Skip to main content
SpringerLink
Log in

Long-Lasting Ibogaine Protection against NMDA-Induced Convulsions in Mice

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30min, 24, 48, and 72h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30min or 48h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Goutarel, R., Gollnhofer, O., and Sillans, R. 1993. Pharmacodynamics and therapeutic applications of iboga and ibogaine. Psychedelic Monographs and Essays 6:71-111.

    Google Scholar 

  2. Lotsof, H. S. 1995. Ibogaine in the treatment of chemical dependence disorders: clinical perspectives. MAPS 5:16-27.

    Google Scholar 

  3. Sisko, B. 1993. Interrupting drug dependency with ibogaine: a summary of four case histories. MAPS 4:15-23.

    Google Scholar 

  4. Cappendijk, S. L. T. and Dzoljic, M. R. 1993. Inhibitory effects of ibogaine on cocaine self-administration in rats. Eur. J. Pharmacol. 241:261-265.

    Google Scholar 

  5. Cappendijk, S. L., Vries, R., and Dzoljic, M. R. 1993. Excitatory amino acid receptor antagonists and naloxone-precipitated withdrawal syndrome in morphine-dependent mice. Eur. Neuropsychopharmacol. 3:111-116.

    Google Scholar 

  6. Dzoljic, E. D., Kaplan, C. D., and Dzoljic, M. R. 1988. Effects of ibogaine on naloxone precipitated withdrawal syndrome in chronic morphine dependent rats. Arch. Int. Pharmacodyn. 294:64-70.

    Google Scholar 

  7. Glick, S. D., Kuehne, M. E., Raucci, J., Wilson, T. E., Larson, D., Keller Jr., R. W., and Carlson, J. N. 1994. Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Res. 657:14-22.

    Google Scholar 

  8. Glick, S. D., Rossman, K., Maisonneuve, I. M., and Carlson, J. N. 1992. Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Neuropharmacology 31:497-500.

    Google Scholar 

  9. Glick, S. D., Rossman, K., Steindoff, S., Maisonneuve, I. M., and Carlson, J. N. 1991. Effects and aftereffects of ibogaine on morphine self-administration in rats. Eur. J. Pharmacol. 195:341-345.

    Google Scholar 

  10. Sershen, H., Hashim, A., and Lajtha, A. 1994. Ibogaine reduces preference for cocaine consumption in C57BL/6 by mice. Pharmacol. Biochem. Behav. 47:13-19.

    Google Scholar 

  11. Deecher, D. C., Teitler, M., Soderlund, D. M., Bornmann, W. G., Kuehne, M. E., and Glick, S. D. 1992. Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Res. 571:242-247.

    Google Scholar 

  12. Glick, S. D. and Maisonneuve, I. M. 1998. Mechanisms of antiaddictive actions of ibogaine. Ann. N. Y. Acad. Sci. 844:214-226.

    Google Scholar 

  13. Glick, S. D., Rossman, K., Wang, F., Dong, N., and Keller Jr., R. W. 1993. Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions with D-amphetamine. Brain Res. 628:201-208.

    Google Scholar 

  14. Harsing, L. G., Sershen, H., and Lajtha, A. 1994. Evidence that ibogaine releases dopamine from the cytoplasmic pool in isolated mouse striatum. J. Neural Transm. 96:215-225.

    Google Scholar 

  15. Maisonneuve, I. M., Keller, R. W. Jr, and Glick, S. D. 1992. Interactions of ibogaine and d-amphetamine: in vivo microdyalisis and motor behavior in rats. Brain Res. 579:87-92.

    Google Scholar 

  16. Popik, P., Layer, R. T., and Skolnick, P. 1995. 100 years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug. Pharmacol. Rev. 47:235-253.

    Google Scholar 

  17. Staley, J. K., Ouyang, Q., Pablo, J., Hearn, W. L., Flynn, D. D., Rothman, R. B., Rice, K. C., and Mash, D. C. 1996. Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine. Psychopharmacology 127:10-18.

    Google Scholar 

  18. Ozawa, S., Kamiya, H., and Tsukuki, K. 1998. Glutamate receptors in the mammalian central nervous system. Prog Neurobiol. 54:581-618.

