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Mediation of intracerebellar (ICB) nicotine‐induced attenuation of Δ 9 ‐THC cerebellar ataxia by α 4 β 2 receptor subtype; role of cerebellar nitric oxide (NO)
Author(s) -
Smith Aaron D,
Dar M Saeed
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a681-a
Subject(s) - nicotine , chemistry , pharmacology , ataxia , cerebellum , cerebellar ataxia , agonist , nitric oxide , hypoactivity , medicine , endocrinology , receptor , biochemistry , neuroscience , biology , organic chemistry
We have previously reported that mediation of ICB nicotine‐induced attenuation of Δ 9 ‐THC cerebellar ataxia was via α 4 β 2 nAChR subtype. The present study was meant to investigate the role of CD‐1 male mouse cerebellar NO‐GC (guanylate cyclase) signaling in the α 4 β 2 ‐mediated attenuation. Drugs were given by direct ICB infusion via stereotaxically implanted (AP + 6.4 mm, ML + 0.8 mm, DV – 1.0 mm), stainless steel guide cannulas (gauge 22). Ataxia was evaluated by Rotorod. Isoliquiritigenin, a GC‐activator, and oxadiazole quinoxalin (ODQ), a GC inhibitor, in the presence of RJR‐2403 (selective α 4 β 2 agonist), significantly attenuated and accentuated, respectively, Δ 9 ‐THC ataxia dose dependently, indicating a role of GC in the nicotine‐Δ 9 ‐THC interaction. Also, sodium nitroprusside (NOS‐donor) and SMT (iNOS inhibitor), in the presence of RJR‐2403, significantly attenuated and accentuated, respectively, Δ 9 ‐THC ataxia in a dose‐dependent manner suggesting a role of NO in the nicotine‐Δ 9 ‐THC interaction. Further support of NO role was evidenced via increases in cerebellar NOx (nitrate and nitrite) levels following infusion of nicotine or RJR‐2403 compared to control. Conversely, mice infused with Δ 9 ‐THC alone had NOx levels significantly decreased compared to control. Both “Nicotine + Δ 9 ‐THC” and “RJR‐2403 + Δ 9 ‐THC” treated mice had NOx levels significantly increased compared to mice infused with Δ 9 ‐THC alone. Overall, the results of the present investigation support the role of cerebellar NO‐GC signaling in α 4 β 2 nAChR subtype‐mediated attenuation of Δ 9 ‐THC ataxia.