Behavioral interaction between nicotine and ethanol: possible modulation by mouse cerebellar glutamate.
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.