Attenuation of the reinforcing efficacy of morphine by 18-methoxycoronaridine.
In previous studies, 18-methoxycoronaridine, a novel iboga alkaloid congener, has been reported to decrease the self-administration of morphine, cocaine, ethanol and nicotine, and to attenuate naltrexone-precipitated signs of morphine withdrawal. In the present study, the nature of the interaction between 18-methoxycoronaridine and morphine was further investigated. Using in vivo microdialysis, 18-methoxycoronaridine 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-methoxycoronaridine also enhanced morphine-induced increases in extracellular levels of dopamine's metabolites. These effects, which were more prominent in the nucleus accumbens than in the striatum, suggest that 18-methoxycoronaridine selectively interferes with morphine-induced dopamine release, without altering morphine-induced stimulation of dopamine synthesis. In intravenous morphine self-administration experiments, the effects of acute 18-methoxycoronaridine 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/infusion). 18-Methoxycoronaridine produced a downward shift in the entire morphine dose-response curve without any displacement to the left or right. These results suggest that 18-methoxycoronaridine reduced the reinforcing efficacy of morphine without altering its apparent potency. Together, the microdialysis and self-administration data suggest that 18-methoxycoronaridine profoundly alters mechanisms crucial to the development and maintenance of opioid addiction.
Maisonneuve
I M
IM
Department of Pharmacology and Neuroscience, MC-136, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. maison@ccgateway.amc.edu
Glick
S D
SD
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013997:Time Factors; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
D009294:Narcotics; D015102:3,4-Dihydroxyphenylacetic Acid; D007050:Ibogaine; D009020:Morphine; C103345:18-methoxycoronaridine; D004298:Dopamine; D006719:Homovanillic Acid