Evaluation of the effects of alpha-phenyl-N-tert-butyl nitrone pretreatment on the neurobehavioral effects of methamphetamine.
A relationship between formation of reactive oxygen species (ROS) and energy depletion has been proposed to play an important role in mediating methamphetamine (METH)-induced neurotoxicity. To evaluate this relationship, we examined the effect of the spin-trap agent, alpha-phenyl-N-tert-butyl nitrone (PBN) on hyperthermia and self-injurious behavior (SIB) and striatal dopamine (DA) depletion produced by METH (4 injections of 4 mg/kg, 2 hr intervals, s.c.) in BALB/c mice. Repeated administration of METH induced hyperthermia, incidence of SIB and striatal DA depletion (84% after 3 days). Pretreatment with PBN (4 injections of 60 or 120 mg/kg, i.p.) reduced METH-induced hyperthermia, but did not significantly attenuate METH-induced SIB or the striatal DA depletion. On the other hand, pretreatment with high doses of PBN (4 injections of 180 or 240 mg/kg, i.p.) protected against METH-induced hyperthermia and SIB, and PBN (180 mg/kg) also completely protected against the acute striatal DA depletion 60 min after the last injection of the drug. However, the long-lasting striatal DA depletion was only attenuated by 52 or 56%, respectively. These results indicate that METH-induced hyperthermia contributes to, but is not solely responsible for METH-induced neurotoxicity, and supports a role for formation of ROS and other mechanisms in the generation of METH-induced striatal dopaminergic neurotoxicity. In addition, the difference in the efficacy of PBN to protect against the acute or long-lasting striatal DA depletion induced by METH may indicate that both ROS formation and other mechanisms are required for METH-induced neurotoxicity to develop.
Kita
T
T
Department of Pharmacology, Nara Medical University, Japan. tkita@nmu-gw.cc.naramed-u.ac.jp
Matsunari
Y
Y
Saraya
T
T
Shimada
K
K
O'Hara
K
K
Kubo
K
K
Wagner
G C
GC
Nakashima
T
T
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009589:Nitrogen Oxides / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016728:Self-Injurious Behavior / Q000139:chemically induced / Q000517:prevention & control*
D000697:Central Nervous System Stimulants; D003497:Cyclic N-Oxides; D015259:Dopamine Agents; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D008694:Methamphetamine; D004298:Dopamine