Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity

Jie Yuan, Brian T. Callahan, Una D McCann, George Ricaurte

Research output: Contribution to journalArticle

Abstract

The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)-induced dopaminergic neurotoxicity while controlling for temperature-related neuroprotective effects of the test compounds, reserpine and α-methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28°C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33°C (to eliminate AMPT's hypothermic effect in METH-treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (<0.05%). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.

Original languageEnglish (US)
Pages (from-to)1338-1347
Number of pages10
JournalJournal of Neurochemistry
Volume77
Issue number5
DOIs
StatePublished - 2001

Fingerprint

Methamphetamine
Dopamine
Brain
Reserpine
Corpus Striatum
Tyrosine
Temperature
Poisons
Neuroprotective Agents
Animals

Keywords

  • α-methyl-p-tyrosine
  • Dopamine
  • Methamphetamine
  • Neurotoxicity
  • Reserpine
  • Temperature

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity. / Yuan, Jie; Callahan, Brian T.; McCann, Una D; Ricaurte, George.

In: Journal of Neurochemistry, Vol. 77, No. 5, 2001, p. 1338-1347.

Research output: Contribution to journalArticle

@article{e24d96ab9d324758a966d597c0ec0566,
title = "Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity",
abstract = "The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)-induced dopaminergic neurotoxicity while controlling for temperature-related neuroprotective effects of the test compounds, reserpine and α-methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28°C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33°C (to eliminate AMPT's hypothermic effect in METH-treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (<0.05{\%}). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.",
keywords = "α-methyl-p-tyrosine, Dopamine, Methamphetamine, Neurotoxicity, Reserpine, Temperature",
author = "Jie Yuan and Callahan, {Brian T.} and McCann, {Una D} and George Ricaurte",
year = "2001",
doi = "10.1046/j.1471-4159.2001.00339.x",
language = "English (US)",
volume = "77",
pages = "1338--1347",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity

AU - Yuan, Jie

AU - Callahan, Brian T.

AU - McCann, Una D

AU - Ricaurte, George

PY - 2001

Y1 - 2001

N2 - The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)-induced dopaminergic neurotoxicity while controlling for temperature-related neuroprotective effects of the test compounds, reserpine and α-methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28°C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33°C (to eliminate AMPT's hypothermic effect in METH-treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (<0.05%). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.

AB - The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)-induced dopaminergic neurotoxicity while controlling for temperature-related neuroprotective effects of the test compounds, reserpine and α-methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28°C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33°C (to eliminate AMPT's hypothermic effect in METH-treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (<0.05%). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.

KW - α-methyl-p-tyrosine

KW - Dopamine

KW - Methamphetamine

KW - Neurotoxicity

KW - Reserpine

KW - Temperature

UR - http://www.scopus.com/inward/record.url?scp=0035006623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035006623&partnerID=8YFLogxK

U2 - 10.1046/j.1471-4159.2001.00339.x

DO - 10.1046/j.1471-4159.2001.00339.x

M3 - Article

VL - 77

SP - 1338

EP - 1347

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 5

ER -