1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pretreatment attenuates methamphetamine-induced dopamine toxicity.
The effects of pretreatment with MPTP (1-methyl4-phenyl-1,2,3,6-tetrahydropyridine) on the acute and long-term effects of methamphetamine on striatal dopamine were evaluated in BALB/c mice. Four subcutaneous injections of a non-toxic dose of MPTP (8 mg/kg, at 2 hr intervals) were followed three days later by a toxic regimen of methamphetamine (four injections of 4 mg/kg, at 2 hr intervals) and mice were sacrificed immediately or three days later. Control mice received saline in place of the MPTP or methamphetamine and mice were observed for acute changes in body temperature, self-injurious behaviour, and striatal dopamine metabolites, or long-term changes in striatal dopamine levels, tyrosine hydroxylase immunoreactivity and glial fibrillary acidic protein. It was observed that pretreatment with MPTP protected mice against the acute increase in body temperature caused by the methamphetamine but, at the same time, delayed the occurrence of self-injurious behaviour following the repeated injections of methamphetamine. Likewise, pretreatment with MPTP attenuated the long-term depletion of striatal dopamine induced by the methamphetamine as well as the large increase in glial fibrillary acidic protein and the reduction in tyrosine hydroxylase immunoreactivity. The MPTP-treatment itself did not alter any of these neurotoxic markers. Finally, the acute decrease in 3,4-dihydroxyphenyacetic acid levels and increased ratio of 3-methoxytyramine/dopamine observed 60 min. after a single injection of methamphetamine (4 mg/kg) were also attenuated in MPTP-treated mice. These results are discussed in the context of the hypothesis that the low-dose treatment with MPTP may modify exchange diffusion across the striatal cell membrane thereby altering the acute and long-lasting effects of methamphetamine.
Kita
Taizo
T
Department of Pharmacology, Nara Medical University, Kashihara, Nara 634-8521, Japan. tkita@k4.dion.ne.jp
Saraya
Tutomu
T
Konishi
Noboru
N
Matsunari
Yasunori
Y
Shimada
Keiji
K
Nakamura
Mitsutoshi
M
O'Hara
Kiichi
K
Wagner
George C
GC
Nakashima
Toshikatsu
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008694:Methamphetamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine