The potential anti-addictive agent, 18-methoxycoronaridine, blocks the sensitized locomotor and dopamine responses produced by repeated morphine treatment.
18-Methoxycoronaridine (18-MC), a novel synthetic iboga congener, attenuates the reinforcing efficacy of morphine, disrupts some signs of morphine withdrawal in physically dependent rats and attenuates the dopamine response in the nucleus accumbens to acute morphine. The present study further investigated the interactions between 18-MC and morphine by examining the effects of 18-MC (40 mg/kg, i.p., 19 h earlier) on the expression of dopamine sensitization in the nucleus accumbens in response to morphine (20 mg/kg, i.p.) and on the dose-effect curves for morphine-induced locomotion (0-30 mg/kg, i.p.) in rats treated either acutely or repeatedly (five, once daily, injections of 20 mg/kg, i.p.) with morphine. Compared to vehicle pretreated controls, 18-MC increased the potency of morphine, shifting the dose-response curve to the left, in acute morphine treated rats; however, 18-MC did not alter the potency of morphine in rats treated repeatedly with morphine. Repeated morphine administration induced locomotor sensitization in approximately 50% of the rats tested; in vehicle pretreated rats, the morphine dose-response curve was shifted to the left in sensitized as compared to non-sensitized rats. In 18-MC pretreated rats, sensitized and non-sensitized rats responded similarly to morphine, revealing a blockade of sensitization by 18-MC. Consistent with this behavioural finding, 18-MC pretreatment completely abolished the sensitized dopamine response in the nucleus accumbens expressed by rats repeatedly treated with morphine. It is suggested that the potential anti-addictive efficacy of 18-MC might be related to an ability to restore normal functioning to a hypersensitive mesolimbic dopamine system produced by previous repeated morphine administration.
Szumlinski
K K
KK
Department of Pharmacology and Neuroscience (MC-136), Albany Medical College, 47 New Scotland Avenue, Albany, NY, USA. kszumlinski@ccgateway.amc.edu
Maisonneuve
I M
IM
Glick
S D
SD
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy* / Q000503:physiopathology*; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D007050:Ibogaine; D009020:Morphine; C103345:18-methoxycoronaridine; D004298:Dopamine