Al-Rejaie Salim, Dar M Saeed
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC 27834, USA.
Brain Res Bull. 2006 Mar 31;69(2):187-96. doi: 10.1016/j.brainresbull.2005.12.002. Epub 2005 Dec 20.
We have reported previously that intracerebellar nicotine attenuates ethanol ataxia via nicotinic-cholinergic receptors. We report now that attenuation of ethanol ataxia by intracerebellar nicotine is modulated by cerebellar nitric oxide-guanylyl cyclase (GC) messenger system. Intracerebellar microinfusion of SNP (sodium nitroprusside, a nitric oxide donor; 15, 30, and 60 pg) and SMT (S-methylisothiourea; 70, 140, and 280 fg; an inhibitor of inducible nitric oxide synthase), significantly enhanced and reduced, respectively, intracerebellar nicotine-induced attenuation of ethanol ataxia in a dose-related manner. Similarly, intracerebellar isoliquiritigenin (an activator of GC; 1, 2, and 4 pg) and ODQ (1H [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, an inhibitor of GC; 375, 750, and 1500 fg), significantly enhanced and reduced, respectively, intracerebellar nicotine-induced attenuation of ethanol ataxia in a dose-related fashion. These results suggest that the functional interaction between nicotine and ethanol may involve modulation by cerebellar nitric oxide and cGMP. Intracerebellar microinfusion of isoliquiritigenin (4, 8, and 16 pg) in the absence of nicotine significantly attenuated ethanol ataxia dose-dependently indicating a tonic involvement of cGMP in ethanol ataxia. Finally, intracerebellar nicotine (5 ng) significantly increased and ethanol 2 g/kg i.p. decreased levels of total cerebellar nitrite+nitrate (NOx) which were functionally correlated with ethanol ataxia and its attenuation by intracerebellar nicotine. The ethanol-induced decrease in NOx was significantly antagonized by intracerebellar nicotine. The NOx data further supported an involvement of nitric oxide in the behavioral interaction between nicotine and ethanol. Overall, the results of the present investigation demonstrate a functional correlation between cerebellar nitric oxide messenger system and the behavioral interaction between nicotine and ethanol.
我们之前曾报道，小脑内注射尼古丁可通过烟碱型胆碱能受体减轻乙醇性共济失调。我们现在报告，小脑内尼古丁对乙醇性共济失调的减轻作用受小脑一氧化氮-鸟苷酸环化酶（GC）信使系统调节。小脑内微量注射硝普钠（SNP，一种一氧化氮供体；15、30和60皮克）和S-甲基异硫脲（SMT；70、140和280飞克；诱导型一氧化氮合酶抑制剂），分别以剂量相关的方式显著增强和降低了小脑内尼古丁诱导的乙醇性共济失调的减轻作用。同样，小脑内注射异甘草素（一种GC激活剂；1、2和4皮克）和ODQ（1H-[1,2,4]恶二唑并-[4,3-a]喹喔啉-1-酮，一种GC抑制剂；375、750和1500飞克），也分别以剂量相关的方式显著增强和降低了小脑内尼古丁诱导的乙醇性共济失调的减轻作用。这些结果表明，尼古丁与乙醇之间的功能相互作用可能涉及小脑一氧化氮和环鸟苷酸的调节。在无尼古丁的情况下，小脑内微量注射异甘草素（4、8和16皮克）可剂量依赖性地显著减轻乙醇性共济失调，表明环鸟苷酸在乙醇性共济失调中具有紧张性作用。最后，小脑内注射尼古丁（5纳克）可显著增加，而腹腔注射2克/千克乙醇可降低小脑总亚硝酸盐+硝酸盐（NOx）水平，这与乙醇性共济失调及其被小脑内尼古丁减轻在功能上相关。乙醇诱导的NOx降低被小脑内尼古丁显著拮抗。NOx数据进一步支持了一氧化氮参与尼古丁与乙醇之间的行为相互作用。总体而言，本研究结果表明小脑一氧化氮信使系统与尼古丁和乙醇之间的行为相互作用存在功能相关性。
