title: Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms.
abstract: 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.
authors.affiliation: CNS Discovery, Pfizer Global Research and Development, MS 8220-4130, Eastern Point Road-Bldg 100, Groton, CT 06340, USA.
authors.forename: Andres D
authors.initials: AD
authors.lastname: Ramirez
authors.forename: Stephen K-F
authors.initials: SK
authors.lastname: Wong
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
mesh_terms: 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*
chemical_list: 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