Effect of Ibogaine on the Various Sites of the NMDA Receptor Complex and Sigma Binding Sites in Rat Braina.

Ibogaine, a hallucinogenic alkaloid, may help treat opioid and cocaine addiction. Its neurochemical mechanisms are unclear. In rat cortex and cerebellum membrane preparations, ibogaine bound to high- and low-affinity phencyclidine (PCP) sites in the cortex (Ki(H) = 0.01-0.05 μM; Ki(L) = 2-4 μM) and only low-affinity sites in the cerebellum (Ki = 2-4 μM). It showed no affinity for NMDA receptor binding sites at concentrations >100 μM. Affinity for sigma-1 and sigma-2 sites ranged from 1.5-3 μM. Binding to PCP sites may contribute to ibogaine's potential anti-addiction properties, while sigma site interactions may cause adverse effects.

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Abstract

Although the alkaloid ibogaine is a potent hallucinogenic agent some indications suggest that it may be useful for the treatment of opioid and cocaine addiction. The neurochemical mechanism(s) underlying ibogaine effects remain unclear. In the present study we investigated the interaction of ibogaine with the phencyclidine (PCP) site located in the ionophore of the N-methyl-d-aspartate (NMDA) receptor complex, with the NMDA receptor binding site, and with sigma binding sites. In well-washed membrane preparations of rat cortex and cerebellum, the PCP sites were labeled with [3H]MK-801 or [3H]1-[1(2-theinyl)-cyclohexyl]-piperidine ([3H]TCP), and the NMDA receptor with [3H]-CGP 39653. The sigma-1 and sigma-2 binding site in rat cortex and cerebellum were labeled with [3H]pentazocine and [3H]1,3-di-o-tolyl-guanidine ([3H]DTG), respectively. Results indicated that ibogaine interacts with high- and low-affinity PCP binding sites in the cortex: Ki(H) = 0.01-0.05 μM; Ki(L) = 2-4μM, and only with low-affinity sites in the cerebellum: Ki = 2-4, μM. In contrast, ibogaine (>100 μM) had no affinity for [3H]-CGP 39653 binding sites (cortex and cerebellum). The affinity of ibogaine for sigma-1 and -2 binding sites in cortex and cerebellum ranged from 1.5-3μM. Since NMDA receptor antagonists (e.g., MK-801) are thought to attenuate opioid withdrawal symptoms and cocaine sensitization, it is possible that binding of ibogaine to the PCP sites contributes to its potential 'endabuse' properties. In turn, ibogaine interaction with sigma binding sites may be associated with its adverse effects.