Al-Rejaie Salim, Dar M Saeed
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
Alcohol Clin Exp Res. 2006 Jul;30(7):1223-33. doi: 10.1111/j.1530-0277.2006.00143.x.
Epidemiological studies show that people who drink alcoholic beverages also smoke cigarettes and vice versa. Furthermore, animal studies provide circumstantial evidence for ethanol and nicotine interaction. Previously, we demonstrated that intracerebellar nicotine attenuates ethanol ataxia. This study investigated the possible role of glutamate in modulating the interaction of nicotine and ethanol.
Glutamate drugs N-methyl-d-aspartate (NMDA) and (+)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) as well as their antagonists were directly microinfused into the cerebellum of CD-1 male mice to evaluate their effect on ethanol (2 g/kg i.p.) ataxia. Drug microinfusions were made via stereotaxically implanted stainless-steel guide cannulas. Rotorod was used to evaluate the ataxic response of ethanol.
Microinfusion of nicotine (0.3125, 1.25, 5 ng) significantly attenuated ethanol ataxia dose-dependently, confirming the functional interaction between nicotine and ethanol as reported earlier. Intracerebellar pretreatment with hexamethonium, a nicotinic receptor (nAChR) antagonist, significantly blocked nicotine-induced attenuation of ethanol ataxia suggesting participation of nAChRs. When ethanol was injected before nicotine microinfusion, nicotine failed to attenuate ethanol ataxia, indicating the critical importance of initial activation of nAChRs by nicotine. Intracerebellar microinfusion of NMDA (30, 60, 125 ng) and its antagonist, (+)-MK-801 (50, 100, 200 ng), significantly increased and decreased, respectively, the nicotine-induced attenuation of ethanol ataxia in a dose-related manner, suggesting participation of the NMDA receptor. Similarly, intracerebellar microinfusion of AMPA (7.5, 15, 30 ng) and its antagonist, nitro -2, 3-dioxobenzoquinoxaline-sulfonamide (NBQX; 25, 50, 100 ng), significantly increased and decreased, respectively, the nicotine-induced attenuation of ethanol ataxia in a dose-dependent manner. This suggests participation of the AMPA receptor and further supports involvement of the glutamate system in the ethanol-nicotine interaction. Intracerebellar nicotine failed to attenuate sodium-pentobarbital (25 mg/kg i.p.) ataxia, suggesting the relative specificity of the nicotine-ethanol interaction.
The results suggested that glutamate modulates the functional interaction between nicotine and ethanol because NMDA and AMPA enhanced the nicotine-induced attenuation of ethanol ataxia, whereas (+)-MK-801 and NBQX reduced the attenuation.
流行病学研究表明，饮酒者也吸烟，反之亦然。此外，动物研究为乙醇和尼古丁的相互作用提供了间接证据。此前，我们证明小脑内注射尼古丁可减轻乙醇诱导的共济失调。本研究调查了谷氨酸在调节尼古丁与乙醇相互作用中的可能作用。
将谷氨酸药物N-甲基-D-天冬氨酸（NMDA）和（+）-α-氨基-3-羟基-5-甲基异恶唑-4-丙酸水合物（AMPA）及其拮抗剂直接微量注入CD-1雄性小鼠的小脑，以评估它们对乙醇（2克/千克腹腔注射）诱导的共济失调的影响。药物微量注射通过立体定位植入的不锈钢引导套管进行。使用转棒试验评估乙醇的共济失调反应。
微量注射尼古丁（0.3125、1.25、5纳克）可剂量依赖性地显著减轻乙醇诱导的共济失调，证实了先前报道的尼古丁与乙醇之间的功能相互作用。用烟碱受体（nAChR）拮抗剂六甲铵进行小脑内预处理，可显著阻断尼古丁诱导的乙醇共济失调减轻，提示nAChRs参与其中。当在微量注射尼古丁之前注射乙醇时，尼古丁未能减轻乙醇诱导的共济失调，表明尼古丁对nAChRs的初始激活至关重要。小脑内微量注射NMDA（30、60、125纳克）及其拮抗剂（+）-MK-801（50、100、200纳克），分别以剂量相关的方式显著增加和降低了尼古丁诱导的乙醇共济失调减轻，提示NMDA受体参与其中。同样，小脑内微量注射AMPA（7.5、15、30纳克）及其拮抗剂硝基-2,3-二氧苯并喹喔啉-磺酰胺（NBQX；25、50、100纳克），分别以剂量依赖性方式显著增加和降低了尼古丁诱导的乙醇共济失调减轻。这表明AMPA受体参与其中，并进一步支持谷氨酸系统参与乙醇-尼古丁相互作用。小脑内注射尼古丁未能减轻戊巴比妥钠（25毫克/千克腹腔注射）诱导的共济失调，提示尼古丁-乙醇相互作用具有相对特异性。
结果表明，谷氨酸调节尼古丁与乙醇之间的功能相互作用，因为NMDA和AMPA增强了尼古丁诱导的乙醇共济失调减轻，而（+）-MK-801和NBQX则降低了这种减轻作用。
