Reduced MPTP toxicity in noradrenaline transporter knockout mice.
The noradrenergic neurons of the locus coeruleus (LC) are damaged in Parkinson's disease (PD). Neurotoxin ablation of the LC noradrenergic neurons has been shown to exacerbate the dopaminergic toxicity of MPTP, suggesting that the noradrenergic system protects dopamine neurons. We utilized mice that exhibit elevated synaptic noradrenaline (NA) by genetically deleting the noradrenaline transporter (NET), a key regulator of the noradrenergic system (NET KO mice). NET KO and wild-type littermates were administered MPTP and striatal dopamine terminal integrity was assessed by HPLC of monoamines, immmunoblotting for dopaminergic markers and tyrosine hydroxylase (TH) immunohistochemistry. MPTP significantly reduced striatal dopamine in wild-type mice, but not in the NET KO mice. To confirm that the protection observed in the NET KO mice was due to the lack of NET, we treated wild-type mice with the specific NET inhibitor, nisoxetine, and then challenged them with MPTP. Nisoxetine conferred protection to the dopaminergic system. These data indicate that NA can modulate MPTP toxicity and suggest that manipulation of the noradrenergic system may have therapeutic value in PD.
Rommelfanger
Karen S
KS
Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA.
Weinshenker
David
D
Miller
Gary W
GW
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020267:MPTP Poisoning / Q000235:genetics / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; D027981:Symporters; D050492:Vesicular Biogenic Amine Transport Proteins; D005473:Fluoxetine; D015102:3,4-Dihydroxyphenylacetic Acid; C011386:nisoxetine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid