Yoshimoto K, Ueda S, Nishi M, Yang Y, Matsushita H, Takeuchi Y, Kato B, Kawai Y, Noritake K, Kaneda S, Sorimachi Y, Yasuhara M
Department of Legal Medicine, Kyoto Prefectural University of Medicine, Japan.
Alcohol Clin Exp Res. 2000 Mar;24(3):361-5.
We have shown that neurochemical functions of 5-HT3 receptors in regulating dopamine (DA) release in the nucleus accumbens (ACC) after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance, and that the development of alcohol dependence may be mediated by ACC 5-HT3 receptors. In the present study, the effects of chronic alcohol consumption on the functions of the dopamine transporter (DAT) and the expression of c-Fos proteins were investigated using in vivo brain microdialysis and immunocytochemistry.
Perfusion of cocaine and 1-(2-Bis-(4-fluorophenyl) methoxy) ethyl)-4-(3-phenylpropyl) piperizine (GBR 12909) through the microdialysis probe membrane increased the extracellular levels of DA in ACC of alcohol-treated rats that had developed alcohol tolerance by drinking 10% EtOH for 30 days.
The magnitudes of DA reuptake or DAT inhibitors, cocaine, and GBR 12909 that induced DA availability in the ACC were significantly higher in alcohol-treated rats than in controls. When compared with control rats, the alcohol-treated rats exhibited higher levels of DA and its metabolite, DOPAC, in the ACC. Increased expression of the c-Fos-like protein was found in the ACC of alcohol-treated rats. These results show that (1) chronic alcohol consumption desensitizes or decreases the DAT of DA terminals in the ACC and that (2) EtOH causes cellular hyperexcitability of ACC dopaminergic neurons with increased Fos expression during alcohol tolerance.
The findings suggested that an abnormality of the dopaminergic neurons in the ACC that are involved with DAT dysfunction is associated with the development of alcohol tolerance.
我们已经表明，酒精暴露后，5-羟色胺3（5-HT3）受体在调节伏隔核（ACC）中多巴胺（DA）释放的神经化学功能可补偿血清素能活性的功能障碍，以恢复处理酒精耐受性的原始特性，并且酒精依赖的发展可能由ACC 5-HT3受体介导。在本研究中，使用体内脑微透析和免疫细胞化学研究了长期饮酒对多巴胺转运体（DAT）功能和c-Fos蛋白表达的影响。
通过微透析探针膜灌注可卡因和1-（2-双-（4-氟苯基）甲氧基）乙基）-4-（3-苯基丙基）哌嗪（GBR 12909）可增加酒精处理大鼠ACC中DA的细胞外水平，这些大鼠通过饮用10%乙醇30天已产生酒精耐受性。
诱导ACC中DA可用性的DA再摄取或DAT抑制剂、可卡因和GBR 12909的量在酒精处理大鼠中显著高于对照组。与对照大鼠相比，酒精处理大鼠的ACC中DA及其代谢物DOPAC水平更高。在酒精处理大鼠的ACC中发现c-Fos样蛋白表达增加。这些结果表明：（1）长期饮酒使ACC中DA终末的DAT脱敏或减少；（2）乙醇导致ACC多巴胺能神经元细胞过度兴奋，在酒精耐受期间Fos表达增加。
研究结果表明，与DAT功能障碍相关的ACC中多巴胺能神经元异常与酒精耐受性的发展有关。
