Akash K G, Anju T R, Peeyush K T, Paulose C S
Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin 682022, Kerala, India.
J Biomed Sci. 2008 Sep;15(5):623-31. doi: 10.1007/s11373-008-9259-6. Epub 2008 Jun 7.
Dopamine D(2) receptors are involved in ethanol self- administration behavior and also suggested to mediate the onset and offset of ethanol drinking. In the present study, we investigated dopamine (DA) content and Dopamine D(2) (DA D(2)) receptors in the hypothalamus and corpus striatum of ethanol treated rats and aldehyde dehydrogenase (ALDH) activity in the liver and plasma of ethanol treated rats and in vitro hepatocyte cultures. Hypothalamic and corpus striatal DA content decreased significantly (P < 0.05, P < 0.001 respectively) and homovanillic acid/dopamine (HVA/DA) ratio increased significantly (P < 0.001) in ethanol treated rats when compared to control. Scatchard analysis of [(3)H] YM-09151-2 binding to DA D(2) receptors in hypothalamus showed a significant increase (P < 0.001) in B(max) without any change in K(d) in ethanol treated rats compared to control. The K(d) of DA D(2) receptors significantly decreased (P < 0.05) in the corpus striatum of ethanol treated rats when compared to control. DA D(2) receptor affinity in the hypothalamus and corpus striatum of control and ethanol treated rats fitted to a single site model with unity as Hill slope value. The in vitro studies on hepatocyte cultures showed that 10(-5) M and 10(-7) M DA can reverse the increased ALDH activity in 10% ethanol treated cells to near control level. Sulpiride, an antagonist of DA D(2), reversed the effect of dopamine on 10% ethanol induced ALDH activity in hepatocytes. Our results showed a decreased dopamine concentration with enhanced DA D(2) receptors in the hypothalamus and corpus striatum of ethanol treated rats. Also, increased ALDH was observed in the plasma and liver of ethanol treated rats and in vitro hepatocyte cultures with 10% ethanol as a compensatory mechanism for increased aldehyde production due to increased dopamine metabolism. A decrease in dopamine concentration in major brain regions is coupled with an increase in ALDH activity in liver and plasma, which contributes to the tendency for alcoholism. Since the administration of 10(-5) M and 10(-7) M DA can reverse the increased ALDH activity in ethanol treated cells to near control level, this has therapeutic application to correct ethanol addicts from addiction due to allergic reaction observed in aldehyde accumulation.
多巴胺D(2)受体参与乙醇自我给药行为，也被认为介导乙醇饮用的开始和停止。在本研究中，我们调查了乙醇处理大鼠下丘脑和纹状体中的多巴胺（DA）含量、多巴胺D(2)（DA D(2)）受体，以及乙醇处理大鼠肝脏和血浆及体外肝细胞培养物中的乙醛脱氢酶（ALDH）活性。与对照组相比，乙醇处理大鼠的下丘脑和纹状体DA含量显著降低（分别为P < 0.05，P < 0.001），高香草酸/多巴胺（HVA/DA）比值显著升高（P < 0.001）。对下丘脑DA D(2)受体上[(3)H] YM - 09151 - 2结合的Scatchard分析显示，与对照组相比，乙醇处理大鼠的B(max)显著增加（P < 0.001），而K(d)无变化。与对照组相比，乙醇处理大鼠纹状体中DA D(2)受体的K(d)显著降低（P < 0.05）。对照组和乙醇处理大鼠下丘脑和纹状体中的DA D(2)受体亲和力符合单一部位模型，希尔斜率值为1。对肝细胞培养物的体外研究表明，10(-5) M和10(-7) M的DA可将10%乙醇处理细胞中增加的ALDH活性逆转至接近对照水平。DA D(2)拮抗剂舒必利可逆转多巴胺对肝细胞中10%乙醇诱导的ALDH活性的影响。我们的结果表明，乙醇处理大鼠的下丘脑和纹状体中多巴胺浓度降低，DA D(2)受体增强。此外，在乙醇处理大鼠的血浆和肝脏以及10%乙醇体外肝细胞培养物中观察到ALDH增加，这是由于多巴胺代谢增加导致醛生成增加的一种代偿机制。主要脑区多巴胺浓度降低与肝脏和血浆中ALDH活性增加相关，这有助于酗酒倾向。由于给予10(-5) M和10(-7) M的DA可将乙醇处理细胞中增加的ALDH活性逆转至接近对照水平，这在治疗上可用于纠正因醛积累中观察到的过敏反应导致的乙醇成瘾者的成瘾问题。
