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Neurotoxic Effects of Substituted Amphetamines in Rats and Mice

Challenges to the Current Dogma

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Handbook of Neurotoxicology

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Abstract

Whether you read about it in the popular press or in the scientific literature, there is no lack of coverage of the issue of amphetamine-induced neurotoxicity. Included among these articles are reports on the adverse effects in both animals and humans of methamphetamine (1–3) and methylenedioxymethamphetamine (MDMA; “Ecstasy”) (4–7). Until it was withdrawn from the market for the potential to affect heart valvular function, the anorectic agent dexfenfluramine drew attention in the experimental and clinical literature for reported neurotoxic effects, even at the prescribed anorectic dosage (8). Lastly and most recently, attention has been focused on the fact that a large percentage of school-age children are maintained on stimulants, including amphetamines, for the treatment of attention deficit/hyperactivity disorder (ADHD) (9). The potential for neurotoxic effects associated with such long-term human exposures is just now being raised (10). Clearly, the term “neurotoxicity” has been very broadly applied to describe the effects of these drugs in both humans and experimental animals. Unfortunately, emphasis has been placed on documenting effects of these agents without distinguishing how and why these effects should be considered “neurotoxic.” Thus, there are many descriptions of drug-induced neurotoxicity but there are very few attempts to link these purported neurotoxic effects to pathological actions on the nervous system or to functional changes meaningful to the human condition. Here, we will briefly review the current status of our understanding of the neurotoxic effects of substituted amphetamines. Emphasis will be placed on defining the neurotoxic condition beyond effects attributable to the neuropharmacological actions of a specific compound. In so doing, we will challenge current dogma with regard to describing neuro-toxic effects of this class of drugs. A detailed and comprehensive review of methamphetamine and amphetamine neurotoxicity recently has appeared (2) and it should be considered the authoritative source on this topic, especially with reference to effects in rats and the modulating role of body temperature. We will cover some of the issues raised by Bowyer and Holson (2), and agree with all of their points, but we will discuss effects of amphetamines in the context of the toxic actions of many known and potential chemical neurotoxicants (11).

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References

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

    PubMed  Google Scholar 

  2. Bowyer, J. F. and Holson, R. R. (1995) Methamphetamine and amphetamine neurotoxicity, in Handbook of Neurotoxicology ( Chang, L. W. and Dyer, R. S., eds.), Marcel Dekker, New York, pp. 845–870.

    Google Scholar 

  3. Wilson, J. M., Kalasinsky, K. S., Levey, A. I., Bergeron, C., Reiber, G., Anthony, R. M., et al. (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat. Med. 2, 699–703.

    Article  PubMed  CAS  Google Scholar 

  4. Steele, T. D., McCann, U. D., and Ricaurte, G. A. (1994) 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans. Addiction 89, 539–551.

    Google Scholar 

  5. Schmidt, C. J. and Kehne, J. H. (1990) Neurotoxicity of MDMA: neurochemical effects. Ann. NY Acad. Sci. 600, 665–680.

    Article  PubMed  CAS  Google Scholar 

  6. Kish, S. J., Furukawa, Y., Ang, L., Vorce, S. P., and Kalasinsky, K. S. (2000) Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user. Neurology 55, 294–296.

    Article  PubMed  CAS  Google Scholar 

  7. Gouzoulis-Mayfrank, E., Daumann, J., Tuchtenhagen, F., Pelz, S., Becker, S., Kunert, H. J., et al. (2000) Impaired cognitive performance in drug free users of recreational ecstasy (MDMA). J. Neurol. Neurosurg. Psychiatry 68, 719–725.

    Article  PubMed  CAS  Google Scholar 

  8. McCann, U. D., Seiden, L. S., Rubin, L. J., and Ricaurte, G. A. (1997) Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence. JAMA 278, 666–672.

    Article  PubMed  CAS  Google Scholar 

  9. Angold, A., Erkanli, A., Egger, H. L., and Costello, E. J. (2000) Stimulant treatment for children: a community perspective. J. Am. Acad. Child Adolesc. Psychiatry 39, 975–984.

    Article  PubMed  CAS  Google Scholar 

  10. Rowland, A. S., Umbach, D. M., O’Callaghan, J. P., Miller, D. B., and Dunnick, J. K. (2001) Public health and toxicological issues concerning stimulant treatment of ADHD, in Diagnosis and Treatment ofAttention-Deficit/Hyperactivity Disorder: An Evidenee-Based Approach ( Jensen, P., ed.), AMA Press, Chicago, in a press.

    Google Scholar 

  11. O’Callaghan, J. P., Jensen, K. F., and Miller, D. B. (1995) Quantitative aspects of drug and toxicant-induced astrogliosis. Neurochem. Int. 26, 115–124.

    Article  PubMed  Google Scholar 

  12. 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  PubMed  CAS  Google Scholar 

  13. 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  PubMed  CAS  Google Scholar 

  14. 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.

    PubMed  CAS  Google Scholar 

  15. 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.

    PubMed  CAS  Google Scholar 

  16. 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  PubMed  CAS  Google Scholar 

  17. Fleckenstein, A. E., Haughey, H. M., Metzger, R. R., Kokoshka, J. M., Riddle, E. L., Hanson, J. E., et al. (1999) Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function. Eur. J. Pharmacol. 382, 45–49.

    Article  PubMed  CAS  Google Scholar 

  18. Kim, S., Westphalen, R., Callahan, B., Hatzidimitriou, G., Yuan, J., and Ricaurte, G. A. (2000) Toward development of an in vitro model of methamphetamine-induced dopamine nerve terminal toxicity. J. Pharmacol. Exp. Ther. 293, 625–633.

    PubMed  CAS  Google Scholar 

  19. 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 

  20. Kalia, M., O’Callaghan, J. P., Miller, D. B., and Kramer, M. (2000) Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry. Brain Res. 858, 92–105.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  23. Ricaurte, G. A., Form), 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 

  24. Johannessen, J. N., Chiueh, C. C., Burns, R. S., and Markey, S. P. (1985) Differences in the metabolism of MPTP in the rodent and primate parallel differences in sensitivity to its neurotoxic effects. Life Sci. 36, 219–224.

    Article  PubMed  CAS  Google Scholar 

  25. Chiueh, C. C., Markey, S. P., Burns, R. S., Johannessen, J. N., Jacobowitz, D. M., and Kopin, I. J. (1984) Neurochemical and behavioral effects of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) in rat, guinea pig, and monkey. Psychopharmacol. Bull. 20, 548–553.

    PubMed  CAS  Google Scholar 

  26. Giovanni, A., Sonsalla, P. K., and Heikkila, R. E. (1994) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2: Central administration of 1-methyl-4-phenylpyridinium. J. Pharmacol. Exp. Ther. 270, 1008–1014.

    PubMed  CAS  Google Scholar 

  27. Giovanni, A., Sieber, B. A., Heikkila, R. E., and Sonsalla, P. K. (1994) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1: Systemic administration. J. Pharmacol. Exp. Ther. 270, 1000–1007.

    PubMed  CAS  Google Scholar 

  28. Chance, M. R. A. (1946) Aggregation as a factor influencing the toxicity of sympathomimetic amines in mice. J. Pharmacol. Exp. Ther. 87, 214–219.

    PubMed  CAS  Google Scholar 

  29. Askew, B. M. (1962) Hyperpyrexia as a contributory factor in the toxicity of amphetamine to aggregated mice. Eur. J. Pharmacol. 19, 245–257.

    CAS  Google Scholar 

  30. 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 

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

    Article  PubMed  CAS  Google Scholar 

  32. Ali, S. F., Newport, R. R., Holson, W., Slikker, Jr., W., and Bowyer, J. F. (1995) Low environmental temperatures or pharmacologic agents that produce hyperthermia decrease methamphetamine neurotoxicity in mice. Ann. NYAcad. Sci. 765, 338.

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  34. Miller, D. B. and O’Callaghan, J. P. (1995) The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine. Mol. Neurobiol. 11, 177–192.

    Article  PubMed  CAS  Google Scholar 

  35. Miller, D. B. and O’Callaghan, J. P. (1996) Neurotoxicity of d-amphetamine in the C57BL/ 6J and CD-1 mouse. Interactions with stress and the adrenal system. Ann. NYAcad. Sci. 801, 148–167.

    Article  CAS  Google Scholar 

  36. Johnson, E. A., Sharp, D. S., and Miller, D. B. (2000) Restraint as a stressor in mice against the dopaminergic neurotoxicity of D-MDMA, low body weight mitigates restraint-induced hypothermia and consequent neuroprotection. Brain Res. 895, 107–118.

    Article  Google Scholar 

  37. Malberg, J. E. and Seiden, L. S. (1998) Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J. Neurosci. 18, 5086–5094.

    PubMed  CAS  Google Scholar 

  38. 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 in the rat. J. Pharmacol. Exp. Ther. 278, 258–267.

    PubMed  CAS  Google Scholar 

  39. 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  PubMed  CAS  Google Scholar 

  40. Miller, D. B. and O’Callaghan, J. P. (1993) The interactions of MK-801 with the amphetamine analogues D-methamphetamine (D-METH), 3,4-methylenedioxymethamphetamine (D-MDMA) or D-fenfluramine (D-FEN): neural damage and neural protection. Ann. NY Acad. Sci. 679, 321–324.

    Article  PubMed  CAS  Google Scholar 

  41. 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  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. O’Callaghan, J. P. and Miller, D. B. (1997) Brain serotonin neurotoxicity and fenfluramine and dexfenfluramine. JAMA 278, 2141–2142.

    PubMed  Google Scholar 

  44. O’Callaghan, J. P. and Miller, D. B. (1993) Quantification of reactive gliosis as an approach to neurotoxicity assessment. NIDA Res. Monogr. 136, 188–212.

    PubMed  Google Scholar 

  45. O’Callaghan, J. P. (1994) Biochemical analysis of glial fibrillary acidic protein as a quantitative approach to neurotoxicity assessment: advantages, disadvantages and application to the assessment of NMDA receptor antagonist-induced neurotoxicity. Psychopharmacol. Bull. 30, 549–554.

    PubMed  Google Scholar 

  46. O’Callaghan, J. P. (1993) Quantitative features of reactive gliosis following toxicant-induced damage of the CNS. Ann. NYAcad. Sci. 679, 195–210.

    Article  Google Scholar 

  47. Adams, J. H. and Duchen, L. W. (eds.) (1992) Greenfield’s Neuropathology, 5th ed. Oxford University Press, Oxford, UK.

    Google Scholar 

  48. Clark, C. M. and Trojanowski, J. Q. (eds.) (2000) Neurodegenerative Dementias. McGraw-Hill, New York.

    Google Scholar 

  49. Jellinger, K. (1987) The pathology of parkinsonism, in Movement Disorders ( Marsden, C. D. and Fahn, S., eds.), Butterworth Press, London, pp. 124–165.

    Google Scholar 

  50. Dunnett, S. B. and Bjorklund, A. (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature 399, A32–A39.

    Article  PubMed  CAS  Google Scholar 

  51. Simuni, T. and Hurtig, H. I. (2000) Parkinson’s disease: the clinical picture, in Neurodegenerative Dementias ( Clark, C. M. and Trojanowski, J. Q., eds.), McGraw-Hill, New York, pp. 219–228.

    Google Scholar 

  52. Miller, D. B., Reinhard, Jr., J. F., Daniels, A. J., and O’Callaghan, J. P. (1991) Diethyldithiocarbamate potentiates the neurotoxicity of in vivo 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine and of in vitro 1-methyl-4-phenylpyridinium. J. Neurochem. 57, 541–549.

    Google Scholar 

  53. Curzon, G. (1990) Serotonin and appetite. Ann. NYAcad. Sci. 600, 521–530.

    Article  CAS  Google Scholar 

  54. Gorzalka, B. B., Mendelson, S. D., and Watson, N. V. (1990) Serotonin receptor subtypes and sexual behavior. Ann. NYAcad. Sci. 600, 435–444.

    Google Scholar 

  55. Meltzer, H. Y. (1990) Role of serotonin in depression. Ann. NYAcad. Sci. 600, 486–499.

    Article  CAS  Google Scholar 

  56. Cooper, J. R., Bloom, F. E., and Roth, R. H. (eds.) (1996) The Biochemical Basis of Neuropharmacology, 7th ed. Oxford University Press, New York.

    Google Scholar 

  57. Spencer, P. S. and Schaumburg, H. H. (eds.) (1980) Experimental and Clinical Neurotoxicology, 1st ed. Williams and Wilkins, Baltimore.

    Google Scholar 

  58. Spencer, P. S. and Schaumburg, H. H. (eds.) (2000) Experimental and Clinical Neurotoxicology, 2nd ed. Oxford University Press, New York.

    Google Scholar 

  59. Klaassen, C. D. (ed.) (1996) Cassarett and Doull’s Toxicology, 5th ed. McGraw-Hill, New York.

    Google Scholar 

  60. Monaghan, D. T., Bridges, R. J., and Cotman, C. W. (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 29, 365–102.

    Article  PubMed  CAS  Google Scholar 

  61. Fix, A. S., Stitzel, S. R., Ridder, G. M., and Switzer, R. C. (2000) MK-801 neurotoxicity in cupric silver-stained sections: lesion reconstruction by 3-dimensional computer image analysis. Toxicol. Pathol. 28, 84–90.

    Article  PubMed  CAS  Google Scholar 

  62. Wozniak, D. F., Dikranian, K., Ishimaru, M. J., Nardi, A., Corso, T. D., Tenkova, T., et al. (1998) Disseminated corticolimbic neuronal degeneration induced in rat brain by MK-801: potential relevance to Alzheimer’s disease. Neurobiol. Dis. 5, 305–322.

    Article  PubMed  CAS  Google Scholar 

  63. Fix, A. S., Wightman, K. A., and O’Callaghan, J. P. (1995) Reactive gliosis induced by MK-801 in the rat posterior cingulate/retrosplenial cortex: GFAP evaluation by sandwich ELISA and immunocytochemistry. Neurotoxicology 16, 229–237.

    PubMed  CAS  Google Scholar 

  64. Switzer, R. C., Murphy, M. R., Campbell, S. K., Kerenyi, S. A., and Miller, S. A. (1988) Soman in multiple low doses: famage to selected populations of neurons in rat brain. Soc.Neurosci. Abstr. 14, 774–774.

    Google Scholar 

  65. Switzer, R. C., III. (2000) Application of silver degeneration stains for neurotoxicity testing. Toxicol. Pathol. 28, 70–83.

    Article  PubMed  CAS  Google Scholar 

  66. Tanaka, D., Jr. and Bursian, S. J. (1989) Degeneration patterns in the chicken central nervous system induced by ingestion of the organophosphorus delayed neurotoxin tri-orthotolyl phosphate. A silver impregnation study. Brain Res. 484, 240–256.

    Article  PubMed  CAS  Google Scholar 

  67. Schmued, L. C. and Hopkins, K. J. (2000) Fluoro-Jade: novel fluorochromes for detecting toxicant-induced neuronal degeneration. Toxicol. Pathol. 28, 91–99.

    Article  PubMed  CAS  Google Scholar 

  68. O’Callaghan, J. P. and Jensen, K. F. (1992) Enhanced expression of glial fibrillary acidic protein and the cupric silver degeneration reaction can be used as sensitive and early indicators of neurotoxicity. Neurotoxicology 13, 113–122.

    PubMed  Google Scholar 

  69. Switzer, R. C., (1993) Silver staining methods: their role in detecting neurotoxicity. Ann. NYAcad. Sci. 679, 341–348.

    Article  Google Scholar 

  70. Switzer, R. C., III (1991) Strategies for assessing neurotoxicity. Neurosci. Biobehay. Rev. 15, 89–93.

    Article  Google Scholar 

  71. O’Callaghan, J. P. and Miller, D. B. (1986) Diethyldithiocarbamate increases distribution of cadmium to brain but prevents cadmium-induced neurotoxicity. Brain Res. 370, 354–358.

    Article  PubMed  Google Scholar 

  72. Llorens, J., Crofton, K. M., and O’Callaghan, J. P. (1993) Administration of 3,3’iminodipropionitrile to the rat results in region-dependent damage to the central nervous system at levels above the brain stem. J. Pharmacol. Exp. Ther. 265, 1492–1498.

    PubMed  CAS  Google Scholar 

  73. Balaban, C. D., O’Callaghan, J. P., and Billingsley, M. L. (1988) Trimethyltin-induced neuronal damage in the rat brain: comparative studies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins. Neuroscience 26, 337–361.

    Article  PubMed  CAS  Google Scholar 

  74. Brock, T. O. and O’Callaghan, J. P. (1987) Quantitative changes in the synaptic vesicle proteins synapsin I and p38 and the astrocyte-specific protein glial fibrillary acidic protein are associated with chemical-induced injury to the rat central nervous system. J. Neurosci. 7, 931–942.

    PubMed  CAS  Google Scholar 

  75. O’Callaghan, J. P., Miller, D. B., and Reinhard, Jr. J. F. (1990) 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced damage of striatal dopaminergic fibers attenuates subsequent astrocyte response to MPTP. Neurosci. Lett. 117, 228–233.

    Google Scholar 

  76. Gramsbergen, J. B. and Van Den Berg, K. J. (1994) Regional and temporal profiles of calcium accumulation and glial fibrillary acidic protein levels in rat brain after systemic injection of kainic acid. Brain Res. 667, 216–228.

    Article  PubMed  CAS  Google Scholar 

  77. Appel, N. M., Rapoport, S. I., O’Callaghan, J. P., Bell, J. M., and Freed, L. M. (1997) Sequelae of parenteral domoic acid administration in rats: comparison of effects on different metabolic markers in brain. Brain Res. 754, 55–64.

    Article  PubMed  CAS  Google Scholar 

  78. Appel, N. M., Rapoport, S. I., and O’Callaghan, J. P. (1997) Sequelae of parenteral domoic acid administration in rats: comparison of effects on different anatomical markers in brain. Synapse 25, 350–358.

    Article  PubMed  CAS  Google Scholar 

  79. Miller, P. J. and Zaborszky, L. (1997) 3-Nitropropionic acid neurotoxicity: visualization by silver staining and implications for use as an animal model of Huntington’s disease. Exp. Neurol. 146, 212–229.

    Google Scholar 

  80. O’Callaghan, J. P. and Miller, D. B. (1985) Cerebellar hypoplasia in the Gunn rat is associated with quantitative changes in neurotypic and gliotypic proteins. J. Pharmacol. Exp. Ther. 234, 522–533.

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  82. Frankfurt, M., O’Callaghan, J., and Beaudet, A. (1991) 5,7-Dihydroxytryptamine injections increase glial fibrillary acidic protein in the hypothalamus of adult rats. Brain Res. 549, 138–140.

    Google Scholar 

  83. Dugar, A., Patanow, C., O’Callaghan, J. P., and Lakoski, J. M. (1998) Immunohistochemical localization and quantification of glial fibrillary acidic protein and synaptosomal-associated protein (mol. wt 25000) in the ageing hippocampus following administration of 5,7-dihydroxytryptamine. Neuroscience 85, 123–133.

