Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.
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.
Sotnikova
Tatyana D
TD
Department of Cell Biology, Center for Models of Human Disease, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, USA.
Beaulieu
Jean-Martin
JM
Barak
Larry S
LS
Wetsel
William C
WC
Caron
Marc G
MG
Gainetdinov
Raul R
RR
D000662:Amphetamines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001479:Basal Ganglia / Q000473:pathology; D001763:Blepharoptosis / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency* / Q000627:therapeutic use; D015259:Dopamine Agents / Q000008:administration & dosage / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009627:Nomifensine / Q000008:administration & dosage / Q000627:therapeutic use; D009638:Norepinephrine / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000662:Amphetamines; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D009627:Nomifensine; D007980:Levodopa; D019805:alpha-Methyltyrosine; C043425:vanoxerine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine