Involvement of the alpha4beta2 nicotinic receptor subtype in nicotine-induced attenuation of delta9-THC cerebellar ataxia: role of cerebellar nitric oxide.
We have recently reported that mediation of intracerebellar nicotine-induced attenuation of cerebellar delta9-THC ataxia was via the alpha4beta2 nAChR. The present study was meant to investigate the role of cerebellar nitric oxide (NO)-guanylyl cyclase (GC) signaling in the alpha4beta2-mediated attenuation in CD-1 male mice. Drugs were given via intracerebellar microinfusion using stereotaxically implanted guide cannulas, with ataxia evaluated by Rotorod. Intracerebellar microinfusion of SNP (sodium nitroprusside, NO donor; 15, 30, 60 pg) and SMT (S-methylisothiourea, inhibitor of inducible NO synthase; 70, 140, 280 fg) significantly enhanced and reduced, respectively, intracerebellar RJR-2403 (selective alpha4beta2 agonist)-induced attenuation of delta9-THC ataxia dose-dependently. Intracerebellar isoliquiritigenin (GC-activator; 1, 2, 4 pg) and ODQ (1H[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, GC inhibitor; 200, 400, 800 fg), significantly enhanced and reduced, respectively, intracerebellar RJR-2403-induced attenuation of delta9-THC ataxia dose-dependently. Further support for the role of NO was evidenced via increases in cerebellar NO(x) (nitrate+nitrite) levels following microinfusion of nicotine or RJR-2403 as compared to control, whereas delta9-THC significantly decreased NO(x) levels. "Nicotine/RJR-2403+delta9-THC" treated mice had cerebellar NO(x) levels significantly increased as compared to mice infused with delta9-THC alone. Results of the present investigation support the role of cerebellar NO-GC signaling in alpha4beta2 nAChR subtype-mediated attenuation of delta9-THC ataxia.
Smith
Aaron David
AD
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
Dar
M Saeed
MS
D000818:Animals; D019540:Area Under Curve; D002524:Cerebellar Ataxia / Q000139:chemically induced* / Q000188:drug therapy*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D047188:Chalcones / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D013759:Dronabinol / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D051379:Mice; D008845:Microinjections; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D011978:Receptors, Nicotinic / Q000502:physiology*; D013238:Stereotaxic Techniques
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D047188:Chalcones; D004791:Enzyme Inhibitors; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011810:Quinoxalines; D043884:Receptor, Cannabinoid, CB1; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009599:Nitroprusside; D009569:Nitric Oxide; C012419:metanicotine; D009538:Nicotine; D013759:Dronabinol; C040920:isoliquiritigenin; D006162:Guanylate Cyclase; D006152:Cyclic GMP