Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
Alcohol Clin Exp Res. 2011 Mar;35(3):540-9. doi: 10.1111/j.1530-0277.2010.01371.x. Epub 2010 Dec 8.
Many epidemiological studies report that alcoholics overwhelmingly smoke tobacco and vice versa, which suggests a possible functional interaction between ethanol and nicotine. Although nicotine-ethanol interaction is well documented within the central nervous system, the mechanism is not well understood. Therefore, it is important from a public health standpoint to understand the mechanisms involved in nicotine and ethanol functional interaction. The intracerebellar (ICB) administration of nicotine significantly attenuates ethanol ataxia through nicotinic acetylcholine receptor (nAChR) α(4)β(2) subtype. This study, an extension of earlier work, was intended to investigate the possible role of nAChR subtype α(7) in mitigating ethanol ataxia.
The effect of ICB injection of PNU-282987 (α(7) agonist; 25 ng to 2.5 μg) and the antagonist methyllycaconitine was evaluated on ethanol (2 g/kg; i.p.)-induced ataxia with a Rotorod. Cerebellar nitric oxide was determined fluorometrically in the presence of ethanol and/or PNU-282987.
Attenuation of ethanol-induced ataxia following PNU-282987 microinfusion was dose-dependent suggesting the participation of α(7) subtype in nicotine and ethanol interaction. Intracerebellar pretreatment with methyllycaconitine (α(7) -selective antagonist; 6 ng) virtually abolished the attenuating effect of PNU-282987 as well as the effect of nicotine, but not of RJR-2403 (α(4)β(2) -selective agonist; 125 ng) on ethanol-induced ataxia. Finally, ethanol administration significantly decreased cerebellar NO(x), whereas ICB PNU-282987 significantly increased and/or opposed ethanol-induced decrease in NO(x). These results were functionally in agreement with our Rotorod data.
These observations confirmed the following: (i) α(7) participation in nicotine-ethanol interaction and (ii) α(7) selectivity of methyllycaconitine. Overall, the results demonstrate the role of cerebellar nAChR α(7) subtype in nicotine-induced attenuation of ethanol-induced ataxia in cerebellar NO(x)-sensitive manner.
许多流行病学研究报告表明，酗酒者绝大多数都吸烟，反之亦然，这表明乙醇和尼古丁之间可能存在功能相互作用。虽然中枢神经系统内的尼古丁-乙醇相互作用已得到充分证实，但机制尚不清楚。因此，从公共卫生的角度来看，了解尼古丁和乙醇功能相互作用所涉及的机制非常重要。小脑内（ICB）给予尼古丁可通过烟碱型乙酰胆碱受体（nAChR）α（4）β（2）亚型显著减轻乙醇性共济失调。这项研究是早期工作的延伸，旨在研究 nAChR 亚型α（7）在减轻乙醇性共济失调中的可能作用。
通过 Rotorod 评估小脑内注射 PNU-282987（α（7）激动剂；25ng 至 2.5μg）和拮抗剂甲基六氢烟碱对乙醇（2g/kg；ip）诱导的共济失调的影响。在存在乙醇和/或 PNU-282987 的情况下，用荧光法测定小脑内一氧化氮。
PNU-282987 微注射后对乙醇诱导的共济失调的抑制作用呈剂量依赖性，提示 α（7）亚型参与了尼古丁和乙醇的相互作用。小脑内预先给予甲基六氢烟碱（α（7）-选择性拮抗剂；6ng）几乎消除了 PNU-282987 的抑制作用以及尼古丁的作用，但不消除 RJR-2403（α（4）β（2）-选择性激动剂；125ng）对乙醇诱导的共济失调的作用。最后，乙醇给药显著降低小脑内的 NO（x），而小脑内 PNU-282987 显著增加和/或对抗乙醇诱导的 NO（x）降低。这些结果与我们的 Rotorod 数据在功能上是一致的。
这些观察结果证实了以下几点：（i）α（7）参与尼古丁-乙醇相互作用和（ii）甲基六氢烟碱的α（7）选择性。总的来说，这些结果表明小脑 nAChR α（7）亚型在尼古丁诱导的小脑 NO（x）敏感方式减轻乙醇诱导的共济失调中起作用。
