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Highly Selective Neurotoxins pp 235–268Cite as

Evidence for and Mechanism of Action of Neurotoxicity of Amphetamine Related Compounds

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Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

The purpose of this chapter is to review the evidence that substituted amphetamines (AMPHs), such as methamphetamine (METH), have neurotoxic potential, discuss critical determinants of AMPH neurotoxicity, and consider possible mechanisms underlying the neurotoxic action of AMPH and some of its derivatives. This evidence indicates that METH, AMPH, methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), m-trifluoromethyl-N-ethylamphetamine fenfluramine (FEN), and the combination of phentermine (PHEN) and FEN can cause long-lasting deficits in brain dopamine (DA) and/or serotonin (5HT) systems. For many of these drugs, the pharmacological properties are quite similar across species, including humans. Therefore, the possibility that the neurotoxic effects of AMPH derivatives may generalize from nonhuman mammals to humans must be considered.

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References

  1. Cavanagh, J. B. (1994) Principles of neurotoxicology, in Principles of Neurotoxicology ( Chang, L. W., ed.), Marcel Decker, New York, pp. xv-xviii.

    Google Scholar 

  2. Seiden, L. S., Sabol, K. E., and Dyer, R. S. (1995) Neurotoxicity of methamphetaminerelated drugs and cocaine, in Handbook of Neurotoxicology ( Chang, L. W., ed.), Marcel Dekker, New York, pp. 825–843.

    Google Scholar 

  3. Uretsky, N. J. and Snodgrass, S. R. (1977) Studies on the mechanism of stimulation of dopamine synthesis by amphetamine in striatal slices. J. Pharmacol. Exp. Ther. 202, 565–580.

    Google Scholar 

  4. Hedreen, J. C. and Chalmers, J. P. (1972) Neuronal degeneration in rat brain induced by 6-hydroxydopamine; a histological and biochemical study. Brain Res. 47, 1–36.

    Article  CAS  PubMed  Google Scholar 

  5. Baumgarten, H. B. and Zimmerman, B. (1992) Neurotoxic phenylalkalyamines and indolealkylamines, in Handbook of Experimental Pharmacology: Selective Neurotoxicity ( Herken, H. and Hucho, F., eds.), Springer-Verlag, New York, 225–276.

    Google Scholar 

  6. Sanders-Busch, E., Bushing, J. A., and Sulser, F. (1972) 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. Pharm. 20, 385–388.

    Article  Google Scholar 

  7. Seiden, L. S., Sabol, K. E., and Ricaurte, G. A. (1993) Amphetamine: effects on catecholamine systems and behavior [Review]. Annu. Rev. Pharmacol. Toxicol. 33, 639–677.

    Article  CAS  PubMed  Google Scholar 

  8. Raiteri, M., Cerrito, F., Cervoni, A. M., and Levi, G. (1979) Dopamine can be released by two mechanisms differentially affected by the dopamine transport inhibitor nomifensine. J. Pharmacol. Exp. Ther. 208, 195–202.

    CAS  PubMed  Google Scholar 

  9. Kandel, E. R. and Schwartz, J. H. (1985) Principles of Neural Science, Elsevier, New York.

    Google Scholar 

  10. Wichems, C. H., Hollingsworth, C. K., and Bennet, B. A. (1995) Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release. Brain Res. 695, 10–18.

    Article  CAS  PubMed  Google Scholar 

  11. Heikkila, R. E., Orlansky, H., and Cohen, G. (1975) Studies on the distinction between uptake inhibition and release of (3H)dopamine in rat brain tissue slices. Biochem. Pharmacol. 24, 847–852.

    Article  CAS  PubMed  Google Scholar 

  12. Fischer, J. F. and Cho, A. K. (1979) Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J. Pharmacol. Exp. Ther. 208, 203–209.

    CAS  PubMed  Google Scholar 

  13. Parker, E. M. and Cubeddu, L. X. (1986) Effects of d-amphetamine and dopamine synthesis inhibitors on dopamine and acetylcholine neurotransmission in the striatum. Release in the absence of vesicular transmitter stores. J. Pharmacol. Exp. Ther. 237, 179–192.

    CAS  PubMed  Google Scholar 

  14. Liang, N. Y. and Rutledge, C. O. (1982) Comparison of the release of [3H]dopamine from isolated corpus striatum by amphetamine, fenfluramine and unlabelled dopamine. Biochem. Pharmacol. 31, 983–992.

    Article  CAS  PubMed  Google Scholar 

  15. Rudnick, G. and Wall, S. C. (1992) The molecular mechanism of “ecstasy” [3,4-methylenedioxymethamphetamine (MDMA)]: serotonin transporters are targets for MDMAinduced serotonin release. Proc. Acad. Sci. USA 89, 1817–1821.

    Article  CAS  Google Scholar 

  16. Berger, U. V., Gu, X. E, and Azmitia, E. C. (1992) The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur. J. Pharmacol. 215, 153–160.

    Article  CAS  PubMed  Google Scholar 

  17. Johnson, M. P., Conarty, P. F., and Nichols D. (1991) [3H] Monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloramphetamine analogues. Eur. J. Pharm. 200, 9–16.

    Google Scholar 

  18. Laferrere, B. and Wurtman, R. J. (1989) Effect of D-fenfluramine on serotonin release in brains of anaesthetized rats. Brain Res. 504, 258–263.

    Article  CAS  PubMed  Google Scholar 

  19. McKenna, D. J., Guan, X. M., and Shulgin, A. T. (1991) Methylenedioxyamphetamine (MDA)) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine. Pharmacol. Biochem. Behay. 38, 505–512.

    Article  CAS  Google Scholar 

  20. Nichols, D. E., Lloyd, D. H., Hoffman, A. J., Nichols, M. B., and Yim, G. K. W. (1982) Effects of certain hallucinogenic amphetamine analogues on the release of [3H]serotonin from rat brain synaptosomes. J. Med. Chem. 25, 530–535.

    Article  CAS  PubMed  Google Scholar 

  21. Sabol, K. E., Richards, J. B., and Seiden, L. S. (1992) Fenfluramine-induced increases in extracellular hippocampal serotonin and progressively attentuated in vivo during a four-day fenfluramine regimen in rats. Brain Res. 571, 64–72.

    Article  CAS  PubMed  Google Scholar 

  22. Mennini, T., Garattini, S., and Caccia, S. (1985) Anorectic effect of fenfluramine isomers and metabolites: relationship between brain levels and in vitro potencies on serotonergic mechanisms. Psychopharmacology 85, 111–114.

    Article  CAS  PubMed  Google Scholar 

  23. Sarkissian, C. R, Wurtman, R. J., Morse, A. N., and Gleason, R. (1990) Effects of fluoxetine or D-fenfluramine on serotonin release from, and levels in, rat frontal cortex. Brain Res. 529, 294–301.

    Article  CAS  PubMed  Google Scholar 

  24. Schmidt, C. J. (1987) Acute administration of methylenedioxymethamphetamine: comparison with the neurochemical effects of its N-desmethyl and N-ethyl analogs. Eur. J. Pharmacol. 136, 81–88.

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt, C. J., Wu, L., and Lovenberg, W. (1986) Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur. J. Pharmacol. 124, 175–178.

    Article  CAS  PubMed  Google Scholar 

  26. Ellinwood, E. H. (1969) Amphetamine psychosis: a multidimensional process. Simin. Psychiatry 1, 208–226.

    Google Scholar 

  27. Schuster, C. R. and Thompson, T. (1969) Self administration of and behavioral dependence on drugs. Annu. Rev. Pharmacol. 9, 483–502.

    Article  CAS  PubMed  Google Scholar 

  28. Angrist, B. M., Schweitzer, J. W., Gershon, S., and Friedhoff, A. J. (1970) Mephentermine psychosis: misuse of the Wyamine inhaler. Am. J. Psychiatry 126, 1315–1317.

    CAS  PubMed  Google Scholar 

  29. Griffith, J. (1966) A study of illicit amphetamine drug traffic in Oklahoma City. Am. J. Psychiatry 123, 560–569.

    CAS  PubMed  Google Scholar 

  30. Kramer, J. C., Fischman, V. S., and Littlefield, D. C. (1967) Amphetamine abuse. Pattern and effects of high doses taken intravenously. JAMA 201, 305–309.

    Article  CAS  PubMed  Google Scholar 

  31. Seiden, L. S. and Ricaurte, G. (1987) Neurotoxicity of methamphetamine and related drugs, in Psychopharmacology: The Third Generation of Progress ( Meltzer, H. Y., ed.), Raven, New York, pp. 359–365.

    Google Scholar 

  32. Seiden, L. S., Fischman, M. W., and Schuster, C. R. (1977) Changes in brain catecholamines induced by long-term methamphetamine administration in rhesus monkeys, in Cocaine and Other Stimulants ( Ellinwood, E. H., ed.), Plenum, New York, pp. 179–185.

    Chapter  Google Scholar 

  33. Wagner, G. C., Ricaurte, G. A., Seiden, L. S., Schuster, C. R., Miller, R. J., and Westley, J. (1980) Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res. 181, 151–160.

    Article  CAS  PubMed  Google Scholar 

  34. Axt, K. J., Commins, D. L., Vosmer, G., and Seiden, L. S. (1990) Alpha-methyl-ptyrosine pretreatment partially prevents methamphetamine-induced endogenous neurotoxin formation. Brain Res. 515, 269–276.

    Article  CAS  PubMed  Google Scholar 

  35. O’Hearn, E., Battaglia, G., Desouza, E. B., Kuhar, M. J., and Molliver, M. E. (1988) Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J. Neurosci. 8, 2788–2803.

    PubMed  Google Scholar 

  36. Ryan, L. J., Linder, J. C., Martone, M. E., and Groves, P. M. (1990) Histological and ultrastructural evidence that D-amphetamine causes degeneration in neostriatum and frontal cortex of rats. Brain Res. 518, 67–77.

    Article  CAS  PubMed  Google Scholar 

  37. Steranka, L. R. and Sanders, B. E. (1980) Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice. Eur. J. Pharmacol. 65, 439–443.

    Article  CAS  PubMed  Google Scholar 

  38. Wagner, G. C., Ricaurte, G. A., Johanson, C. E., Schuster, C. R., and Seiden, L. S. (1980) Amphetamine induces depletion of dopamine and loss of dopamine uptake sites in caudate. Neurology 30, 547–550.

    Article  CAS  PubMed  Google Scholar 

  39. Seiden, L. S., Fischman, M. W., and Schuster, C. R. (1976) Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys. Drug Alcohol Depend. 1, 215–219.

    Article  CAS  PubMed  Google Scholar 

  40. Ricaurte, G. A., Schuster, C. R., and Seiden, L. S. (1980) Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study. Brain Res. 193, 153–163.

    Article  CAS  PubMed  Google Scholar 

  41. Hotchkiss, A. and Gibb, J. W. (1980) Blockade of methamphetamine-induced depression of tyrosine hydroxylase by GABA transaminase inhibitors. Eur. J. Pharmacol. 66, 201–205.

    Article  CAS  PubMed  Google Scholar 

  42. Wagner, G. C., Schuster, C. R., and Seiden, L. S. (1979) Methamphetamine induced changes in brain catecholamines in rats and guinea pigs. Drug Alcohol Depend. 4, 435–439.

    Article  CAS  PubMed  Google Scholar 

  43. Levine, M., Hull, C. D., Garcia-Rill, E., Erinoff, L., Buchwald, N. A., and Heller, A. (1980) Long-term decreases in spontaneous firing of caudate neurons induced by amphetamine in cats. Brain Res. 194, 263–268.

    Article  CAS  PubMed  Google Scholar 

  44. Hotchkiss, A. J. and Gibb, J. W. (1980) Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. J. Pharmacol. Exp. Ther. 214, 257–262.

    CAS  PubMed  Google Scholar 

  45. Nwanze, E. and Jonsson, G. (1980) Amphetamine toxicity on dopamine nerve terminals in the caudate nucleus of mice. Neurosci. Lett. 26, 163–168.

    Article  Google Scholar 

  46. Wagner, G. C., Ricaurte, G. A., Seiden, L. S., Schuster, C. R., Miller, R. J., and Westley, J. (1980) Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res. 181, 151–160.

    Article  CAS  PubMed  Google Scholar 

  47. Wagner, G. C., Seiden, L. S., and Schuster, C. R. (1979) Methamphetmine-induced changes in brain catecholamines in rats and guinea pigs. Drug Alcohol Depend. 4, 435–438.

    Article  CAS  PubMed  Google Scholar 

  48. Lorez, H. (1981) Fluorescence histochemistry indicates damage of striatal dopamine nerve terminals in rats after multiple doses of methamphetamine. Life Sci. 28, 911–916.

    Article  CAS  PubMed  Google Scholar 

  49. Ricaurte, G. A., Guillery, R. W., Seiden, L. S., Schuster, C. R., and Moore, R. Y. (1982) Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain. Brain Res. 235, 93–103.

    Article  CAS  PubMed  Google Scholar 

  50. Woolverton, W. L., Ricaurte, G. A., Forno, L. S., and Seiden, L. S. (1989) Long-term effects of chronic methamphetamine administration in rhesus monkeys. Brain Res. 486, 73–78.

    Article  CAS  PubMed  Google Scholar 

  51. Walsh, S. L. and Wagner, G. C. (1990) The effects of methamphetamine-induced neurotoxicity on motor performance in the rat (56.8) [Abstract]. Soc. Neurosci. Abstracts 16.

    Google Scholar 

  52. Richards, J. B., Baggott, M. J., Sabol. K. E., and Seiden, L. S. (1993) A high-dose methamphetamine regimen results in long lasting deficits on the performance of a reaction time task. Brain Res. 627, 254–260.

    CAS  Google Scholar 

  53. Ando, K., Johanson, C. E., and Schuster, C. R. (1986) Effects of dopaminergic agents on eye tracking before and after repeated methamphetamine. Pharmacol. Biochem. Behay. 24, 693–699.

    Article  CAS  Google Scholar 

  54. Ando, K., Johanson, C. E., Seiden, L. S., and Schuster, C. R. (1985) Sensitivity changes to dopaminergic agents in fine motor control of rhesus monkeys after repeated methamphetamine administration. Pharmacol. Biochem. Behay. 22, 737–743.

    Article  CAS  Google Scholar 

  55. Finnegen, K. T., Ricaurte, G., Seiden, L. S., and Schuster, C. R. (1982) Altered sensitivity to d-methylamphetamine, apomorphine, and haloperidol in rhesus monkeys depleted of caudate dopamine by repeated administration of d-methylamphetamine Psychopharmacology (Berlin) 77, 43–52.

    Article  Google Scholar 

  56. Fischman, M. W. and Schuster, C. R. (1977) Long-term behavioral changes in the rhesus monkey after multiple daily injections of d-methylamphetamine. J. Pharmacol. Exp. Ther. 201, 593–605.

    CAS  PubMed  Google Scholar 

  57. Nencini, P., Woolverton, W. L., and Seiden, L. S. (1988) Enhancement of morphine-induced analgesia after repeated injections of methylenedioxymethamphetamine Brain Res. 457, 136–142.

    Article  CAS  PubMed  Google Scholar 

  58. Johanson, C. E., Aigner, T. G., Seiden, L. S., and Schuster, C. R. (1979) The effects of methamphetamine on fine motor control in rhesus monkeys. Pharmacol. Biochem. Behay. 11, 273–278.

    Article  CAS  Google Scholar 

  59. Preston, K. L. and Schuster, C. R. (1982) A comparison of the central and peripheral effects of atropine on force lever performance Pharmacol. Biochem. Behay. 16, 423–427.

    Article  CAS  Google Scholar 

  60. Carter, C. J. and Pycock, C. J. (1978) Differential effects of central serotonin manipulation on hyperactive and stereotyped behaviour. Life Sci. 23, 953–960.

    Article  CAS  PubMed  Google Scholar 

  61. Zenick, H. and Goldsmith, M. (1981) Drug discrimination learning in lead-exposed rats. Science 212, 569–571.

    Article  CAS  PubMed  Google Scholar 

  62. Green, A. R., Cross, A. J., and Goodwin, G. M. (1995) Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or “ecstacy”). Psychopharmacology 119, 247–260.

    Article  CAS  PubMed  Google Scholar 

  63. Steele, T. D., McCann, U. D., and Ricaurte, G. A. (1994) Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans [Review]. Addiction 89, 539–551.

    Article  CAS  PubMed  Google Scholar 

  64. Nichols, D. (1986) Differences between the mechanism of action of MDMA, MBDB and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J. Psychoactive Drugs 18, 305–313.

    Article  CAS  PubMed  Google Scholar 

  65. Eisner, B. (1989) Ecstacy: The MDMA Story. Ronin Publications, Berkeley, CA.

    Google Scholar 

  66. Peroutka, S. J., Newman, H., and Harris, H. (1988) Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology 1, 273–277.

    CAS  PubMed  Google Scholar 

  67. Grinspoon, L. and Bakalar, J. B. (1986) Can drugs be used to enhance the psychotherapeutic process? Am. J. Psychother. 40, 393–404.

    CAS  PubMed  Google Scholar 

  68. Henry, J. A. (1992) Toxicity and deaths from 3,4-methylenedioxymethamphetamine (“ecstacy”). Lancet 340, 384–387.

    Article  CAS  PubMed  Google Scholar 

  69. Peroutka, S. J. (1987) Incidence of recreational use of 3,4-methylenediomethoxymethamphetamine (MDMA, “ecstasy”) on an undergraduate campus [Letter]. N. Engl. J. Med. 317, 1542–1543.

    CAS  PubMed  Google Scholar 

  70. Cuomo, M. J., Dyment, P. G., and Gammino, V. M. (1994) Increasing use of “Ecstasy” (MDMA) and other hallucinogens on a college campus. J. Am. Coll. Health 42, 271–274.

    Article  CAS  PubMed  Google Scholar 

  71. Randall, T. (1992) Ecstacy-fueled “Rave” parties become dances of death for english youths. JAMA 268, 1505–1506.

    Article  CAS  PubMed  Google Scholar 

  72. Farfel, G. M. and Seiden, L. S. (1995) Role of hypothermia in the mechanism of protection against serotonergic toxicity. I. Experiments using 3,4-methylenedioxymethamphetamine, dizocilpine, CGS 19755 and NBQX. J. Pharmacol. Exp. Ther. 272, 860–867.

    CAS  PubMed  Google Scholar 

  73. Battaglia, G., Yeh, S. Y., and Desouza, E. B. (1988) MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons. Pharmacol. Biochem. Behan 29, 269–274.

    Article  CAS  Google Scholar 

  74. Stone, D. M., Hanson, G. R., and Gibb, J. W. (1987) Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats. Neuropharmacology 26, 1657–1661.

    Article  CAS  PubMed  Google Scholar 

  75. Battaglia, G., Brooks, B. P., Kulsakdinun, C., and De S. E. (1988) Pharmacologie profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. Eur. J. Pharmacol. 149, 159–163.

    Article  CAS  PubMed  Google Scholar 

  76. Insel, T. R., Battaglia, G., Johanssen, J., Marra, S., and Desouza, E. B. (1989) 3,4-Methylenedioxymethamphetamine (“Ecstacy”) selectively destroys brain serotonin nerve terminals in rhesus monkeys. J. Pharmacol. Exp. Ther. 249, 713–720.

    Google Scholar 

  77. Ricaurte, G. A., Martello, A. L., Katz, J. L., and Martello, M. B. (1992) Lasting effects of (+-)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J. Pharmacol. Exp. Ther. 261, 616–622.

    CAS  PubMed  Google Scholar 

  78. Ricaurte, G. A. and McCann, U. D. (1992) Neurotoxic amphetamine analogues: effects in monkeys and implications for humans [Review]. Ann. NYAcad. Sci. 648, 371–382.

    Article  CAS  PubMed  Google Scholar 

  79. Schmidt, C. J. and Taylor, V. L. (1987) Depression of rat brain tryptophan hydroxylase activity following the acute administration of methylenedioxymethamphetamine. Biochem. Pharmacol. 36, 4095–4102.

    Article  CAS  PubMed  Google Scholar 

  80. Stone, D. M., Johnson, M., Hanson, G. R., and Gibb, J. W. (1988) Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine. J. Pharmacol. Exp. Ther. 247, 79–87.

    CAS  PubMed  Google Scholar 

  81. Commins, D. L., Vosmer, G., Virus, R. M., Woolveerton, W. L., Schuster, C. R., and Seiden, L. S. (1987) Biochemical and histological evidence that methylenedioxymethamphetamine (MDMA) is toxic to neurons in the rat brain. J. Pharmacol. Exp. Ther. 241, 338–345.

    CAS  PubMed  Google Scholar 

  82. Lew, R., Sabol, K. E., Chou, C., Vosmer, G. L., Richards, J., and Seiden, L. S. (1996) Methylenedioxymethamphetamine (MDMA)-induced serotonin deficits are followed by partial recovery over a 52 week period. Part II: Radioligand binding and autoradiographic studies. J. Pharmacol. Exp. Ther. 276, 855–865.

    CAS  PubMed  Google Scholar 

  83. Molliver, M. E., Mamounas, L. A., and Wilson, M. A. (1989) Effects of neurotoxic amphetamines on serotonergic neurons: immunocytochemical studies, in Pharmacology and Toxicology of Amphetamine and Related Designer Drugs ( Asghar, K. and De Souza, E., eds.), NIDA Research Monograph, US Department of Health and Human Service, Washington, DC, pp. 270–305.

    Google Scholar 

  84. Scanzello, C. R., Hatzidimitriou, G., Martello, A. L., Katz, J. L., and Ricaurte, G. A. (1993) Serotonergic recovery after (+/—)3,4-(methylenedioxy) methamphetamine injury: observations in rats. J. Pharmacol. Exp. Ther. 264, 1484–1491.

    CAS  PubMed  Google Scholar 

  85. Scheffel, U. and Ricaurte, G. A. (1990) Paroxetine as an in vivo indicator of 3,4-methylenedioxymethamphetamine neurotoxicity: a presynaptic serotonergic positron emission tomography ligand? Brain Res. 527, 89–95.

    Article  CAS  PubMed  Google Scholar 

  86. Bowyer, J. F., Davies, D. L., Schmued, L., Broening, H. W., Newport, G. D., Slikker, W. J., and Holson, R. R. (1994) Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J. Pharmacol. Exp. Ther. 268, 1571–1580.

    CAS  PubMed  Google Scholar 

  87. Fischer, C., Hatzidimitriou, G., Wlos, J., Katz, J., and Ricaurte, G. (1995) Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/—)3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). J. Neuroscience 15, 5476–5485.

    CAS  Google Scholar 

  88. Sabol, K. E., Lew, R., Richards, J. B., Vosmer, G. L., and Seiden, L. S. (1996) Methylenedioxymethamphetamine (MDMA)-induced serotonin deficits are followed by partial recovery over a 52 week period. Part I: Synaptosomal uptake and tissue concentrations. J. Pharmacol. Exp. Ther. 276, 846–854.

    CAS  PubMed  Google Scholar 

  89. Ricaurte, G. A., Forno, L. S., Wilson, M. A., Delanney, L. E., Irwin, I., Molliver, M. E., and Langston, J. W. (1988) (+/—)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA 260, 51–55.

    Google Scholar 

  90. Ricaurte, G. A., Delanney, L. E., Irwin, I., and Langston, J. W. (1988) Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration. Brain Res. 446, 165–168.

    Article  CAS  PubMed  Google Scholar 

  91. Battaglia, G., Yeh, S. Y., O’Hearn, E., Molliver, M. E., Kuhar, M. J., and De Souza, E. B. (1987) 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. J. Pharmacol. Exp. Ther. 242, 911–916.

    Google Scholar 

  92. Ricaurte, G. A., Finnegan, K. T., Irwin, I., and Langston, J. W. (1990) Aminergic metabolites in cerebrospinal fluid of humans previously exposed to MDMA: Preliminary observations. Ann. NYAcad. Sci. 600, 699–710.

    Article  CAS  PubMed  Google Scholar 

  93. Atkinson, R. L. and Hubbard, V. S. (1994) Report on the NIH workshop on pharmacologic treatment of obesity. Am. J. Clin.. Nutr. 60, 153–156.

    CAS  PubMed  Google Scholar 

  94. Le Douarec, P., Neveu, C., and Garattini, S. (1970) Pharmacology and biochemistry of fenfluramine, in Amphetamine and Related Compounds ( Costa, E., ed.), Raven, New York, pp. 75–105.

    Google Scholar 

  95. Kleven, M. S. and Seiden, L. S. (1989) DL-fenfluramine cause long-lasting depletions of serotonin in rat brain. Brain Res. 505, 351–353.

    Article  CAS  PubMed  Google Scholar 

  96. Nicolaidis, S. (1997) Obesity Management Redux. Academic, San Diego.

    Google Scholar 

  97. Clineschmidt, B. V., Zacchei, A. G., Totaro, J. A., Pfluger, A. B., McGuffin, J. C., and Wishousky, T. I. (1978) Fenfluramine and brain serotonin. Ann. NY Acad. Sci. 305, 222–241.

    Article  CAS  PubMed  Google Scholar 

  98. Harvey, J. A., McMaster, S. E., and Fuller, R. W. (1977) Comparison between the neurotoxic and serotonin depleting effects of various halogenated derivatives of amphetamine in the rat. J. Pharmacol. Exp. Ther. 202, 581–589.

    CAS  PubMed  Google Scholar 

  99. Harvey, J. A. and McMaster, S. E. (1975) Fenfluramine: evidence for a neurotoxic action on a long-term depletion of serotonin. Psychopharmacol. Commun. 1, 217–228.

    CAS  PubMed  Google Scholar 

  100. Kleven, M. S., Schuster, C. R., and Seiden, L. S. (1988) Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine. J. Pharmacol. Exp. Ther. 246, 822–828.

    CAS  PubMed  Google Scholar 

  101. Sanders-Bush, E., Bushing, J. A., and Sulser, F. (1975) Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms. J. Pharmacol. Exper. Ther. 192, 33–41.

    CAS  Google Scholar 

  102. Schuster, C. R., Lewis, M., and Seiden, L. S. (1986) Fenfluramine: neurotoxicity. Psychopharmacol. Bull. 22, 148–151.

    CAS  PubMed  Google Scholar 

  103. Steranka, L. R. and Sanders-Bush, E. (1979) Long-term effects of fenfluramine on central serotonergic mechanisms. Neuropharmacology 18, 895–903.

    Article  CAS  PubMed  Google Scholar 

  104. Zaczek, R., Battaglia, G., Culp, S., Appel, N. M., Contrera, J. F., and DeSouza, E. B. (1990) Effects of repeated fenfluramine administration on indices of monoamine function in rat brain: pharmacokinetic, dose response, regional specificity and time course data. Pharmacol. Exp. Ther. 253, 104–112.

    CAS  Google Scholar 

  105. McCann, U., Hatzidimitriou, G., Ridenour, A., Fischer, C., Yuan, J., Katz, J., and Ricaurte, G. (1994) Dexfenfluramine and serotonin neurotoxicity: further preclinical evidence that clinical caution is indicated. J. Pharmacol. Exp. Ther. 269, 792–798.

    CAS  PubMed  Google Scholar 

  106. Ricaurte, G. A., Molliver, M. E., Martello, M. B., Katz, J. L., Wilson, M. A., and Martello, A. L. (1991) Dexfenfluramine neurotoxicity in brains of non-human primates [see comments]. Lancet 338, 1487–1488.

    Article  CAS  PubMed  Google Scholar 

  107. Scheffel, U., Szabo, Z., Mathews, W. B., Finley, P. A., Yuan, J., Callahan, B., Hatzidimitriou, G., Dannals, R. F., Ravert, H. T., and Ricaurte, G. A. (1996) Fenfluramine-induced loss of serotonin transporters in baboon brain visualized with PET. Synapse.

    Google Scholar 

  108. Appel, N. M., Contrera, J. F., and De Souza, E. B. (1989) Fenfluramine selectively and differentially decreases the density of serotonergic nerve terminals in rat brain: evidence from immunocytochemical studies. J. Pharmacol. Exp. Ther. 249, 928–943.

    CAS  PubMed  Google Scholar 

  109. Molliver, D. C. and Molliver, M. E. (1990) Anatomic evidence for a neurotoxic effect of (+/—)-fenfluramine upon serotonergic projections in the rat. Brain Res. 511, 165–168.

    Article  CAS  PubMed  Google Scholar 

  110. Appel, N. M., Mitchell, W. M., Contrera, J. F., and De Souza, E. B. (1990) Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography. Synapse 6, 33–44.

    Article  CAS  PubMed  Google Scholar 

  111. Lew, R., Weisenberg, B., Vosmer, G., and Seiden, L. S. (1997) Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields. Synapse 26, 36–45.

    Article  CAS  PubMed  Google Scholar 

  112. Kalia, M. (1991) Reversible, short-lasting, and dose-dependent effect of (+)-fenfluramine on neocortical serotonergic axons. Brain Res. 548, 111–125.

    Article  CAS  PubMed  Google Scholar 

  113. Sotelo, C. (1991) Immunohistochemical study of short-and long-term effects of DL-fenfluramine on the serotonergic innervation of the rat hippocampal formation. Brain Res. 541, 309–326.

    Article  CAS  PubMed  Google Scholar 

  114. Caccia, S., Ballabio, M., Guiso, G., Rocchetti, M., and Garattini, S. (1982) Species diffrences in the kinetics and metabolism of fenfluramine isomers. Arch. Int. Pharmacodyn. 258, 15–28.

    CAS  PubMed  Google Scholar 

  115. Westphalen, R. I. and Dodd, P. R. (1995) The nature of d,l-fenfluramine-induced 5-HT reuptake transporter loss in rats. Mol. Neurobiol. 11, 165–175.

    Article  CAS  PubMed  Google Scholar 

  116. Westphalen, R. I. and Dodd, P. R. (1993) New evidence for a loss of serotonergic nerve terminals in rats treated with d,l-fenfluramine. Pharmacol. Toxicol. 72, 249–255.

    Article  CAS  PubMed  Google Scholar 

  117. Westphalen, R. I. and Dodd, P. R. (1993) The regeneration of d,/-fenfluraminedestroyed serotonergic nerve terminals. Eur. J. Pharmacol. 238, 399–402.

    Article  CAS  PubMed  Google Scholar 

  118. Battaglia, G., Norman, A. B., Newton, P. L., and Creese, I. (1986) In vitro and in vivo irreversible blockade of cortical S2 serotonin receptors by N-ethoxycarbonyl-2ethoxy-1,2-dihydroquinoline: a technique for investigating S2 serotonin receptor recovery. J. Neurochem. 46, 589–593.

    Article  CAS  PubMed  Google Scholar 

  119. Norton, W. T., Aquino, D. A., Hozumi, I., Chiu, F. C., and Brosnan, C. F. (1992) Quantitative aspects of reactive gliosis: a review. Neurochem. Res. 17, 877–885.

    Article  CAS  PubMed  Google Scholar 

  120. O’Callaghan, J. P. and Miller, D. B. (1994) Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J. Pharmacol. Exp. Ther. 270, 741–751.

    PubMed  Google Scholar 

  121. Miller, D. B. and O’Callaghan, J. P. (1994) Environment-, drug-and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse. J. Pharmacol. Exp. Ther. 270, 752–760.

    CAS  PubMed  Google Scholar 

  122. Rowland, N. E., Kalehua, A. N., Li, B. H., Semple-Rowland, S. L., and Streit, W. J. (1993) Loss of serotonin uptake sites and immunoreactivity in rat cortex after dexfenfluramine occur without parallel glial cell reactions. Brain Res. 624, 35–43.

    Article  CAS  PubMed  Google Scholar 

  123. Roth, B. L. (1994) Multiple serotonin receptors: clinical and experimental aspects [Review]. Ann. Clin. Psychiatry 6, 67–78.

    Article  CAS  PubMed  Google Scholar 

  124. Hoebel, B. G., Hernandez, L., Schwartz, D. H., Mark, G. P., and Hunter, G. A. (1989) Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications [Review]. Ann. of Acad. Sci. 575, 171–191.

    Article  CAS  Google Scholar 

  125. Kleven, M. S., Woolverton, W. L., and Seiden, L. S. (1991) Evaluation of potential neurotoxic effects of amphetamine-related anorectic agents on brain serotonin and dopamine in the rat [Abstract]. Proc. Soc. Neurosci. 17.

    Google Scholar 

  126. Weintraub, M., Sundaresan, P. R., Madan, M., Schuster, B., Balder, A., Lasagna, L., and Cox, C. (1992) Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin. Pharmacol. Ther. 51, 586–594.

    Article  CAS  PubMed  Google Scholar 

  127. Weintraub, M., Sundaresan, P. R., Schuster, B., Ginsberg, G., Madan, M., Balder, A., Stein, E. C., and Byrne, L. (1992) Long-term weight control study. II (weeks 34 to 104). An open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin. Pharmacol. Ther. 51, 595–601.

    Article  CAS  PubMed  Google Scholar 

  128. Weintraub, M., Sundaresan, P. R., Schuster, B., Moscucci, M., and Stein, E. C. (1992) Long-term weight control study. III (weeks 104 to 156). An open-label study of dose adjustment of fenfluramine and phentermine. Clin. Pharmacol. Ther. 51, 602–607.

    Article  CAS  PubMed  Google Scholar 

  129. Weintraub, M., Sundaresan, P. R., Schuster, B., Averbuch, M., Stein, E. C., Cox, C., and Byrne, L. (1992) Long-term weight control study. IV (weeks 156 to 190). The second double-blind phase. Clin. Pharmacol. Ther. 51, 608–614.

    Article  CAS  PubMed  Google Scholar 

  130. Weintraub, M., Sundaresan, P. R., Schuster, B., Averbuch, M., Stein, E. C., and Byrne, L. (1992) Long-term weight control study. V (weeks 190 to 210). Follow-up of participants after cessation of medication. Clin. Pharmacol. Ther. 51, 615–618.

