The role of membrane and vesicular monoamine transporters in the neurotoxic and hypothermic effects of 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH(2)-MPTP).
The neurotoxin 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH(2)-MPTP) damages forebrain serotonin (5-HT) and norepinephrine (NE) nerve terminals while sparing striatal dopaminergic innervation. Previous studies suggest that 2'-NH(2)-MPTP acts by a mechanism that involves uptake by the plasma membrane 5-HT and NE transporters. The present investigation further explores the molecular mechanism of 2'-NH(2)-MPTP with regard to cellular transport and effects on body temperature. Mice with genetically controlled decreases in serotonin transporter (SERT) expression were studied to corroborate pharmacologic evidence implicating SERT in 2'-NH(2)-MPTP-induced serotonin neurotoxicity. To investigate whether sequestration by the intracellular vesicular monoamine transporter type 2 (VMAT2) occurs, mice with reduced VMAT2 expression or mice receiving the VMAT2 inhibitor Ro 4-1284 (2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydrobenzo[alpha]chinolizin hydrochloride) were treated with 2'-NH(2)-MPTP. Body temperature was measured as a function of reduced SERT or VMAT2 expression. 2'-NH(2)-MPTP caused a 2 degrees C drop in temperature that was attenuated by decreased SERT but not VMAT2. In addition, complete loss of SERT attenuated cortical and hippocampal depletions in 5-HT but not NE. In contrast, mice with a 50% reduction in VMAT2 exhibited similar 5-HT and NE toxicity when compared with wild-type mice at higher doses of 2'-NH(2)-MPTP, whereas a slight potentiation of toxicity was observed at very low doses of 2'-NH(2)-MPTP. Pharmacologic inhibition of VMAT2 caused minimal potentiation of neurotransmitter depletions in response to moderate doses of 2'-NH(2)-MPTP. Thus, 2'-NH(2)-MPTP seems to be similar to MPTP in its requirement for selective plasma membrane transport and the expression of acute hypothermia; however, unlike MPTP, VMAT2 does not appear to play a major role in the toxic mechanism of 2'-NH(2)-MPTP.
Numis
Adam L
AL
Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802-4615, USA.
Unger
Erica L
EL
Sheridan
Douglas L
DL
Chisnell
Angela C
AC
Andrews
Anne M
AM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing / Q000187:drug effects* / Q000502:physiology; D007036:Hypothermia, Induced; D020267:MPTP Poisoning / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D050486:Serotonin Plasma Membrane Transport Proteins; C493453:Slc18a2 protein, mouse; C493231:Slc6a4 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine