Yoshimoto K, Yayama K, Sorimachi Y, Tani J, Ogata M, Nishimura A, Yoshida T, Ueda S, Komura S
Department of Legal Medicine, Kyoto Prefectural University of Medicine, Japan.
Alcohol Clin Exp Res. 1996 Dec;20(9 Suppl):311A-319A.
The present study was performed to examine the involvement of serotonin-3 (5-HT3) receptors in the rat nucleus accumbens (ACC) in alcohol dependence. In alcohol-treated rats, perfusion of 40 mM K+ and 100 mM ethanol (EtOH) through the microdialysis probe increased the extracellular levels of ACC dopamine (DA), compared with controls. Perfusion of the serotonin (5-HT) uptake inhibitor sertlarine enhanced the extracellular levels of ACC 5-HT in both groups. Increased 5-HT availability in the synaptic clefts on the ACC further activated ACC DA release in the alcohol-treated rats, in comparison with controls. In the final experiments, perfusion of the 5.0 microM 5-HT3 receptor agonist 2-methyl-5-HT (2-Me-5-HT) through the microdialysis probe enhanced the extracellular levels of ACC DA. Magnitude of 2-Me-5-HT-induced DA release was significantly higher in alcohol-treated rats than in controls. On the other hand, 40 mM K(+)- and 100 mM EtOH-induced extracellular 5-HT release in alcohol-treated rats were markedly inhibited. These results show that (1) chronic alcohol intake increases the sensitivity of 5-HT3 receptors, (2) 5-HT3 receptors regulate DA release in the ACC, (3) the dopaminergic neuronal systems associated with 5-HT3 ionophore in the ACC were upregulated after chronic alcohol exposure, and (4) chronic alcohol intake desensitizes the serotonergic neuronal systems in rat ACC. These findings suggest that neurochemical functions of 5-HT3 receptors in regulating DA release in the 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.
本研究旨在探讨5-羟色胺3（5-HT3）受体在大鼠伏隔核（ACC）酒精依赖中的作用。与对照组相比，对酒精处理的大鼠通过微透析探针灌注40 mM K+和100 mM乙醇（EtOH）可增加ACC多巴胺（DA）的细胞外水平。5-羟色胺（5-HT）摄取抑制剂舍曲林的灌注在两组中均增强了ACC 5-HT的细胞外水平。与对照组相比，ACC突触间隙中5-HT可用性的增加进一步激活了酒精处理大鼠中ACC DA的释放。在最终实验中，通过微透析探针灌注5.0 microM 5-HT3受体激动剂2-甲基-5-HT（2-Me-5-HT）可提高ACC DA的细胞外水平。酒精处理大鼠中2-Me-5-HT诱导的DA释放幅度显著高于对照组。另一方面，40 mM K(+)和100 mM EtOH诱导的酒精处理大鼠细胞外5-HT释放受到明显抑制。这些结果表明：（1）长期摄入酒精会增加5-HT3受体的敏感性；（2）5-HT3受体调节ACC中DA的释放；（3）长期酒精暴露后，ACC中与5-HT3离子通道相关的多巴胺能神经元系统上调；（4）长期摄入酒精会使大鼠ACC中的5-羟色胺能神经元系统脱敏。这些发现表明，酒精暴露后5-HT3受体在调节ACC中DA释放的神经化学功能可补偿5-羟色胺能活性的功能障碍，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。
