The effect of ibogaine on sigma- and NMDA-receptor-mediated release of [H-3]dopamine

The indole alkaloid ibogaine has been suggested to have potential for inhibiting dependency on stimulant drugs. Radioligand binding studies have suggested possible multisite actions of ibogaine: affinity at the kappa-opioid, NMDA, and sigma receptors, with effects on dopamine (DA) release. To further investigate the multiplicity of sites of action of ibogaine and the presynaptic regulation of the DA release, the effect of ibogaine on NMDA- and sigma-receptor-mediated efflux of [H-3]DA was measured in striatal tissue from C57BL/6By mice. Striatal tissue was incubated in vitro with [H-3]DA and the effect on DA release was measured. Both NMDA (25 mu M) and the sigma receptor agonist (+/-)-pentazocine (20 mu M) alone increased the efflux of DA. (+/-)-Pentazocine (100 nM) did not inhibit the NMDA-evoked release. MK-801 (5 mu M) completely inhibited the NMDA-evoked release and inhibited the (+/-)-pentazocine-evoked release by 49%. Ibogaine (10 mu M) itself increased the efflux of DA; at 1 mu M it was without effect. Ibogaine (1 mu M) inhibited the NMDA-evoked release of DA by 31% and inhibited the (+/-)-pentazocine-evoked release by 48%. In addition, the level of basal release of DA obtained after the NMDA- or (+/-)-pentazocine-evoked-release remained higher in the tissue exposed to ibogaine throughout. The results suggest that sigma receptors can regulate the release of DA, along with an action at the NMDA receptor. We previously reported action of ibogaine at the kappa-opioid site. The elevated basal release of DA in the presence of ibogaine after NMDA-or (+/-)-pentazocine-evoked release may reflect the ibogaine-induced removal of the tonically active kappa-opioid system that acts presynaptically to reduce dopamine release. The kappa-opioid system also appears to be inhibitory on both the NMDA and sigma receptors.