Effect of ibogaine on cocaine-induced efflux of [3H] dopamine and [3H] serotonin from mouse striatum.

Ibogaine, an indole alkaloid with proposed antiaddictive properties, has structural similarity to serotonin and has been shown to have affinity to the kappa-opioid binding site. In addition to the dopamine system, the serotonin system is a major target for cocaine action and the opioid system can affect the serotonin system. Therefore, the present study examined the effect of ibogaine on cocaine-induced, electrically evoked efflux of [3H]dopamine and [3H]serotonin from striatal tissue incubated in vitro, and their modulation by the kappa-opioid system. Cocaine (10(-6) M) added in vitro increased tthe fractional efflux of both [3H]dopamine (FRS2/FRS1 = 2.42 +/- 0.36) and [3H]serotonin (FRS2/FRS1 = 1.31 +/- 0.06). Mice treated in vivo with ibogaine (40 mg/kg or 2 times 40 mg/kg, IP) and killed 2 or 18 h later still showed the cocaine-induced increase in [3H]dopamine, but [3H]serotonin efflux was not increased. The 5-HTIB agonist CGS-12066A (10(-6) M, added in vitro) increased [3H]dopamine release, but did not alter cocaine-induced efflux of [3H]dopamine. CGS-12066A did not affect [3H]serotonin release, but the cocaine-induced increase in [3H]serotonin was inhibited. CGS-12066A (1 mg/kg, SC) potentiated cocaine (25 mg/kg, SC)-induced locomotor activity. Ibogaine pretreatment reduced both the cocaine and the CGS-12066A cocaine-induced increase in locomotor activity. The kappa-opioid agonist U-62066 (10(-6) M, added in vitro) reduced both [3H] dopamine and [3H]serotonin release. This inhibitory effect was blocked by in vivo administration ibogaine. U-62066 did not alter cocaine-induced [3H]dopamine efflux, but reduced cocaine-induced [3H]serotonin efflux. In striatal tissue from ibogaine-pretreated mice, U-62066 restored the cocaine-induced increase in [3H]serotonin release. U-62066 (1 mg/kg, SC) potentiated cocaine-induced behavior and maintained an increased locomotor activity after ibogaine treatment. The results suggest that ibogaine may block the cocainemediated effects on serotonergic transmission, that subsequently modulate dopamine release. The kappa-opioid modulation of serotonergic transmission is also involved.