Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.
The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha 3 beta 4 nicotinic receptors and both agents were more potent at this site than at alpha 4 beta 2 nicotinic receptors or at NMDA or 5-HT(3) receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha 3 beta 4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha 3 beta 4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity.
Glick
Stanley D
SD
Center for Neuropharmacology and Neuroscience, Albany Medical College (MC-136), 47 New Scotland Avenue, Albany, NY 12208, USA. glicks@mail.amc.edu
Maisonneuve
Isabelle M
IM
Kitchen
Barbara A
BA
Fleck
Mark W
MW
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009294:Narcotics / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3; D012646:Self Administration
D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D007050:Ibogaine; C103345:18-methoxycoronaridine; D000109:Acetylcholine