    Google Scholar 

  19. Choi, D. W. 1988. Glutamate neurotoxicity diseases of the nervous system. Neuron 1:623-634.

    Google Scholar 

  20. Meldrum, B. S. 1994. The role of glutamate in epilepsy and other CNS disorders. Neurology 44: S14-S23.

    Google Scholar 

  21. Meldrum, B. S. 1995. Neurotransmission in epilepsy. Epilepsia 36:S30-S35.

    Google Scholar 

  22. Morris, R. G. M. 1989. Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentation in vivo by the NMDA receptor antagonist AP5. J. Neurosci. 9:3040-3057.

    Google Scholar 

  23. Wieloch, T. 1985. Hypoglycemia-induced neuronal damage prevented by an N-methyl-D-aspartate antagonist. Science 230: 681-683.

    Google Scholar 

  24. Trujillo, K. A. and Akil, H. 1991. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85-87.

    Google Scholar 

  25. Trujillo, K. A. and Akil, H. 1995. Excitatory amino acids and drugs of abuse: a role for N-methyl-D-aspartate receptors in drug tolerance, sensitization and physical dependence. Drug Alcohol Depend. 38:139-154.

    Google Scholar 

  26. Popik, P. and Danysz, W. 1997. Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine. J. Pharmacol. Exp. Ther. 280:854-865.

    Google Scholar 

  27. File, S. E. and Fernandes, C. 1994. Dizocilpine prevents the development of tolerance to the sedative effects of diazepam in rats. Pharmacol. Biochem. Behav. 47:823-826.

    Google Scholar 

  28. Khanna, J. M., Kalant, H., Shah, G., and Chau, A. 1993. Effect of D-cycloserine on rapid tolerance to ethanol. Pharmacol. Biochem. Behav. 45:983-986.

    Google Scholar 

  29. Oh, S., Hoshi, K., and Ho, I. K. 1997. Role of NMDA receptors in pentobarbital tolerance/dependence. Neurochem. Res. 22:767-774.

    Google Scholar 

  30. Popik, P. and Skolnick, P. 1996. The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence. Pharmacol. Biochem. Behav. 53:791-797.

    Google Scholar 

  31. Pudiak, C. M. and Bozarth, M. A. L-1993. NAME and MK-801 attenuate sensitization to the locomotor-stimulating effect of cocaine. Life Sci. 53:1517-1524.

    Google Scholar 

  32. Shoaib, M. and Stolerman, I. P. 1992. MK-801 attenuates behavioural adaptation to chronic nicotine administration in rats. Br. J. Pharmacol. 105:514-515.

    Google Scholar 

  33. Tsuda, M., Suzuki, T., and Misawa, M. 1997. Recovery of decreased seizure threshold for pentylenetetrazole during diazepam withdrawal by NMDA receptor antagonists. Eur. I. Pharmacol. 324:63-66.

    Google Scholar 

  34. Tsuda, M., Suzuki, T., and Misawa, M. 1998. Region-specific changes in [3H]dizocilpine binding in diazepam-withdrawn rats. Neurosci. Lett. 240:113-115.

    Google Scholar 

  35. Wolf, M. E. and Khansa, M. R. 1991. Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine. Brain Res. 562:164-168.

    Google Scholar 

  36. Layer, R. T., Skolnick, P., Bertha, C. M., Bandarage, U. K., Kuehne, M. E., and Popik, P. 1996. Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors. Eur. J. Pharmacol. 309:159-165.

    Google Scholar 

  37. Mash, D. C., Kovera, C. A., Buck, B. E., Norenberg, M. D., Shapshak, P., Hearn, W. L., and Sanchez-Ramos, J. 1998. Medication development of ibogaine as a pharmacotherapy for drug dependence. Ann. N. Y. Acad. Sci. 844:274-292.

    Google Scholar 

  38. Mash, D. C., Staley, J. K., Pablo, J. P., Holohean, A. M., Hackman, J. C., and Davidoff, R. A. 1995. 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.

    Google Scholar 

  39. Popik, P., Layer, R. T., Fossom, L. H., Benveniste, M., Geter-Douglass, B., Witkin, J. M., and Skolnick, P. 1995. NMDA antagonist properties of the putative anti-addictive drug ibogaine. J. Pharmacol. Exp. Ther. 275:753-760.

    Google Scholar 

  40. Popik, P., Layer, R. T., and 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.

    Google Scholar 

  41. Sweetnam, P. M., Lancaster, J., Showman, A., Collins, J. L., Perschke, S., Bauer, C., and Ferkany, J. 1995. Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine' putative anti-addictive activity. Psychopharmacology 118:369-376.

    Google Scholar 

  42. Chen, K., Kokate, T. G., Donevan, S. D., Carrol, F. I., and Rogawski, M. A. 1996. Ibogaine block of the NMDA receptor: In vitro and in vivo studies. Neuropharmacology 35:423-431.

    Google Scholar 

  43. Chen, G. and Bohner, B. 1958. A study of central nervous system stimulants. J. Pharmacol. Exp. Ther. 123:212-215.

    Google Scholar 

  44. Geter-Douglass, B. and Witkin, J. M. 1999. Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive MDA antagonists in mice. Psychopharmacology 146:280-289.

    Google Scholar 

  45. Czuczwar, S. J., Frey, H-H., and Löscher, W. 1985. Antagonism of N-Methyl-D,L-Aspartic Acid-induced convulsions by antiepileptic drugs and other agents. Eur. J. Pharmacol. 108:273-280.

    Google Scholar 

  46. Bristow, L. J., Flatman, K. L., Hutson, P. H., Kulagowski, J. J., Leeson, P. D., Young, L., and Tricklebank, M. D. 1996. The atypical neuroleptic profile of the glycine/N-Methyl-D-Aspartate receptor antagonist, L-701,324, in rodents. J. Pharmacol. Exp. Ther. 277:578-585.

    Google Scholar 

  47. Emanuelli, T., Antunes, V. F., and Souza, D. O. G. 1998. Characterisation of L-[3H] Glutamate binding to fresh and frozen crude plasma membranes isolated from cerebral cortex of adults rats. Biochem. Mol. Biol. Int. 44:1265-1272.

    Google Scholar 

  48. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265-275.

    Google Scholar 

  49. Piggott, M. A., Perry, E. K., Perry, R. H., and Court, J. A. 1992. [3H] MK-801 binding to the NMDA receptor complex, and its modulation in human frontal cortex during development and aging. Brain Res. 588:277-286.

    Google Scholar 

  50. Nakanishi, S., Nakajima, Y., Masu, M., Ueda, Y., Nakahara, K., Watanabe, D., Yamaguchi, S., Kawabata, S., and Okada, M. 1998. Glutamate receptors: brain function and signal transduction. Brain Res. Rev. 26:230-235.

    Google Scholar 

  51. Scallet, A. C., Ye, X., Rountree, R., Nony, P., and Ali, S. F. 1996. Ibogaine produces neurodegeneration in rat, but not mouse, cerebellum. Ann. N. Y. Acad. Sci. 801:217-226.

    Google Scholar 

  52. Hough, L. B., Pearl, S. M., and Glick, S. D. 1996. Tissue distribution of ibogaine after intraperitoneal and subcutaneous administration. Life Sci. 58:PL 119-122.

    Google Scholar 

  53. Hyman, S. E. and Nestler, E. J. 1996. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am. J. Psychiatry 153:151-162.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Curso de Pós-graduação em Ciências Biológicas-Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Mirna Bainy Leal & Diogo O. G. de Souza

  2. Laboratório de Etnofarmacologia, Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Curso de Pós-graduação em Ciências Biológicas-Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Elaine Elisabetsky

Authors
  1. Mirna Bainy Leal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diogo O. G. de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elaine Elisabetsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leal, M.B., de Souza, D.O.G. & Elisabetsky, E. Long-Lasting Ibogaine Protection against NMDA-Induced Convulsions in Mice. Neurochem Res 25, 1083–1087 (2000). https://doi.org/10.1023/A:1007665911622

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007665911622

Search

Navigation