currents (IC50, 3.1 microM at -60 mV). In contrast, ibogaine failed to affect either kainate- or gamma-aminobutyric acid-evoked currents. The blockade of NMDA currents was use- and voltage-dependent, and the long lasting ibogaine block could be occluded by co-application of Mg2+. Ibogaine also inhibited equilibrium [3H]dizocilpine binding to NMDA receptors in rat forebrain membranes (IC50, 3.2 microM). We conclude that ibogaine is an open channel NMDA receptor antagonist. Administration of ibogaine to mice resulted in complete protection in the maximal electroshock test (ED50, 31 mg/kg, i.p.) and partial protection against NMDA-induced lethality, confirming that ibogaine can block NMDA receptors in vivo.