Effects of N-acetyl-L-cysteine on the reduction of brain dopamine transporters in monkey treated with methamphetamine.
Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). The present study undertakes to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography (PET) studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [11C]b-CFT (for DAT). In contrast, the binding of [11C]DASB to 5-hydroxytryptamine transporter (5-HTT) in the monkey brain was slightly decreased after the administration of MAP, although the difference was not statistically significant. The binding of [11C]SCH 23390 to dopamine D1 receptors in the striatum was also not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before administration of MAP and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity on dopaminergic nerve terminals related to chronic use of MAP in humans.
Hashimoto
Kenji
K
Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. hashimoto@faculty.chiba-u.jp
Tsukada
Hideo
H
Nishiyama
Shingo
S
Fukumoto
Dai
D
Kakiuchi
Takehau
T
Shimizu
Eiji
E
Iyo
Masaomi
M
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008694:Methamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000975:Antioxidants; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D008694:Methamphetamine; D000111:Acetylcysteine