The nNOS inhibitor, AR-R17477AR, prevents the loss of NF68 immunoreactivity induced by methamphetamine in the mouse striatum.
The present study examined the time-course and regionally-selective changes in the levels of the neurofilament protein NF68 in the mouse brain induced by methamphetamine (METH). The ability of low ambient temperature, or of the specific neuronal nitric oxide synthase (nNOS) inhibitor AR-R17477AR, to protect against both long-term striatal NF68 and dopamine loss induced by METH (3 mg/kg, i.p.) was also studied. Seven days after METH administration (3, 6 and 9 mg/kg, i.p., three times at 3 h intervals), mice showed a reduction of about 40% in immunoreactivity for NF68 in the striatum. This effect was not produced in cortex after METH administration at the dose of 3 mg/kg. No difference from controls was observed when measurements were carried out 1 h and 24 h after the last METH injection at the dose of 3 mg/kg. The loss of NF68 immunoreactivity seems to be associated with the long-term dopamine depletion induced by METH, since no change in serotonin concentration is observed in either the striatum or cortex 7 days after dosing. Animals kept at a room temperature of 4 degrees C showed a loss of NF68 similar to those treated at 22 degrees C but an attenuation of dopamine depletion in the striatum. Pre-treatment with AR-R17477AR (5 mg/kg, s.c.) 30 min before each of the three METH (3 mg/kg, i.p.) injections provided complete protection against METH-induced loss of NF68 immunoreactivity and attenuated the decrease in striatal dopamine and HVA concentrations by about 50%. These data indicate that both the reduction of NF68 immunoreactivity and the loss of dopamine concentration are due to an oxidative stress process mediated by reactive nitrogen species, and are not due to changes in body temperature.
Sanchez
Veronica
V
Departamento de Farmacologia and Facultad de Medicina Instituto de Bioquimica CSIC-UCM, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. colado@med.ucm.es
Zeini
Miriam
M
Camarero
Jorge
J
O'Shea
Esther
E
Bosca
Lisardo
L
Green
A Richard
AR
Colado
M Isabel
MI
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005334:Fever / Q000139:chemically induced; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016900:Neurofilament Proteins / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D013696:Temperature; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D016900:Neurofilament Proteins; C066858:neurofilament protein NF 68; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D008694:Methamphetamine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D004298:Dopamine; D006719:Homovanillic Acid