    Article  CAS  PubMed  Google Scholar 

  131. Weintraub, M., Hasday, J. D., Mushlin, A. I., and Lockwood, D. H. (1984) A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch. Int. Med. 144, 1143–1148.

    Article  CAS  Google Scholar 

  132. Weintraub, M. (1992) Long-term weight control study: Conclusions. Clin. Pharmacol. Ther. 51, 642–646.

    Article  CAS  PubMed  Google Scholar 

  133. Silverstone, T. (1992) Appetite suppressants. A review [Review]. Drugs 43, 820–36.

    Article  CAS  PubMed  Google Scholar 

  134. Chappell, W. R. (1989) Interspecific scaling of toxicity data: A question of interpretation. Risk Anal. 9, 13–14.

    Article  CAS  PubMed  Google Scholar 

  135. Mordenti, J., Chen, S. A., Moore, J. A., Ferraiolo, B. L., and Green, J. D. (1991) Inter-species scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm. Res. 8, 1351–1359.

    Article  CAS  PubMed  Google Scholar 

  136. Alvares, A. P., Pratt, W. B., and Taylor, P. (1990) Pathways of drug metabolism, in Principles of Drug Action: The Basis of Pharmacology ( Pratt, W. B., ed.), pp. 365–422, Churchill Livingstone, New York.

    Google Scholar 

  137. Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H., and Skipper, H. E. (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Cherother. Rep. 50, 219–226.

    CAS  Google Scholar 

  138. Guy-Grand, B. (1992) Clinical studies with d-fenfluramine. Am. J. Clin. Nutr. 55, 1735–176S.

    Google Scholar 

  139. Schmidt, C. J., Ritter, J. K., Sonsalla, P. K., Hanson, G. R., and Gibb, J. W. (1985) Role of dopamine in the neurotoxic effects of methamphetamine. J. Pharmacol. Exp. Ther. 233, 539–544.

    CAS  PubMed  Google Scholar 

  140. Carlsson, A. (1993) Search for the neuronal circuitries and neurotransmitters involved in “Positive” and “Negative” schizophrenic symptomatology. Fidia Research Foundation Lecture Series 7.

    Google Scholar 

  141. Wagner, G. C., Lowndes, H. E., and Kita, T. (1993) Methamphetamine-induced 6-hydroxydopamine formation following MAO and COMT inhibition [Abstract]. Soc. Neurosci. Abstracts 19.

    Google Scholar 

  142. Axt, K. J. and Seiden, L. S. (1990) alpha-Methyl-p-tyrosine partially attenuates p-chloroamphetamine-induced 5-hydroxytryptamine depletions in the rat brain. Pharmacol. Biochem. Behay. 35, 995–997.

    Google Scholar 

  143. Giovanni, A., Hastings, T. G., Liang, L. P., and Zigmond, M. J. (1992) Metamphetamine increases hydroxyl radicals in rat striatum: Role of dopamine [Abstract] Soc. Neurosci. Abstracts 18.

    Google Scholar 

  144. Hastings, T. G., and Zigmond, M. J. (1992) Prostaglandin synthase-catalyzed oxidation of dopamine [Abstract]. Soc. Neurosci. Abstracts 18.

    Google Scholar 

  145. Liang, L. P., Hastings, T. G., Zigmond, M. J., and Giovanni, A. (1992) Use of salicylate to trap hydroxyl radicals in rat brain: a methodological study [Abstract]. Soc. Neurosci. Abstracts 18.

    Google Scholar 

  146. Seiden, L. S. and Vosmer, G. (1984) Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methylamphetamine. Pharmacol. Biochem. Behay. 21, 29–31.

    Article  CAS  Google Scholar 

  147. Zigmond, M. J. and Hastings, T. G. (1992) A method for measuring dopamine-protein conjugates as an index of dopamine oxidation [Abstract]. Soc. Neurosci. Abstracts 18.

    Google Scholar 

  148. Butcher, S. P., Fairbrother, I. S., Kelly, J. S., and Arbuthnott, G. W. (1988) Amphetamine-induced dopamine release in the rat striatum: an in vivo microdialysis study. J. Neurochem. 50, 346–355.

    Article  CAS  PubMed  Google Scholar 

  149. Sonsalla, P. K., Gibb, J. W., and Hanson, G. R. (1986) Roles of Dl and D2 dopamine receptor subtypes in mediating the methamphetamine-induced changes in monoamine systems. J. Pharmacol. Exp. Ther. 238, 932–937.

    CAS  PubMed  Google Scholar 

  150. Creese, I., Sibley, D. R., Hamblin, M. W., and Leff, S. E. (1983) Dopamine receptors in the central nervous system [Review] Adv. Biochem. Psychopharmacol. 36, 125–134.

    CAS  PubMed  Google Scholar 

  151. Carlsson, A. and Lindqvist, M. (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol. Toxicol. 20, 140–144.

    Article  CAS  Google Scholar 

  152. Brownstein, M. J. and Palkovits, M. (1984) Catecholamines, serotonin, acetylcholine, and y-aminobutyric acid in the rat brain: biochemical studies, in Handbook of Chemical Neuroanatomy: Classical Transmitters in the CNS ( Bjorklund, A. and Hokfelt, T., eds.), Elsevier, Amsterdam, pp. 23–54.

    Google Scholar 

  153. Nash, J. F. (1990) Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis. Life Sci. 47, 2401–2408.

    Article  CAS  PubMed  Google Scholar 

  154. Schmidt, C. J., Black, C. K., Taylor, V. L., Fadayel, G. M., Hymphreys, T. M., Nieduzak, T. R., and Sorensen, S. M. (1992) The 5-HT2 receptor antagonist, MDL, 133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine Eur. J. Pharmacol. 220, 151–159.

    Article  CAS  PubMed  Google Scholar 

  155. Schmidt, C. J., Fadayel, G. M., Sullivan, C. K., and Taylor, V. L. (1992) 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine. Eur. J. Pharmacol. 223, 65–74.

    Google Scholar 

  156. Schmidt, C. J., Taylor, V. L., Abbate, G. M., and Nieduzak, T. R. (1991) 5-HT2 antagonists stereoselectively prevent the neurotoxicity of 3,4-methylenedioxymethamphetamine by blocking the acute stimulation of dopamine synthesis: reversal by L-dopa. J. Pharmacol. Exp. Ther. 256, 230–235.

    Google Scholar 

  157. Minchin, M. C. W. (1985) Inositol phospholipid breakdown as an index of serotonin receptor function, in Neuropharmacology of Serotonin ( Green, A. R., ed.), Oxford, New York, pp. 117–130.

    Google Scholar 

  158. Berridge, M. J. and Galione, A. (1988) Cytosolic calcium oscillators. FASEB J 2, 3074–3082.

    CAS  PubMed  Google Scholar 

  159. Gandhi, C. R. and Ross, D. H. (1988) Characterization of a high-affinity Mgt+-independent Ca2+-ATPase from rat brain synaptosomal membranes. J. Neurochem. 50, 248–256.

    Article  CAS  PubMed  Google Scholar 

  160. Sonsalla, P. K., Nicklas, W. J., and Heikkila, R. E. (1989) Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity. Science 243, 398–400.

    Article  CAS  PubMed  Google Scholar 

  161. Farfel, G. M., Vosmer, G. L., and Seiden, L. S. (1992) The N-methyl-D-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine. Brain Res. 595, 121–127.

    Article  CAS  PubMed  Google Scholar 

  162. Johnson, M., Hanson, G. R., and Gibb, J. W. (1989) Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog. Eur. J. Pharm. 165, 315–318.

    Article  CAS  Google Scholar 

  163. Frandsen, A. and Schousboe, A. (1991) Dantrolene prevents glutamate cytotoxicity and Ca2+ release from intracellular stores in cultured cerebral cortical neurons. J. Neurochem. 56, 1075–1078.

    Article  CAS  PubMed  Google Scholar 

  164. Lei, S. Z., Zhang, D., Abele, A. E., and Lipton, S. A. (1992) Blockade of NMDA receptor-mobilization of intracellular Ca2+ prevents neurotoxicity. Brain Res. 598, 196–202.

    Article  CAS  PubMed  Google Scholar 

  165. Weihmuller, F. B., O’Dell, S. J., Cole, B. N., and Marshall, J. F. (1991) MK-801 attenuates the dopamine-releasing but not the behavioral effects of methamphetamine: an in vivo microdialysis study. Brain Res. 549, 230–235.

    Article  CAS  PubMed  Google Scholar 

  166. Kashihara, K., Okumura, K., Onishi, M., and Otsuki, S. (1991) MK-801 fails to modify the effect of methamphetamine on dopamine release in the rat striatum. Neuroreport 2, 236–238.

    Article  CAS  PubMed  Google Scholar 

  167. Bowyer, J. F., Scallet, A. C., Holson, R. R., Lipe, G. W., Slikker, W., and Ali, S. F. (1991) Interactions of MK-801 with glutamate-, glutamine-and methamphetamineevoked release of [3H]dopamine from striatal slices. J. Pharmacol. Exp. Ther. 257, 262–270.

    CAS  PubMed  Google Scholar 

  168. Wagner, G. C., Carelli, R. M., and Jarvis, M. F. (1986) Ascorbic acid reduces the dopamine depletion induced by methamphetamine and the 1-methyl-4-phenyl pyridinium ion. Neuropharmacology 25, 559–561.

    Article  CAS  PubMed  Google Scholar 

  169. Commins, D. L., Axt, K. J., Vosmer, G., and Seiden, L. S. (1987) 5,6-Dihydroxytryptamine, a serotonergic neurotoxin, is formed endogenously in the rat brain. Brain Res. 403, 7–14.

    Google Scholar 

  170. O’Dell, S. J., Weihmuller, F. B., McPherson, R. J., and Marshall, J. F. (1992) Excitotoxic lesions in rat striatum protect against subsequent methamphetamine-induced dopamine terminal damage [Abstract]. Soc. Neurosci. Abstracts 18.

    Google Scholar 

  171. Fuller, R. W. and Hemrick-Luecke, S. (1980) Long-lasting depletion of striatal dopamine by a single injection of amphetamine in iprindole-treated rats. Science 209, 305–307.

    Article  CAS  PubMed  Google Scholar 

  172. Marek, G. J., Vosmer, G., and Seiden, L. S. (1990) Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons. Brain Res. 513, 274–279.

    Article  CAS  PubMed  Google Scholar 

  173. Ricaurte, G. A., Fuller, R. W., Perry, K. W., Seiden, L. S., and Schuster, C. R. (1983) Fluoxetine increases long-lasting neostriatal dopamine depletion after administration of d-methamphetamine and d-amphetamine. Neuropharmacology 22, 1165–1169.

    Article  CAS  PubMed  Google Scholar 

  174. Green, A. R., DeSouza, R. J., Williams, J. L., Murray, T. K., and Cross, A. J. (1992) The neurotoxic effects of methamphetamine on 5-hydroxytryptamine and dopamine in brain: Evidence for the protective effect of chlormethiazole. Neuropharmacology 31, 315–321.

    Article  CAS  PubMed  Google Scholar 

  175. Cadet, J. L., Ladenheim, B., Baum, I., Carlson, E., and Epstein C. (1994) CuZnsuperoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA). Brain Res. 655, 259–262.

    Article  CAS  PubMed  Google Scholar 

  176. Cadet, J. L., Sheng, P., Ali, S., Rothman, R., Carlson, E., and Epstein, C. (1994) Attenuation of methamphetamine-induced neurotoxicity in copper/zinc superoxide dismutase transgenic mice. J. Neurochem. 62, 380–383.

    Article  CAS  PubMed  Google Scholar 

  177. Hiramatsu, M., Kumagai, Y., Unger, S. E., and Cho, A. K. (1990) Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct. J. Pharmacol. Exp. Ther. 254, 521–527.

    CAS  PubMed  Google Scholar 

  178. Chiueh, C. C., Miyake, H., and Peng, M. T. (1993) Role of dopamine autoxidation, hydroxyl radical generation, and calcium overload in underlying mechanisms involved in MPTP-induced parkinsonism. Adv. Neurol. 60, 251–258.

    CAS  PubMed  Google Scholar 

  179. Colado, M. I. and Green, A. R. (1994) A study of the mechanism of MDMA (“ecstasy”)-induced neurotoxicity of 5-HT neurones using chlormethiazole, dizocilpine and other protective compounds. Br. J. Pharmacol. 111, 131–36.

    Article  CAS  PubMed  Google Scholar 

  180. Murray, T. K., Williams, J. L., Misra, A., Colado, M. I., and Green, A. R. (1996) The spin trap reagent PBN attenuates degeneration of 5-HT neurons in rat brain induced by p-chloroamphetamine but not fenfluramine. Neuropharmacology 35, 1615–1620.

    Article  CAS  PubMed  Google Scholar 

  181. Colado, M. I. and Green, A. R. (1995) The spin trap reagent alpha-phenyl-N-tert-butyl nitrone prevents “ecstasy”-induced neurodegeneration of 5-hydroxytryptamine neurones. Eur. J. Pharmacol. 280, 343–346.

    Article  CAS  PubMed  Google Scholar 

  182. Che, S., Johnson, M., Hanson, G. R., and Gibb, J. W. (1995) Body temperature effect on methylenedioxymethampheatmine-induced acute decrease in tryptophan hydroxylast acitvity. Eur. J. Pharmacol. 293, 447–453.

    Article  CAS  PubMed  Google Scholar 

  183. Carney, J. M. and Floyd, R. A. (1991) Protection against oxidative damage to CNS by alpha-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: a novel series of nonlipid free radical scavengers. J. Mol. Neurosci. 3, 47–57.

    Article  CAS  PubMed  Google Scholar 

  184. Albers, D. S. and Sonsalla, P. K. (1995) Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: Pharmacological profile of protective and non-protective agents. J. Pharmacol. Exp. Ther. 275, 1104–1114.

    CAS  PubMed  Google Scholar 

  185. Farfel, G. M. and Seiden, L. S. (1995) Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. J. Pharmacol. Exp. Ther. 272, 868–875.

    CAS  PubMed  Google Scholar 

  186. Malberg, J. E., Sabol, K. E., and Seiden, L. S. (1996) Co-administration of MDMA with drugs that protect against MDMA neurotoxicity produces different effects on body temperature. J. Pharmacol. Exp. Ther. 278, 258–267.

    CAS  PubMed  Google Scholar 

  187. Malberg, J. E. and Seiden, L. S. (1996) 3,4-Methylenedioxymethamphetamine (MDMA) 5HT neurotoxicity is a function of ambient temperature and core body temperature in rats [Abstract]. Soc. Neurosci. Abstracts 22.

    Google Scholar 

  188. Hewitt, K. E. and Green, A. R. (1994) Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA (Ecstacy) to rats. Neuropharmacology 33, 1589–1595.

    Article  CAS  PubMed  Google Scholar 

  189. Gordon, C. J., Watkinson, W. P., O’Callaghan, J. P., and Miller, D. B. (1991) Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat. Pharmacol. Biochem. Behay. 38, 339–344.

    Article  CAS  Google Scholar 

  190. Ali, S. E, Newport, G. D., Holson, R. R., Slikker, W. J., and Bowyer, J. E (1994) Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice. Brain Res. 658, 33–38.

    Article  CAS  PubMed  Google Scholar 

  191. Malberg, J. E. and Seiden, L. S. (1997) Administration of Fenfluramine at different ambient temperatures produces different core temperature and 5HT neurotoxicity profiles. Brain Res.,in press.

    Google Scholar 

  192. Dafters, R. I. (1994) Effect of ambient temperature on hyperthermia and hyperkinesis induced by 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) in rats. Psychopharmacology 114, 505–508.

    Article  CAS  PubMed  Google Scholar 

  193. Frey, H. H. (1975) Hyperthermia induced by amphetamine, p-chloroamphetamine and fenfluramine in the rat. Pharmacology 13, 163–176.

    Article  CAS  Google Scholar 

  194. Preston, E., Ma, S., and Hass, N. (1990) Ambient temperature modulation of fenfluramine-induced thermogenesis in the rat. Neuropharmacology 29, 277–283.

    Article  CAS  PubMed  Google Scholar 

  195. Wilkinson, L. O., Auerbach, S. B., and Jacobs, B. L. (1991) Extracellular serotonin levels change with behavioral state but not with pyrogen-induced hyperthermia. J. Neurosci. 11, 2732–2741.

    CAS  PubMed  Google Scholar 

  196. Gordon, C. J. and Fogelson, L. (1994) Metabolic and thermoregulatory responses of the rat maintained in acrylic or wire-screen cages: implications for pharmacological studies. Physiol. Behay. 56, 73–79.

    Article  CAS  Google Scholar 

  197. Lehninger, A. L. (1975) Biochemistry. Worth Publishers, New York.

    Google Scholar 

  198. Bowyer, J. E, Gough, B., Slikker, W. J., Lipe, G. W., Newport, G. D., and Holson, R. R. (1993) Effects of a cold environment or age on methamphetamine-induced dopamine release in the caudate putamen of female rats. Pharmacol. Biochem. Behan 44, 87–98.

    Article  CAS  Google Scholar 

  199. Pileblad, E., Slivka, A., Bratvold, B., and Cohen, G. (1988) Studies on the autoxidation of dopamine: Interaction with ascorbate. Arch. Biochem. Biophys. 263, 447–452.

    Article  CAS  PubMed  Google Scholar 

  200. Cohen, G. and Heikkila, R. E. (1974) The generation of hydrogen peroxide, superoxide radical, and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic agents. J. Biol. Chem. 249, 2447–2452.

    CAS  PubMed  Google Scholar 

  201. Senoh, S. and Wiktop, B. (1959) Non-enzymatic conversions of dopamine to norephinephrine and trihydroxy phenethylamines. J. Am. Chem. Soc. 81, 6222–6235.

    Article  CAS  Google Scholar 

  202. Riederer, P., Dirr, A., Goetz, M., Sofic, E., Jellinger, K., and Youdim, M. B. (1992) Distribution of iron in different brain regions and subcellular compartments in Parkinson’s disease [Review]. Ann. Neuro. 32 (Suppl), 5101–104.

    Article  Google Scholar 

  203. Halliwell, B. and Gutteridge, J. M. (1984) Role of iron in oxygen radical reactions. Methods Enzymol. 105, 47–56.

    Article  CAS  PubMed  Google Scholar 

  204. Fornstedt, B. and Carlsson, A. (1989) A marked rise in 5-S-cysteinyl-dopamine levels in guinea-pig striatum following reserpine treatment. J. Neural Transm. 76, 155–161.

    Article  CAS  PubMed  Google Scholar 

  205. Fornstedt, B., Rosengren, E., and Carlsson, A. (1986) Occurrence and distribution of 5-S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eight mammalian species. Neuropharmacology 25, 451–454.

    Article  CAS  PubMed  Google Scholar 

  206. Rollema, H., De, V. J. B., Westerink, B. H., Van, P. F. M., and Horn, A. S. (1986) Failure to detect 6-hydroxydopamine in rat striatum after the dopamine releasing drugs dexamphetamine, methylamphetamine and MPTP. Eur. J. Pharmacol. 132, 65–69.

    Article  CAS  PubMed  Google Scholar 

  207. Marek, G. J., Vosmer, G., and Seiden, L. S. (1990) Pargyline increases 6-hydroxydopamine levels in the neostriatum of methamphetamine-treated rats. Pharm. Biochem. Behay. 36, 187–190.

    Article  CAS  Google Scholar 

  208. Ricaurte, G., Bryan, G., Strauss, L., Seiden, L., and Schuster, C. (1985) Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science 229, 986–988.

    Article  CAS  PubMed  Google Scholar 

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Authors
  1. R. Lew
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  2. J. E. Malberg
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  3. George A. Ricuarte
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  4. Lewis S. Seiden
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Editors and Affiliations

  1. Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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© 1998 Springer Science+Business Media New York

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Lew, R., Malberg, J.E., Ricuarte, G.A., Seiden, L.S. (1998). Evidence for and Mechanism of Action of Neurotoxicity of Amphetamine Related Compounds. In: Kostrzewa, R.M. (eds) Highly Selective Neurotoxins. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-477-1_9

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  • DOI: https://doi.org/10.1007/978-1-59259-477-1_9

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-047-2

  • Online ISBN: 978-1-59259-477-1

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