    Article  PubMed  CAS  Google Scholar 

  84. Desclin, J. C. and Escubi, J. (1974) Effects of 3-acetylpyridine on the central nervous system of the rat, as demonstrated by silver methods. Brain Res. 77, 349–364.

    Article  PubMed  CAS  Google Scholar 

  85. O’Callaghan, J. P., Rogers, T. S., Rodman, L. E., and Page, J. G. (1996) Acute and chronic administration of ibogaine to the rat results in astrogliosis that is not confined to the cerebellar vermis. Ann. NYAcad. Sci. 801, 205–216.

    Article  Google Scholar 

  86. Goodlett, C. R., Leo, J. T., O’Callaghan, J. P., Mahoney, J. C., and West, J. R. (1993) Transient cortical astrogliosis induced by alcohol exposure during the neonatal brain growth spurt in rats. Brain Res. Dev. Brain Res. 72, 85–97.

    Article  PubMed  CAS  Google Scholar 

  87. Goldey, E. S., O’Callaghan, J. P., Stanton, M. E., Barone, Jr., S., and Crofton, K. M. (1994) Developmental neurotoxicity: evaluation of testing procedures with methylazoxymethanol and methylmercury. Fundam. Appl. Toxicol. 23, 447–464.

    Article  PubMed  CAS  Google Scholar 

  88. O’Callaghan, J. P. and Miller, D. B. (1988) Acute exposure of the neonatal rat to triethyltin results in persistent changes in neurotypic and gliotypic proteins. J. Pharmacol. Exp. Ther. 244, 368–378.

    PubMed  Google Scholar 

  89. Schmued, L. and Hopkins K J. (2000) Fluoro-Jade B: A high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res. 874, 123–130.

    Article  PubMed  CAS  Google Scholar 

  90. Schmued, L. and Slikker, Jr., W. (1999) Black-gold: a simple, high-resolution histochemical label for normal and pathological myelin in brain tissue sections. Brain Res. 837, 289–297.

    Article  PubMed  CAS  Google Scholar 

  91. Streit, W. J., Walter, S. A., and Pennell, N. A. (1999) Reactive microgliosis. Prog. Neurobiol. 57, 563–581.

    Article  PubMed  CAS  Google Scholar 

  92. Streit, W. J. (1996) The role of microglia in brain injury. Neurotoxicology 17, 671–678.

    PubMed  CAS  Google Scholar 

  93. Kreutzberg, G. W. (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318.

    Article  PubMed  CAS  Google Scholar 

  94. Eng, L. F. (1988) Regulation of glial intermediate filaments in astrogliosis, in Biochemical Pathology of Astrocytes ( Norenberg, M. D., Hertz, L., and Schousboe, A., eds.), Alan R. Liss, New York, pp. 79–90.

    Google Scholar 

  95. 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  PubMed  CAS  Google Scholar 

  96. Bignami, A. and Dahl, D. (1995) Gliosis, in Neuroglia (Kettenmann, H. and Ransom B. R., eds.), Oxford University Press, New York, pp. 843–858.

    Google Scholar 

  97. Little, A. R. and O’Callaghan, J. P. (2001) The astrocyte response to neural injury: a review and reconsideration of key features, in Site-Selective Neurotoxicity ( Lester, D., Slikker, Jr., W., Johannessen, J. N., and Lazarovici, P., eds.), Harwood Academic Publishers, Amsterdam, Netherlands.

    Google Scholar 

  98. Eng, L. F. (1985) Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes. J. Neuroimmunol. 8, 203–214.

    Article  PubMed  CAS  Google Scholar 

  99. Martin, P. M. and O’Callaghan, J. P. (1995) A direct comparison of GFAP immunocytochemistry and GFAP concentration in various regions of ethanol-fixed rat and mouse brain. J. Neurosci. Methods 58, 181–192.

    Article  PubMed  CAS  Google Scholar 

  100. Martin, P. M. and O’Callaghan, J. P. (1995) Biochemical immunohistology, in Central Nervous System Trauma-Research Techniques ( Ohnishi, S. T. and Ohnishi, T., eds.), CRC Press, Boca Raton, FL, 509–516.

    Google Scholar 

  101. O’Callaghan, J. P. (1991) Quantification of glial fibrillary acidic protein: comparison of slot-immunobinding assays with a novel sandwich ELISA. Neurotoxicol. Teratol. 13, 275–281.

    Article  PubMed  Google Scholar 

  102. McCann, M. J., O’Callaghan, J. P., Martin, P. M., Bertram, T., and Streit, W. J. (1996) Differential activation of microglia and astrocytes following trimethyl tin-induced neurodegeneration. Neuroscience 72, 273–281.

    Article  PubMed  CAS  Google Scholar 

  103. Moskowitz, M. A., Rubin, D., Nowak, Jr., T. S., Baliga, B. S., and Munro, H. N. (1978) Site of action of neurotoxins on protein synthesis. Ann. NYAcad. Sci. 305, 96–106.

    Article  CAS  Google Scholar 

  104. Stone, D. M., Johnson, M., Hanson, G. R., and Gibb, J. W. (1989) Acute inactivation of tryptophan hydroxylase by amphetamine analogs involves the oxidation of sulfhydryl sites. Eur. J. Pharmacol. 172, 93–97.

    Article  PubMed  CAS  Google Scholar 

  105. Kuhn, D. M. and Arthur, Jr., R. (1998) Dopamine inactivates tryptophan hydroxylase and forms a redox-cycling quinoprotein: possible endogenous toxin to serotonin neurons. J. Neurosci. 18, 7111–7117.

    PubMed  CAS  Google Scholar 

  106. Lavoie, M. J. and Hastings, T. G. (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J. Neurosci. 19, 1484–1491.

    PubMed  CAS  Google Scholar 

  107. Pennypacker, K. R., Hong, J. S., and McMillian, M. K. (1995) Implications of prolonged expression of Fos-related antigens. Trends Pharmacol. Sci. 16, 317–321.

    Article  PubMed  CAS  Google Scholar 

  108. Pennypacker, K. R. (1995) AP-1 transcription factor complexes in CNS disorders and development. J. Fla. Med. Assoc. 82, 551–554.

    PubMed  CAS  Google Scholar 

  109. Bowyer, J. F., Tank, A. W., Newport, G. D., Slikker, W., Jr., Ali, S. F., and Holson, R. R. (1992) The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum. J. Pharmacol. Exp. Ther. 260, 817–824.

    PubMed  CAS  Google Scholar 

  110. Kekuda, R., Torres-Zamorano, V., Leibach, F. H., and Ganapathy, V. (1997) Human serotonin transporter: regulation by the neuroprotective agent aurintricarboxylic acid and by epidermal growth factor. J. Neurochem. 68, 1443–1450.

    Article  PubMed  CAS  Google Scholar 

  111. Lesch, K. P., Aulakh, C. S., Wolozin, B. L., Tolliver, T. J., Hill, J. L., and Murphy, D. L. (1993) Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants. Brain Res. Mol. Brain Res. 17, 31–35.

    Article  PubMed  CAS  Google Scholar 

  112. Wilson, J. M. and Kish, S. J. (1996) The vesicular monoamine transporter, in contrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat. J. Neurosci. 16, 3507–3510.

    PubMed  CAS  Google Scholar 

  113. Zhou, D., Huether, G., Wiltfang, J., Hajak, G., and Ruther, E. (1996) Serotonin transporters in the rat frontal cortex: lack of circadian rhythmicity but down-regulation by food restriction. J. Neurochem. 67, 656–661.

    Article  PubMed  CAS  Google Scholar 

  114. Ryan, L. J., Martone, M. E., Linder, J. C., and Groves, P. M. (1988) Continuous amphetamine administration induces tyrosine hydroxylase immunoreactive patches in the adult rat neostriatum. Brain Res. Bull. 21, 133–137.

    Article  PubMed  CAS  Google Scholar 

  115. Molliver, M. E., Berger, U. V., Mamounas, L. A., Molliver, D. C., O’Hearn, E., and Wilson, M. A. (1990) Neurotoxicity of MDMA and related compounds: anatomic studies. Ann. NYAcad. Sci. 600, 649–661.

    Article  CAS  Google Scholar 

  116. O’Hearn, E., Battaglia, G., De Souza, 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 

  117. 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. Neurosci. 15, 5476–5485.

    PubMed  CAS  Google Scholar 

  118. 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.

    PubMed  CAS  Google Scholar 

  119. Cubells, J. F., Rayport, S., Rajendran, G., and Sulzer, D. (1994) Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress. J. Neurosci. 14, 2260–2271.

    PubMed  CAS  Google Scholar 

  120. Kuhn, D. M., Aretha, C. W., and Geddes, T. J. (1999) Peroxynitrite inactivation of tyrosine hydroxylase: mediation by sulfhydryl oxidation, not tyrosine nitration. J. Neurosci. 19, 10,289–10, 294.

    Google Scholar 

  121. Kuhn, D. M. and Geddes, T. J. (1999) Peroxynitrite inactivates tryptophan hydroxylase via sulfhydryl oxidation. Coincident nitration of enzyme tyrosyl residues has minimal impact on catalytic activity. J. Biol. Chem. 274, 29726–29732.

    Article  PubMed  CAS  Google Scholar 

  122. Tsao, L. I., Ladenheim, B., Andrews, A. M., Chiueh, C. C., Cadet, J. L., and Su, T. P. (1998) Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species. J. Pharmacol. Exp. Ther. 287, 322–331.

    PubMed  CAS  Google Scholar 

  123. Kita, T., Takahashi M., Kubo K., Wagner G. C., and Nakashima T. (1999) Hydroxyl radical formation following methamphetamine administration to rats. Pharmacol. Toxicol. 85, 133–137.

    Article  PubMed  CAS  Google Scholar 

  124. Ali, S. F., Martin, J. L., Black, M. D., and Itzhak, Y. (1999) Neuroprotective role of melatonin in methampheta. Ann. NYAcad. Sci. 890, 119.

    Article  CAS  Google Scholar 

  125. Stone, D. M., Hanson, G. R., and Gibb, J. W. (1989) In vitro reactivation of rat cortical tryptophan hydroxylase following in vivo inactivation by methylenedioxymethamphetamine. J. Neurochem. 53, 572–581.

    Article  PubMed  CAS  Google Scholar 

  126. 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  PubMed  CAS  Google Scholar 

  127. Jensen, K. F., Olin, J., Haykal-Coates, N., O’Callaghan, J., Miller, D. B., and De Olmos, J. S. (1993) Mapping toxicant-induced nervous system damage with a cupric silver stain: a quantitative analysis of neural degeneration induced by 3,4-methylenedioxymethamphetamine. NIDA Res. Monogr. 136, 133–149.

    PubMed  CAS  Google Scholar 

  128. Eisch, A. J., Schmued, L. C., and Marshall, J. F. (1998) Characterizing cortical neuron injury with Fluoro-Jade labeling after a neurotoxic regimen of methamphetamine. Synapse 30, 329–333.

    Article  PubMed  CAS  Google Scholar 

  129. Schmued, L., Slikker, W., Clausing, P., and Bowyer, J. (1999) d-Fenfluramine produces neuronal degeneration in localized regions of the cortex, thalamus, and cerebellum of the rat. Toxicol. Sci. 48, 100–106.

    Google Scholar 

  130. Gordon, M. N., Schreier, W. A., Ou, X., Holcomb, L. A., and Morgan, D. G. (1997) Exaggerated astrocyte reactivity after nigrostriatal deafferentation in the aged rat. J. Comp Neurol. 388, 106–119.

    Article  PubMed  CAS  Google Scholar 

  131. Cappon, G. D., Pu, C., and Vorhees, C. V. (2000) Time-course of methamphetamineinduced neurotoxicity in rat caudate-putamen after single-dose treatment. Brain Res. 863, 106–111.

    Article  PubMed  CAS  Google Scholar 

  132. Fukumura, M., Cappon, G. D., Pu, C., Broening, H. W., and Vorhees, C. V. (1998) A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein. Brain Res. 806, 1–7.

    Article  PubMed  CAS  Google Scholar 

  133. Pu, C. and Vorhees, C. V. (1993) Developmental dissociation of methamphetamine-induced depletion of dopaminergic terminals and astrocyte reaction in rat striatum. Brain Res. Dey. Brain Res. 72, 325–328.

    Article  CAS  Google Scholar 

  134. O’Callaghan, J. P., Brinton, R. E., and McEwen, B. S. (1991) Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury. J. Neurochem. 57, 860–869.

    Article  PubMed  Google Scholar 

  135. Akiyama, H. and McGeer, P. L. (1989) Microglial response to 6-hydroxydopamine-induced substantia nigra lesions. Brain Res. 489, 247–253.

    Article  PubMed  CAS  Google Scholar 

  136. Wilson, M. A. and Molliver, M. E. (1994) Microglial response to degeneration of serotonergic axon terminals. Glia 11, 18–34.

    Article  PubMed  CAS  Google Scholar 

  137. Bowyer, J. F., Peterson, S. L., Rountree, R. L., Tor-Agbidye, J., and Wang, G. J. (1998) Neuronal degeneration in rat forebrain resulting from D-amphetamine-induced convulsions is dependent on seizure severity and age. Brain Res. 809, 77–90.

    Article  PubMed  CAS  Google Scholar 

  138. Stewart, C. W. and Slikker, Jr., W. (1999) Hyperthermia-enhanced serotonin (5-HT) depletion resulting from D-fenfluramine (D-Fen) exposure does not evoke a glial-cell response in the central nervous system of rats. Brain Res. 839, 279–282.

    Article  PubMed  CAS  Google Scholar 

  139. Hess, A., Desiderio, C., and McAuliffe, W. G. (1990) Acute neuropathological changes in the caudate nucleus caused by MPTP and methamphetamine: immunohistochemical studies. J. Neurocytol. 19, 338–342.

    Article  PubMed  CAS  Google Scholar 

  140. Deng, X., Ladenheim, B., Tsao, L. I., and Cadet, J. L. (1999) Null mutation of c-fos causes exacerbation of methamphetamine-induced neurotoxicity. J. Neurosci. 19, 10107–10115.

    PubMed  CAS  Google Scholar 

  141. Fumagalli, F., Gainetdinov, R. R., Valenzano, K. J., and Caron, M. G. (1998) Role of dopamine transporter in methamphetamine-induced neurotoxicity: evidence from mice lacking the transporter. J. Neurosci. 18, 4861–4869.

    PubMed  CAS  Google Scholar 

  142. Kita, T., Paku S., Takahashi M., Kubo K., Wagner G. C., and Nakashima T. (1998) Methamphetamine-induced neurotoxicity in BALB/c, DBA/2N and C57BL/6N mice. Neuropharmacology 37, 1177–1184.

    Article  PubMed  CAS  Google Scholar 

  143. O’Dell, S. J., Weihmuller, F. B., and Marshall, J. F. (1991) Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity. Brain Res. 564, 256–260.

    Article  PubMed  Google Scholar 

  144. Miller, G. W., Gainetdinov, R. R., Levey, A. I., and Caron, M. G. (1999) Dopamine transporters and neuronal injury. Trends Pharmacol. Sci. 20, 424–429.

    Article  PubMed  CAS  Google Scholar 

  145. Cadet, J. L., Ali, S. F., Rothman, R. B., and Epstein, C. J. (1995) Neurotoxicity, drugs and abuse, and the CuZn-superoxide dismutase transgenic mice. Mol. Neurobiol. 11, 155–163.

    Article  PubMed  CAS  Google Scholar 

  146. Deng, X. and Cadet, J. L. (1999) Methamphetamine administration causes overexpression of nNOS in the mouse striatum. Brain Res. 851, 254–257.

    Article  PubMed  CAS  Google Scholar 

  147. Imam, S. Z. and Ali, S. F. (2000) Selenium, an antioxidant, attenuates methamphetamineinduced dopaminergic toxicity and peroxynitrite generation. Brain Res. 855, 186–191.

    Article  PubMed  CAS  Google Scholar 

  148. Imam, S. Z., Crow, J. P., Newport, G. D., Islam, F., Slikker, Jr., W., and Ali, S. F. (1999) Methamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: protective effects of peroxynitrite decomposition catalyst. Brain Res. 837, 15–21.

    Article  PubMed  CAS  Google Scholar 

  149. Imam, S. Z., Newport, G. D., Islam, F., Slikker, Jr., W., and Ali, S. F. (1999) Selenium, an antioxidant, protects against methamphetamine-induced dopaminergic neurotoxicity. Brain Res. 818, 575–578.

    Article  PubMed  CAS  Google Scholar 

  150. Itzhak, Y., Gandia, C., Huang, P. L., and Ali, S. F. (1998) Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity. J. Pharmacol. Exp. Ther. 284, 1040–1047.

    PubMed  CAS  Google Scholar 

  151. Jayanthi, S., Ladenheim, B., Andrews, A. M., and Cadet, J. L. (1999) Overexpression of human copper/zinc superoxide dismutase in transgenic mice attenuates oxidative stress caused by methylenedioxymethamphetamine (Ecstasy). Neuroscience 91, 1379–1387.

    Article  PubMed  CAS  Google Scholar 

  152. Jayanthi, S., Ladenheim, B., and Cadet, J. L. (1998) Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice. Ann. NYAcad. Sci. 844, 92–102.

    Article  CAS  Google Scholar 

  153. Kim, H., Jhoo, W., Shin, E., and Bing, G. (2000) Selenium deficiency potentiates methamphetamine-induced nigral neuronal loss; comparison with MPTP model. Brain Res. 862, 247–252.

    Article  PubMed  CAS  Google Scholar 

  154. De Olmos, J. S., Beltramino, C. A., and De Olmos, D. L. (1994) Use of an amino-cupricsilver technique for the detection of early and semiacute neuronal degeneration caused by neurotoxicants, hypoxia, and physical trauma. Neurotoxicol. Teratol. 16, 545–561.

    Article  PubMed  Google Scholar 

  155. Schmued, L. C. and Bowyer, J. F. (1997) Methamphetamine exposure can produce neuronal degeneration in mouse hippocampal remnants. Brain Res. 759, 135–140.

    Article  PubMed  CAS  Google Scholar 

  156. Hebert, M. A. and O’Callaghan, J. P. (2000) Protein phosphorylation cascades associated with methamphetamine-induced glial activation. Ann. NYAcad. Sci. 914, 238–262.

    Article  CAS  Google Scholar 

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Authors
  1. James P. O’Callaghan
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  2. Diane B. Miller
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  1. The National Health and Environmental Effects Research Laboratory, Research Triangle Park, Durham, NC, USA

    Edward J. Massaro

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O’Callaghan, J.P., Miller, D.B. (2002). Neurotoxic Effects of Substituted Amphetamines in Rats and Mice. In: Massaro, E.J. (eds) Handbook of Neurotoxicology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-165-7_11

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  • DOI: https://doi.org/10.1007/978-1-59259-165-7_11

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