Abstract
The psychostimulant methamphetamine (MA) is toxic to nigro-striatal dopaminergic terminals in both experimental animals and humans. In mice, three consecutive injections of MA (5 mg/kg, i.p. with 2 h of interval) induced a massive degeneration of the nigro-striatal pathway, as reflected by a 50% reduction in the striatal levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC), by a substantial reduction in striatal tyrosine hydroxylase and high-affinity DA transporter immunostaining, and by the development of reactive gliosis. MA-induced nigro-striatal degeneration was largely attenuated in mice lacking alpha1b-adrenergic receptors (ARs). MA-stimulated striatal DA release (measured by microdialysis in freely moving animals) and locomotor activity were also reduced in alpha1b-AR knockout mice. Pharmacological blockade of alpha-adrenergic receptors with prazosin also protected wild-type mice against MA toxicity. These results suggests that alpha1b-ARs may play a role in the toxicity of MA on nigro-striatal DA neurons.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
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3,4-Dihydroxyphenylacetic Acid / analysis
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3,4-Dihydroxyphenylacetic Acid / metabolism
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Adrenergic alpha-1 Receptor Antagonists
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Adrenergic alpha-Antagonists / pharmacology
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Animals
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Behavior, Animal / drug effects
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Body Temperature / drug effects
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Central Nervous System Stimulants / toxicity*
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Corpus Striatum / drug effects*
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Cytoprotection / drug effects
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Cytoprotection / genetics
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Dopamine / analysis
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Dopamine / metabolism
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Dopamine Plasma Membrane Transport Proteins
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Gliosis / chemically induced
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Gliosis / pathology
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Homovanillic Acid / analysis
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Homovanillic Acid / metabolism
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MPTP Poisoning / chemically induced
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MPTP Poisoning / drug therapy
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Male
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Membrane Glycoproteins*
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Membrane Transport Proteins / metabolism
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Methamphetamine / toxicity*
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Mice
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Mice, Knockout
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Microdialysis
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Motor Activity / drug effects
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Nerve Tissue Proteins*
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Prazosin / pharmacology
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Receptors, Adrenergic, alpha-1 / deficiency*
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Receptors, Adrenergic, alpha-1 / genetics
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Tyrosine 3-Monooxygenase / metabolism
Substances
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ADRA1B protein, human
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Adra1b protein, mouse
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Adrenergic alpha-1 Receptor Antagonists
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Adrenergic alpha-Antagonists
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Central Nervous System Stimulants
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Dopamine Plasma Membrane Transport Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Receptors, Adrenergic, alpha-1
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3,4-Dihydroxyphenylacetic Acid
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Methamphetamine
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Tyrosine 3-Monooxygenase
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Dopamine
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Homovanillic Acid
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Prazosin