Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms

Eur J Pharmacol. 2003 Aug 15;475(1-3):29-35. doi: 10.1016/s0014-2999(03)02087-9.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzothiazoles
  • Dopamine / metabolism*
  • Dopamine D2 Receptor Antagonists
  • Dose-Response Relationship, Drug
  • MPTP Poisoning / metabolism*
  • MPTP Poisoning / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Piperazines / pharmacology
  • Pramipexole
  • Pyrimidines / pharmacology
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use*

Substances

  • 2-(3-(4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl)propylsulfanyl)-3H-pyrimidin-4-one fumarate
  • Benzothiazoles
  • Dopamine D2 Receptor Antagonists
  • Drd3 protein, mouse
  • Piperazines
  • Pyrimidines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Thiazoles
  • Pramipexole
  • Dopamine