Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Behav Brain Res. 2010 Apr 2;208(2):636-42. doi: 10.1016/j.bbr.2010.01.011. Epub 2010 Jan 18.
Alcohol-sensitive type 1 equilibrative nucleoside transporter (ENT1) regulates adenosine-mediated glutamate neurotransmission in the brain. Our behavioral studies suggest that the diminished aversive effects of ethanol and the increased resistance to acute ethanol intoxication in mice lacking ENT1, could be related to increased voluntary ethanol self-seeking behavior. In addition, we found that ENT1 null mice were resistant to the ataxic effects of glutamate antagonists when tested on a rotarod. Using microdialysis experiments, we examined glutamate levels in the dorsal and ventral striatum in response to ethanol. In the dorsal striatum of ENT1 null mice, a low intoxicating dose of ethanol (1.5 g/kg) induced a greater increase of glutamate levels, while a higher hypnotic dose of ethanol (3.0 g/kg) decreased to a lesser degree the glutamate levels, compared with that of wild-type mice. In the ventral striatum, however, the low (1.5 g/kg) and the high (3.0 g/kg) ethanol doses altered glutamate levels similarly in both genotypes. Our results suggest that adenosine-regulated glutamatergic signaling contributes to a reduced level of alcohol response, which might be associated with a higher susceptibility for alcoholism in humans.
酒精敏感型 1 型平衡核苷转运蛋白（ENT1）调节大脑中腺苷介导的谷氨酸能神经传递。我们的行为研究表明，缺乏 ENT1 的小鼠对乙醇的厌恶作用减弱，对急性乙醇中毒的抵抗力增强，可能与自愿性乙醇自我寻求行为增加有关。此外，我们发现 ENT1 缺失小鼠在旋转棒上对谷氨酸拮抗剂的共济失调作用具有抗性。使用微透析实验，我们检测了乙醇对背侧和腹侧纹状体谷氨酸水平的影响。在 ENT1 缺失小鼠的背侧纹状体中，低致醉剂量的乙醇（1.5 g/kg）诱导谷氨酸水平更大程度的增加，而较高的催眠剂量的乙醇（3.0 g/kg）则使谷氨酸水平降低的程度较小，与野生型小鼠相比。然而，在腹侧纹状体中，低（1.5 g/kg）和高（3.0 g/kg）乙醇剂量在两种基因型中均相似地改变谷氨酸水平。我们的结果表明，腺苷调节的谷氨酸能信号有助于降低酒精反应水平，这可能与人类更高的酗酒易感性有关。
