Nomifensine attenuates d-amphetamine-induced dopamine terminal neurotoxicity in the striatum of rats.
Long-term or high dose administration of d-amphetamine (AMPH) in the rat has been shown to result in dopamine terminal neurotoxicity in the striatum of rats. This phenomenon includes depletion of dopamine content, decreased activity of tyrosine hydroxylase and diminish in the number of dopamine reuptake transporter. Recent studies implicate a role of oxidative stress induced by dopamine in the AMPH-induced neurotoxicity. However, the primary source of dopamine responsible for radical formation during AMPH challenge has remained elusive. To elucidate this issue, the study was designed to examine the effects of nomifensine, a dopamine transporter blocker, and deprenyl, a monoamine oxidase B (MAO-B) inhibitor, on the prevention of striatal dopamine neurotoxicity in AMPH-treated rats. The results showed that nomifensine but not deprenyl protected against AMPH-induced long-term dopamine depletion. Correspondingly, the hydroxyl radical formation caused by AMPH in the striatum was attenuated by nomifensine, whereas its formation was not abolished by deprenyl. In conclusion, this study suggests that intracellular oxidative stress is more likely involved in the AMPH-induced dopamine terminal toxicity in the rat striatum, while this phenomenon is not mediated by MAO-B pathway.
Wan
F J
FJ
Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
Shiah
I S
IS
Lin
H C
HC
Huang
S Y
SY
Tung
C S
CS
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D003913:Dextroamphetamine / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009627:Nomifensine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009627:Nomifensine; D008995:Monoamine Oxidase; D003913:Dextroamphetamine