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. 1994 Jan;111(1):131–136. doi: 10.1111/j.1476-5381.1994.tb14034.x

A study of the mechanism of MDMA ('ecstasy')-induced neurotoxicity of 5-HT neurones using chlormethiazole, dizocilpine and other protective compounds.

M I Colado 1, A R Green 1
PMCID: PMC1910050  PMID: 7516800

Abstract

1. An investigation has been made in rats into the neurotoxic effect of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') using chlormethiazole and dizocilpine, both known neuroprotective compounds and also gamma-butyrolactone, ondansetron and pentobarbitone. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in a 50% loss of cortical and hippocampal 5-HT and 5-hydroxyindole acetic acid (5-HIAA) 4 days later. This reflects the long term neurotoxic loss of 5-HT that occurs. Injection of gamma-butyrolactone (GBL; 400 mg kg-1, i.p.) 5 min before and 55 min after the MDMA provided substantial protection. Pentobarbitone (25 mg kg-1, i.p.) using the same dose regime was also protective, but ondansetron (0.5 mg kg-1 or 0.1 mg kg-1, i.p.) was without effect. 3. MDMA (20 mg kg-1) had no significant effect on striatal dopamine concentration 4 days later but did produce a small decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) content. There were few significant changes in rats given MDMA plus GBL, ondansetron or pentobarbitone. 4. A single injection of MDMA (20 mg kg-1, i.p.) resulted in a greater than 80% depletion of 5-HT in hippocampus and cortex 4 h later, reflecting the initial rapid release that had occurred. None of the neuroprotective compounds (chlormethiazole, 50 mg kg-1; dizocilpine, 1 mg kg-1; GBL, 400 mg kg-1; pentobarbitone, 25 mg kg-1) given 5 min before and 55 min after the MDMA injection, altered the degree of 5-HT loss. 5. Acute MDMA injection increased striatal dopamine content (28%) and decreased the DOPAC content. In general, administration of the drugs under investigation did not significantly alter these MDMA-induced changes. Both chlormethiazole and GBL produced a greater increase in dopamine than MDMA alone, but this was apparently an additive effect to the action of either drug alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Addae J. I., Stone T. W. Effects of anticonvulsants on responses to excitatory amino acids applied topically to rat cerebral cortex. Gen Pharmacol. 1988;19(3):455–462. doi: 10.1016/0306-3623(88)90047-x. [DOI] [PubMed] [Google Scholar]
  2. Azmitia E. C., Murphy R. B., Whitaker-Azmitia P. M. MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for Ca2(+)-dependent toxicity linked to release. Brain Res. 1990 Feb 26;510(1):97–103. doi: 10.1016/0006-8993(90)90732-q. [DOI] [PubMed] [Google Scholar]
  3. Baldwin H. A., Colado M. I., Murray T. K., De Souza R. J., Green A. R. Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine. Br J Pharmacol. 1993 Mar;108(3):590–596. doi: 10.1111/j.1476-5381.1993.tb12847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Butler A., Hill J. M., Ireland S. J., Jordan C. C., Tyers M. B. Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol. 1988 Jun;94(2):397–412. doi: 10.1111/j.1476-5381.1988.tb11542.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Callaway C. W., Johnson M. P., Gold L. H., Nichols D. E., Geyer M. A. Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists. Psychopharmacology (Berl) 1991;104(3):293–301. doi: 10.1007/BF02246026. [DOI] [PubMed] [Google Scholar]
  6. Chrapusta S. J., Karoum F., Egan M. F., Wyatt R. J. gamma-Butyrolactone-sensitive and -insensitive dopamine release, and their relationship to dopamine metabolism in three rat brain regions. Eur J Pharmacol. 1992 Nov 3;222(1):129–135. doi: 10.1016/0014-2999(92)90472-g. [DOI] [PubMed] [Google Scholar]
  7. Colado M. I., Murray T. K., Green A. R. 5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine. Br J Pharmacol. 1993 Mar;108(3):583–589. doi: 10.1111/j.1476-5381.1993.tb12846.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Commins D. L., Axt K. J., Vosmer G., Seiden L. S. 5,6-Dihydroxytryptamine, a serotonergic neurotoxin, is formed endogenously in the rat brain. Brain Res. 1987 Feb 10;403(1):7–14. doi: 10.1016/0006-8993(87)90116-8. [DOI] [PubMed] [Google Scholar]
  9. Commins D. L., Axt K. J., Vosmer G., Seiden L. S. Endogenously produced 5,6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine. Brain Res. 1987 Sep 1;419(1-2):253–261. doi: 10.1016/0006-8993(87)90591-9. [DOI] [PubMed] [Google Scholar]
  10. Costall B., Domeney A. M., Naylor R. J., Tyers M. B. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol. 1987 Dec;92(4):881–894. doi: 10.1111/j.1476-5381.1987.tb11394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cross A. J., Misra A., Sandilands A., Taylor M. J., Green A. R. Effect of chlormethiazole, dizocilpine and pentobarbital on harmaline-induced increase of cerebellar cyclic GMP and tremor. Psychopharmacology (Berl) 1993;111(1):96–98. doi: 10.1007/BF02257413. [DOI] [PubMed] [Google Scholar]
  12. Cross A. J., Stirling J. M., Robinson T. N., Bowen D. M., Francis P. T., Green A. R. The modulation by chlormethiazole of the GABAA-receptor complex in rat brain. Br J Pharmacol. 1989 Sep;98(1):284–290. doi: 10.1111/j.1476-5381.1989.tb16893.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dray A. The striatum and substantia nigra: a commentary on their relationships. Neuroscience. 1979;4(10):1407–1439. doi: 10.1016/0306-4522(79)90048-4. [DOI] [PubMed] [Google Scholar]
  14. Fuller R. W., Perry K. W., Molloy B. B. Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine. Eur J Pharmacol. 1975 Aug;33(1):119–124. doi: 10.1016/0014-2999(75)90145-4. [DOI] [PubMed] [Google Scholar]
  15. Gibb J. W., Johnson M., Stone D., Hanson G. R. MDMA: historical perspectives. Ann N Y Acad Sci. 1990;600:601–612. doi: 10.1111/j.1749-6632.1990.tb16913.x. [DOI] [PubMed] [Google Scholar]
  16. Green A. R., De Souza R. J., Williams J. L., Murray T. K., Cross A. J. The neurotoxic effects of methamphetamine on 5-hydroxytryptamine and dopamine in brain: evidence for the protective effect of chlormethiazole. Neuropharmacology. 1992 Apr;31(4):315–321. doi: 10.1016/0028-3908(92)90062-t. [DOI] [PubMed] [Google Scholar]
  17. Hagan R. M., Jones B. J., Jordan C. C., Tyers M. B. Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat. Br J Pharmacol. 1990 Feb;99(2):227–232. doi: 10.1111/j.1476-5381.1990.tb14685.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harrison N. L., Simmonds M. A. Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro. Br J Pharmacol. 1983 Oct;80(2):387–394. doi: 10.1111/j.1476-5381.1983.tb10045.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Harvey J. A., McMaster S. E. Fenfluramine: evidence for a neurotoxic action on midbrain and a long-term depletion of serotonin. Psychopharmacol Commun. 1975;1(2):217–228. [PubMed] [Google Scholar]
  20. Henderson M. G., Hemrick-Luecke S., Fuller R. W. MK-801 protects against amphetamine-induced striatal dopamine depletion in iprindole-treated rats, but not against brain serotonin depletion after p-chloroamphetamine administration. Ann N Y Acad Sci. 1992 May 11;648:286–288. doi: 10.1111/j.1749-6632.1992.tb24558.x. [DOI] [PubMed] [Google Scholar]
  21. Johnson M. P., Huang X. M., Nichols D. E. Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue. Pharmacol Biochem Behav. 1991 Dec;40(4):915–922. doi: 10.1016/0091-3057(91)90106-c. [DOI] [PubMed] [Google Scholar]
  22. Kilpatrick G. J., Jones B. J., Tyers M. B. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature. 1987 Dec 24;330(6150):746–748. doi: 10.1038/330746a0. [DOI] [PubMed] [Google Scholar]
  23. McKenna D. J., Peroutka S. J. Neurochemistry and neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). J Neurochem. 1990 Jan;54(1):14–22. doi: 10.1111/j.1471-4159.1990.tb13277.x. [DOI] [PubMed] [Google Scholar]
  24. Moore N. A., Blackman A., Awere S., Leander J. D. NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists. Eur J Pharmacol. 1993 Jun 11;237(1):1–7. doi: 10.1016/0014-2999(93)90085-v. [DOI] [PubMed] [Google Scholar]
  25. Nash J. F. Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis. Life Sci. 1990;47(26):2401–2408. doi: 10.1016/0024-3205(90)90484-9. [DOI] [PubMed] [Google Scholar]
  26. Ogren S. O. Chlormethiazole--mode of action. Acta Psychiatr Scand Suppl. 1986;329:13–27. [PubMed] [Google Scholar]
  27. Roth R. H., Murrin L. C., Walters J. R. Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid. Eur J Pharmacol. 1976 Mar;36(1):163–171. doi: 10.1016/0014-2999(76)90268-5. [DOI] [PubMed] [Google Scholar]
  28. Sabol K. E., Richards J. B., Seiden L. S. The NMDA receptor antagonist MK-801 does not protect against serotonin depletions caused by high doses of DL-fenfluramine. Brain Res. 1992 Jun 5;582(1):129–133. doi: 10.1016/0006-8993(92)90326-5. [DOI] [PubMed] [Google Scholar]
  29. Sanders-Bush E., Bushing J. A., Sulser F. Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain. Eur J Pharmacol. 1972 Dec;20(3):385–388. doi: 10.1016/0014-2999(72)90204-x. [DOI] [PubMed] [Google Scholar]
  30. Schmidt C. J., Abbate G. M., Black C. K., Taylor V. L. Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methylenedioxymethamphetamine in rats. J Pharmacol Exp Ther. 1990 Nov;255(2):478–483. [PubMed] [Google Scholar]
  31. Schmidt C. J., Ritter J. K., Sonsalla P. K., Hanson G. R., Gibb J. W. Role of dopamine in the neurotoxic effects of methamphetamine. J Pharmacol Exp Ther. 1985 Jun;233(3):539–544. [PubMed] [Google Scholar]
  32. Schmidt C. J., Wu L., Lovenberg W. Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur J Pharmacol. 1986 May 13;124(1-2):175–178. doi: 10.1016/0014-2999(86)90140-8. [DOI] [PubMed] [Google Scholar]
  33. Srinivasan K., Srinivasa Murthy R., Janakiramaiah N. A nosological study of patients presenting with somatic complaints. Acta Psychiatr Scand. 1986 Jan;73(1):1–5. doi: 10.1111/j.1600-0447.1986.tb02656.x. [DOI] [PubMed] [Google Scholar]
  34. Stone D. M., Johnson M., Hanson G. R., Gibb J. W. Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther. 1988 Oct;247(1):79–87. [PubMed] [Google Scholar]
  35. Stone D. M., Stahl D. C., Hanson G. R., Gibb J. W. The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol. 1986 Aug 22;128(1-2):41–48. doi: 10.1016/0014-2999(86)90555-8. [DOI] [PubMed] [Google Scholar]
  36. Thoren P., Sjölander M. Chlormethiazole attenuates the derangement of sensory evoked potential (SEP) induced by ICV administration of NMDA. Psychopharmacology (Berl) 1993;111(2):256–258. doi: 10.1007/BF02245534. [DOI] [PubMed] [Google Scholar]
  37. Walters J. R., Roth R. H., Aghajanian G. K. Dopaminergic neurons: similar biochemical and histochemical effects of gamma-hydroxybutyrate and acute lesions of the nigro-neostriatal pathway. J Pharmacol Exp Ther. 1973 Sep;186(3):630–639. [PubMed] [Google Scholar]
  38. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wrona M. Z., Dryhurst G. Interactions of 5-hydroxytryptamine with oxidative enzymes. Biochem Pharmacol. 1991 Apr 15;41(8):1145–1162. doi: 10.1016/0006-2952(91)90653-m. [DOI] [PubMed] [Google Scholar]
  40. Wrona M. Z., Goyal R. N., Turk D. J., Blank C. L., Dryhurst G. 5,5'-Dihydroxy-4,4'-bitryptamine: a potentially aberrant, neurotoxic metabolite of serotonin. J Neurochem. 1992 Oct;59(4):1392–1398. doi: 10.1111/j.1471-4159.1992.tb08452.x. [DOI] [PubMed] [Google Scholar]
  41. Yoshida Y., Ono T., Kizu A., Fukushima R., Miyagishi T. Striatal N-methyl-D-aspartate receptors in haloperidol-induced catalepsy. Eur J Pharmacol. 1991 Oct 15;203(2):173–180. doi: 10.1016/0014-2999(91)90712-y. [DOI] [PubMed] [Google Scholar]

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