Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity by the novel selective dopamine D3-receptor partial agonist FAUC 329 predominantly in the nucleus accumbens of mice.
We previously synthesised a novel dopamine (DA) partial agonist FAUC 329 with high affinity and selectivity for the DA D(3) receptor. This is the first in vivo study to investigate the protective effects of FAUC 329 in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Adult male C57bl/6 mice were injected with FAUC 329 (0, 0.1, 0.5, 0.75, or 1 mg/kg) 30 min before MPTP (2 x 30 mg/kg, 4 hr apart). One week later, accumbal and striatal tissue was processed for DA and metabolite HPLC determination as well as immunohistochemical analysis of DA transporter positive neurons in the substantia nigra pars compacta and ventral tegmental area was carried out. FAUC 329 showed a significant attenuation of MPTP-induced DA reduction in the nucleus accumbens (0.5, 0.75 and 1 mg/kg) in a dose-dependent manner. FAUC 329 (0.75 mg/kg) partly protected against DA depletion in the dorsal striatum as well as protected against loss of DA transporter immunoreactivity in the substantia nigra pars compacta. The highest dose of FAUC 329 (1 mg/kg), however, showed a non-significant tendency to augment the MPTP-induced striatal DA reduction. The protective effect of FAUC 329 against MPTP-induced DA depletion was most pronounced in the nucleus accumbens and appears to be linked to the preferential abundance of D(3) receptors in this region. Targeting the mesolimbic DA system may have implications for improvement of impaired motor behaviour and particularly non-motor functions related to the nucleus accumbens.
Boeckler
Frank
F
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University of Erlangen-Nuremberg, D-91052 Erlangen, Germany.
Leng
Andreas
A
Mura
Anna
A
Bettinetti
Laura
L
Feldon
Joram
J
Gmeiner
Peter
P
Ferger
Boris
B
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D050483:Dopamine Plasma Membrane Transport Proteins; D020267:MPTP Poisoning / Q000517:prevention & control; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D020258:Neurotoxicity Syndromes; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3
C477900:2-(4-(4-chlorophenyl)piperazin-1-ylmethyl)pyrazolo(1,5-a)-pyridine; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; C493594:Drd3 protein, mouse; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine