Abstract
The discriminative stimulus effects of ibogaine and noribogaine in rats have been examined in relation to their concentrations in blood plasma and brain regions and to receptor systems through which they have been proposed to act. Rats were trained to discriminate ibogaine (10 mg/kg IP), the NMDA antagonist dizocilpine (0.08 mg/kg IP) or the κ-opioid agonist U50,488 (5 mg/kg IP) from vehicle in a standard two-lever operant conditioning procedure with a tandem VI-FR schedule of food reinforcement. Only rats trained on ibogaine generalized to noribogaine, which was approximately twice as potent as the parent compound. Noribogaine was detected in plasma and brain after administration of ibogaine and noribogaine. At the ED50 doses for the discriminative effect, the estimated concentrations of noribogaine in plasma, cerebral cortex, and striatum were similar regardless of whether ibogaine or noribogaine was administered. The findings suggest that the metabolite noribogaine may be devoid of NMDA antagonist and κ-opioid agonist discriminative effects and that it may play a major role in mediating the discriminative stimulus effect of ibogaine.
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References
Bhargava HN, Cao Y-J . (1997): Effects of noribogaine on the development of tolerance to antinociceptive action of morphine in mice. Brain Res 771: 343–346
Cappendijk SLT, Dzoljic MR . (1993): Inhibitory effects of ibogaine on cocaine self-administration in rats. Eur J Pharmacol 241: 261–265
Chamberlain SS, Stolerman IP . (1997): Dissecting the cyclazocine stimulus in rats. J Psychopharmac 11(Suppl):A13
Deecher DC, Teitler M, Soderlund DM, Bornmann WG, Kuehne ME, Glick SD . (1992): Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Res 571: 242–247
Glick SD, Pearl SM, Cai J, Maisonneuve IM . (1996a): Ibogaine-like effects of noribogaine in rats. Brain Res 713: 294–297
Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH . (1996b): 18-methoxycoronaridine, a non-toxic iboga alkaloid congener: Effect on morphine and cocaine self-administration and on mesolimbic dopamine release in rats. Brain Res 719: 29–35
Hearn WL, Pablo J, Hime GW, Mash DC . (1995): Identification and quantitation of ibogaine and an o-demethylated metabolite in brain and biological fluids using gas chromatography-mass spectrometry. J Anal Toxicol 19: 427–434
Helsley S, Rabin RA, Winter JC . (1997): The effects of noribogaine and harmaline in rats trained with ibogaine as a discriminative stimulus. Life Sci 60: 147–153
Helsley S, Fiorella D, Rabin RA, Winter JC . (1998a): Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus. Pharmacol Biochem Behav 59: 419–425
Helsley S, Filipink RA, Bowen WD, Rabin RA, Winter JC . (1998b): The effects of sigma, PCP, and opiate receptors ligands in rats trained with ibogaine as a discriminative stimulus. Pharmacol Biochem Behav 59: 495–503
Hough LB, Pearl SM, Glick SD . (1996): Tissue distribution of ibogaine after intraperitoneal and subcutaneous administration. Life Sci 58: 119–122
Jones HE, Li H, Balster RL . (1998): Failure of ibogaine to produce phencyclidine-like discriminative stimulus effects in rats and monkeys. Pharmacol Biochem Behav 59: 413–418
Ley FR, Jeffcoat AR, Thomas BF . (1996): Determination of ibogaine in plasma by gas chromatography-chemical ionization mass spectrometry. J Chromatogr A 723: 101–109
Lotsof HS . (1985): Rapid method for interrupting the narcotic addiction syndrome. US Patent 4,499,096.
Lotsof HS . (1992): Rapid method for interrupting or attenuating poly-drug dependency syndromes. US Patent 5,152,994.
Maisonneuve IM, Keller RW Jr, Glick SD . (1991): Interactions between ibogaine, a potential anti-addictive agent, and morphine: An in vivo microdialysis study. Eur J Pharmacol 199: 35–42
Maisonneuve IM, Visker KE, Mann GL, Bandarage UK, Kuehne ME, Glick SD . (1997): Time-dependent interactions between iboga agents and cocaine. Eur J Pharmacol 336: 123–126
Mash DC, Staley JK, Baumann MH, Rothman RB, Hearn WL . (1995a): Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Life Sci 57: 45–50
Mash DC, Staley JK, Pablo JP, Holohean AM, Hackman JC, Davidoff RA . (1995b): Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA receptor complex. Neurosci Lett 192: 53–56
Palumbo PA, Winter JC . (1992): Stimulus effects of ibogaine in rats trained with yohimbine, DOM, or LSD. Pharmacol Biochem Behav 43: 1221–1226
Pearl S, Herrick-Davis K, Teitler M, Glick SD . (1995): Radioligand-binding study of noribogaine, a likely metabolite of ibogaine. Brain Res 675: 342–344
Popik P, Layer RT, Skolnick P . (1994): The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex. Psychopharmacology 114: 672–674
Popik P, Layer RT, Fossom LH, Benveniste M, Geter-Douglass B, Witkin JM, Skolnick P . (1995): NMDA antagonist properties of the putative antiaddictive drug, ibogaine. J Pharmacol Exp Ther 275: 753–760
Pratt JA, Stolerman IP, Garcha HS, Giardini V, Feyerabend C . (1983): Discriminative stimulus properties of nicotine: Further evidence for mediation at a cholinergic receptor. Psychopharmacology 81: 54–60
Sanger DJ, Zivkovic B . (1989): The discriminative stimulus effects of MK-801: Generalisation to other N-methyl-D-aspartate receptor antagonists. J Psychopharmacol 3: 198–204
Scallet AC, Ye X, Ali SF . (1996): NOS and fos in rat and mouse brain regions. Possible relation to ibogaine-induced Purkinje cell loss. Ann N Y Acad Sci 801: 227–238
Schechter MD . (1997): Serotonergic mediation of fenfluramine discriminative stimuli in Fawn-Hooded rats. Life Sci 60: 83–90
Schechter MD, Gordon TL . (1993): Comparison of the behavioural effects of ibogaine from three sources: Mediation of discriminative activity. Eur J Pharmacol 249: 79–84
Sheppard SG . (1994): A preliminary investigation of ibogaine: Case reports and recommendations for further study. J Subst Abuse Treat 11: 379–385
Staley JK, Ouyang Q, Pablo J, Hearn WL, Flynn DD, Rothman RB, Rice KC, Mash DC . (1996): Pharmacological screen for activities of 12-hydroxyibogamine: A primary metabolite of the indole alkaloid ibogaine. Psychopharmacology 127: 10–18
Stolerman IP, Garcha HS, Pratt JA, Kumar R . (1984): Role of training dose in discrimination of nicotine and related compounds by rats. Psychopharmacology 84: 413–419
Sweetnam PM, Lancaster J, Snowman A, Collins JL, Perschke S, Bauer C, Ferkany J . (1995): Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity. Psychopharmacology 118: 369–376
Winer BJ . (1970): Statistical Principles in Experimental Design. New York, McGraw-Hill
Witkin JM, Brave S, French D, Geter-Douglass B . (1995): Discriminative stimulus effects of R-(+)-3-amino-1-hydroxypyrrolid-2-one, [(+)-HA-966], a partial agonist of the strychnine-insensitive modulatory site of the N-methyl-D-aspartate receptor. J Pharmacol Exp Ther 275: 1267–1273
Zetler G, Singbartl G, Schlosser L . (1972): Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids. Pharmacology 7: 237–248
Acknowledgements
This research was supported by grants from CAPES (Brazil), the National Institute on Drug Abuse (DA 05543) and the Addiction Research Fund. We thank Sherelle Chamberlain for assistance with training some of the rats.
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Zubaran, C., Shoaib, M., Stolerman, I. et al. Noribogaine Generalization to the Ibogaine Stimulus: Correlation with Noribogaine Concentration in Rat Brain. Neuropsychopharmacol 21, 119–126 (1999). https://doi.org/10.1016/S0893-133X(99)00003-2
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DOI: https://doi.org/10.1016/S0893-133X(99)00003-2
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