Comparison between the role of the neuronal and inducible nitric oxide synthase in methamphetamine-induced neurotoxicity and sensitization.
The involvement of the neuronal and inducible nitric oxide synthase (nNOS and iNOS, respectively) in methamphetamine (METH)-induced dopaminergic neurotoxicity and behavioral sensitization was investigated. To determine METH-induced neurotoxicity, mice deficient in the nNOS and iNOS genes, nNOS(-/-) and iNOS(-/-) mice, and wild-type controls received either saline or METH (5 mg/kg x 3). After 72 h the level of striatal dopaminergic markers were measured. Administration of METH to nNOS(-/-) mice had no significant effect on the level of striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), or dopamine transporter (DAT) binding sites. However, METH caused 25-40% depletion of dopaminergic markers in iNOS(-/-) mice and 63-69% depletion in the wild-type mice. METH-induced locomotor activity was measured following the administration of a low dose (1 mg/kg) on day 1. Subsequently animals received the high dose of METH (5 mg/kg x 3). On day 4, after a 68-72 h drug free period, animals were challenged with 1 mg/kg METH, and locomotor activity was recorded. The intensity of METH-induced locomotion in nNOS(-/-) mice on day 1 and 4 was similar, suggesting that locomotor sensitization did not develop. However, the intensity of METH-induced locomotion in the iNOS(-/-) and wild-type mice on day 4 was doubled compared to day 1, suggesting the development of sensitization. The present findings indicate that nNOS(-/-) mice are more resistant to METH-induced neurotoxicity and behavioral sensitization than iNOS(-/-) mice. These results suggest a major role for nNOS rather than iNOS in the effects of METH.
Itzhak
Y
Y
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Florida 33101, USA. yitzhak@med.miami.edu
Martin
J L
JL
Ali
S F
SF
D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008454:Mazindol / Q000493:pharmacokinetics; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D009498:Neurotoxins; D018377:Neurotransmitter Agents; D014316:Tritium; D008694:Methamphetamine; D008454:Mazindol; D004298:Dopamine