Attenuation of the reinforcing efficacy of morphine by 18-methoxycoronaridine

In previous studies, 18-methoxycoronaridine, a novel iboga alkaloid congene r, has been reported to decrease the self-administration of morphine, cocai ne, ethanol and nicotine, and to attenuate naltrexone-precipitated signs of morphine withdrawal. In the present study, the nature of the interaction b etween 18-methoxycoronaridine and morphine was further investigated. Using in vivo microdialysis, 18-methoxycaronaridine pretreatment (40 mg/kg i.p., 19 h beforehand) was found to markedly inhibit morphine-induced (5 mg/kg, i .p.) dopamine release in the nucleus accumbens and striatum; 18-methoxycoro naridine also enhanced morphine-induced increases in extracellular levels o f dopamine's metabolites. These effects, which were more prominent in the n ucleus accumbens than in the striatum, suggest that 18-methoxycoronaridine selectively interferes with morphine-induced dopamine release, without alte ring morphine-induced stimulation of dopamine synthesis. In intravenous mor phine self-administration experiments, the effects of acute 18-methoxycoron aridine treatment (40 mg/kg, p.o.) were assessed in rats responding for one of several different unit infusion dosages of morphine (0.01-0.16 mg/kg/in fusion). 18-Methoxycoronaridine produced a downward shift in the entire mor phine dose-response curve without any displacement to the left or right. Th ese results suggest that 18-methoxycoronaridine reduced the reinforcing eff icacy of morphine without altering its apparent potency. Together, the micr odialysis and self-administration data suggest that 18-methoxycoronaridine profoundly alters mechanisms crucial to the development and maintenance of opioid addiction. (C) 1999 Elsevier Science B.V. All rights reserved.