Striatal extracellular dopamine levels and behavioural reversal in MPTP-lesioned mice.
Intoxication induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in mice results in a significant loss of nigrostriatal dopamine (DA) neurons. This is accompanied by a change in behavioural phenotype that can be reversed by L-DOPA (3,4-dihydroxy-L-phenylalanine) treatment. Here, we examined the extracellular levels of DA, behavioural deficits and the response to L-DOPA treatment in severely intoxicated mice. The MPTP intoxication produced more than a 90% reduction in tissue DA and a 65% decline in extracellular DA levels. In-vivo binding did not show any increased raclopride binding to the D2 receptor. Administration of L-DOPA, 5 or 20 mg/kg (subcutaneously), significantly increased dialysate DA levels and both doses of L-DOPA reversed the behavioural deficit. Interestingly, only 5 mg/kg L-DOPA normalized DA levels to 56% of controls showing that only a minor increase in DA levels is sufficient to yield motor recovery.
Kirchhoff
Jeppe
J
Departments of aNeurophysiology bIn vivo Neurobiology, H. Lundbeck A/S, Ottiliavej, Valby, Denmark. Jeki@lundbeck.com
Mørk
Arne
A
Brennum
Lise T
LT
Sager
Thomas N
TN
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage; D005110:Extracellular Space / Q000378:metabolism*; D007980:Levodopa / Q000008:administration & dosage; D020267:MPTP Poisoning / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity; D020891:Raclopride / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D015259:Dopamine Agents; D009498:Neurotoxins; D017448:Receptors, Dopamine D2; D014316:Tritium; D020891:Raclopride; D007980:Levodopa; D004298:Dopamine