Abstract
Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amphetamines / administration & dosage
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Amphetamines / pharmacology*
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Animals
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Antiparkinson Agents / administration & dosage
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Antiparkinson Agents / pharmacology*
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Basal Ganglia / pathology
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Blepharoptosis / chemically induced
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Blepharoptosis / drug therapy
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Disease Models, Animal*
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Dopamine / deficiency*
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Dopamine / therapeutic use
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Dopamine Agents / administration & dosage
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Dopamine Agents / therapeutic use
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Dopamine Antagonists / pharmacology
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Dopamine Plasma Membrane Transport Proteins / genetics
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Female
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Levodopa / administration & dosage
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Levodopa / therapeutic use
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Male
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Mice
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Motor Activity / drug effects*
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Nomifensine / administration & dosage
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Nomifensine / therapeutic use
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Norepinephrine / metabolism
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Parkinson Disease, Secondary / chemically induced*
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Parkinson Disease, Secondary / drug therapy
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Parkinson Disease, Secondary / metabolism
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Phenotype
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Piperazines / administration & dosage
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Piperazines / therapeutic use
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Tyrosine 3-Monooxygenase / antagonists & inhibitors
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alpha-Methyltyrosine / pharmacology
Substances
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Amphetamines
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Antiparkinson Agents
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Dopamine Agents
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Dopamine Antagonists
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Dopamine Plasma Membrane Transport Proteins
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Piperazines
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Nomifensine
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Levodopa
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alpha-Methyltyrosine
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vanoxerine
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Tyrosine 3-Monooxygenase
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Dopamine
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Norepinephrine