THE EFFECTS OF SIGMA, PCP, AND OPIATE RECEPTOR LIGANDS IN RATS TRAINED WITH IBOGAINE AS A DISCRIMINATIVE STIMULUS

Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains un known, receptor bi nding studies suggest that ibogaine produces its effects via interacti ons with multiple receptor types. In addition to serotonergic receptor s, which have been studied previously with respect to ibogaine, likely candidates include opiate, ate, sigma (sigma), and phencyclidine (PCP ) binding sites. In an attempt to determine which of these receptor in teractions are involved in the in vivo effects of ibogaine, ligands fo r sigma, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative st imulus (10 mg/kg IF, 60 min presession) in Fischer-344 rats. Inter med iate levels of generalization were observed with the subtype nonselect ive sigma ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-P PP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with th e sigma(1)-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibog aine has appreciable affinity for sigma(2) receptors, suggest that the se receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu a gonist, nor kappa selective agonists (bremazocine,and U-50488) substit uted for ibogaine. However, intermediate levels of generalization were observed with the mixed action opiates (-)-SKF 10,047 (78.9%), (+/-)- pentazocine (73.9%), nalorphine (70.4%), and diprenorphine (75.0%) ind icating a potential role for opiate receptors in the ibogaine stimulus . Partial substitution was also observed with naltrexone (55.6%) but n ot with naloxone or the selective kappa antagonist nor-binaltorphimine (nor-BNI). These agents were largely ineffective as antagonists of th e ibogaine cue, although naloxone produced a moderate but statisticall y significant antagonism (69.8%). In addition, naloxone produced compl ete antagonism of the ibogaine-appropriate responding elicited by both (-)-SKF 10,047 (19.7%) and nalorphine (25.8%), whereas the ibogaine a ppropriate responding produced by diprenorphine was only partially ant agonized (44.4%). The latter observations taken together with the find ing that both nalorphine (>100 mu M) and diprenorphine (30 mu M) have extremely low affinity for sigma(2)-receptors, suggest that the ibogai ne-appropriate responding produced by these agents is not mediated by sigma(2) receptors. These findings imply that opiate effects may be in volved in the ibogaine stimulus. In contrast to sigma(2) and opiate re ceptors, ibogaine's reported interactions with NMDA receptors do not a ppear to be involved in its discriminative stimulus, as neither PCP no r MK-801 produced a significant level of ibogaine appropriate respondi ng. Thus, the present study offers evidence that unlike NMDA receptors ,both sigma(2) and opiate receptors may be involved in the ibogaine di scriminative stimulus. (C) 1998 Elsevier Science Inc.