2'-NH(2)-MPTP [1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine] depletes serotonin and norepinephrine in rats: a comparison with 2'-CH(3)-MPTP [1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine].
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog, 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH(2)-MPTP), depletes brain serotonin and norepinephrine in mice without affecting striatal dopamine. The present study was conducted to determine whether 2'-NH(2)-MPTP would be similarly neurotoxic to rats. Four injections of 20 mg/kg 2'-NH(2)-MPTP caused 80 to 90% depletions in serotonin and norepinephrine in frontal cortex and hippocampus in rats 1 week post-treatment. A lower dose of 2'-NH(2)-MPTP (4 x 15 mg/kg) also produced large decrements in serotonin and norepinephrine levels and in serotonin transporter density measured 3 weeks after neurotoxin administration. Furthermore, this lower dose of 2'-NH(2)-MPTP altered functional serotonin neurotransmission as evidenced by a 2-fold potentiation of 1-(3-chlorophenyl)-piperazine.2HCl-induced hyperthermia, an index of serotonergic denervation supersensitivity. At both doses, 2'-NH(2)-MPTP was without effect on striatal dopamine. For comparison, additional rats were treated with a second 2'-substituted analog of MPTP, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH(3)-MPTP), at 2 x 20 mg/kg. This dosing regimen causes substantial striatal dopamine depletion in mice. 2'-CH(3)-MPTP had no effect on brain levels of serotonin, norepinephrine, or dopamine in rats. Together, these results demonstrate that rats are sensitive to the toxic effects of 2'-NH(2)-MPTP but not to 2'-CH(3)-MPTP at doses known to cause neurotoxicity in mice. Moreover, this study clearly shows that 2'-NH(2)-MPTP can be utilized in rats as a tool to study the serotonergic and noradrenergic neurotransmitter systems.
Unger
Erica L
EL
152 Davey Laboratory, Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.
Mazzola-Pomietto
Pascale
P
Murphy
Dennis L
DL
Andrews
Anne M
AM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C015068:1-(3-chlorophenyl)piperazine; D009638:Norepinephrine