Nitric oxide synthase inhibitors block behavioral sensitization to methamphetamine in mice.
Repeated administration of methamphetamine (1.0 mg/kg) once daily for 7 consecutive days resulted in an augmentation of the locomotor-activating effect of methamphetamine (0.5 mg/kg) challenged 72 h after the last injection. Administration of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (10 and 30 mg/kg), before daily methamphetamine injections dose dependently prevented the development of behavioral sensitization to subsequent methamphetamine challenge. The mice given another NO synthase inhibitor, NG-nitro-L-arginine methyl ester (100 mg/kg), before daily methamphetamine injections showed significantly less locomotor activity in response to 0.5 mg/kg methamphetamine challenge than the mice given daily methamphetamine alone. Such effects were not observed when the inactive isomer, NG-nitro-D-arginine methyl ester (100 mg/kg), was administered daily prior to methamphetamine. Both NO synthase inhibitors exerted the acute effect to reduce spontaneous and methamphetamine-stimulated locomotor activity, while neither spontaneous locomotion nor hyperlocomotion in response to 1.0 mg/kg methamphetamine was altered 72 h after repeated administration of NG-nitro-L-arginine (30 mg/kg) or NG-nitro-L-arginine methyl ester (100 mg/kg) alone once daily for 7 days. On the other hand, pretreatment with the NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate), at 0.2 mg/kg also suppressed the development of sensitization to the locomotor-activating effect of methamphetamine. These findings suggest that NO formation possibly mediated by NMDA receptors is involved in mechanisms underlying the development of behavioral sensitization to methamphetamine.
Ohno
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Watanabe
S
S
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D009569:Nitric Oxide; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester