Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms.
The role of dopamine D3 receptors was investigated in mediating the neuroprotective effect of the dopamine D2/D3 receptor agonist (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (pramipexole) in vivo. Pramipexole retained the ability to inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in mice in which the dopamine D3 receptor had been deleted. However, the neuroprotective efficacy was reduced in the dopamine D3 receptor-deleted mice compared to that in littermates expressing the wildtype receptor. Furthermore, the dopamine D3 receptor selective antagonist 2-(3-[4-(2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio)-4-pyrimidinol (A-437203) partially inhibited the neuroprotective effect of pramipexole in dopamine D3 receptor expressing mice but not in receptor-deleted mice. These results indicate that pramipexole protects dopamine neurons from MPTP-induced toxicity by mechanisms that are both dependent and independent of an interaction with dopamine D3 receptors.
Ramirez
Andres D
AD
CNS Discovery, Pfizer Global Research and Development, MS 8220-4130, Eastern Point Road-Bldg 100, Groton, CT 06340, USA.
Wong
Stephen K-F
SK
Menniti
Frank S
FS
D000818:Animals; D052160:Benzothiazoles; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D020267:MPTP Poisoning / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D000077487:Pramipexole; D011743:Pyrimidines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
C475263:2-(3-(4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl)propylsulfanyl)-3H-pyrimidin-4-one fumarate; D052160:Benzothiazoles; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; D010879:Piperazines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D000077487:Pramipexole; D004298:Dopamine