Involvement of the α 4β 2 nicotinic receptor subtype in nicotine-induced attenuation of Δ 9-THC cerebellar ataxia: Role of cerebellar nitric oxide

Abstract

We have recently reported that mediation of intracerebellar nicotine-induced attenuation of cerebellar Δ 9-THC ataxia was via the α 4β 2 nAChR. The present study was meant to investigate the role of cerebellar nitric oxide (NO)-guanylyl cyclase (GC) signaling in the α 4β 2-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 α 4β 2 agonist)-induced attenuation of Δ 9-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 Δ 9-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 Δ 9-THC significantly decreased NO x levels. “Nicotine/RJR-2403 + Δ 9-THC” treated mice had cerebellar NO x levels significantly increased as compared to mice infused with Δ 9-THC alone. Results of the present investigation support the role of cerebellar NO–GC signaling in α 4β 2 nAChR subtype-mediated attenuation of Δ 9-THC ataxia.