Ortiz J, Fitzgerald L W, Charlton M, Lane S, Trevisan L, Guitart X, Shoemaker W, Duman R S, Nestler E J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Synapse. 1995 Dec;21(4):289-98. doi: 10.1002/syn.890210403.
In previous studies, we have demonstrated that chronic administration of morphine or cocaine produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing actions of these and other drugs of abuse. Since this neural pathway is also implicated in the reinforcing actions of ethanol, it was of interest to determine whether chronic ethanol exposure results in similar biochemical adaptations. Indeed, as seen for chronic morphine and cocaine treatments, we show here that chronic ethanol treatment increased levels of tyrosine hydroxylase and glial fibrillary acidic protein immunoreactivity, and decreases levels of neurofilament protein immunoreactivity, in the VTA. Also like morphine and cocaine, ethanol increases levels of cyclic AMP-dependent protein kinase activity in the NAc. These actions of ethanol required long-term exposure to the drug, and were in most cases not seen in the substantia nigra or caudateputamen, components of the nigrostriatal dopamine system studied for comparison. Altered levels of tyrosine hydroxylase in catecholaminergic cells frequently reflect altered states of activation of the cells. Moreover, increasing evidence indicates that ethanol produces many of its acute effects on the brain by regulating NMDA glutamate and GABAA receptors. We therefore examined the influence of chronic ethanol treatment on levels of expression of specific glutamate and GABA receptor subunits in the VTA. It was found that long-term, but not short-term, ethanol exposure increased levels of immunoreactivity of the NMDAR1 subunit, an obligatory component of NMDA glutamate receptors, and of the GluR1 subunit, a component of many AMPA glutamate receptors; but at the same time, long-term ethanol exposure decreased immunoreactivity levels of the alpha 1 subunit of the GABAA receptor complex. These changes are consistent with an increased state of activation of VTA neurons inferred from the observed increase in tyrosine hydroxylase (TH) expression. These results demonstrate that chronic ethanol exposure results in several biochemical adaptations in the mesolimbic dopamine system, which may underlie prominent changes in the structural and functional properties of this neural pathway related to alcohol abuse and alcoholism.
在先前的研究中，我们已经证明，长期给予吗啡或可卡因会在腹侧被盖区（VTA）和伏隔核（NAc）产生一些共同的生化适应性变化，中脑边缘多巴胺系统的这些组成部分与这些及其他滥用药物的强化作用有关。由于这条神经通路也与乙醇的强化作用有关，因此确定长期乙醇暴露是否会导致类似的生化适应性变化就很有意义。事实上，正如长期吗啡和可卡因治疗所见，我们在此表明，长期乙醇治疗会增加VTA中酪氨酸羟化酶水平和胶质纤维酸性蛋白免疫反应性，并降低神经丝蛋白免疫反应性水平。同样与吗啡和可卡因一样，乙醇会增加NAc中依赖环磷酸腺苷的蛋白激酶活性水平。乙醇的这些作用需要长期接触该药物，并且在大多数情况下，在作为比较研究对象的黑质纹状体多巴胺系统的组成部分黑质或尾状壳核中未观察到。儿茶酚胺能细胞中酪氨酸羟化酶水平的改变常常反映细胞激活状态的改变。此外，越来越多的证据表明，乙醇通过调节NMDA谷氨酸受体和GABAA受体对大脑产生许多急性作用。因此，我们研究了长期乙醇治疗对VTA中特定谷氨酸和GABA受体亚基表达水平的影响。发现长期而非短期乙醇暴露会增加NMDA谷氨酸受体的必需成分NMDAR1亚基以及许多AMPA谷氨酸受体的成分GluR1亚基的免疫反应性水平；但与此同时，长期乙醇暴露会降低GABAA受体复合物α1亚基的免疫反应性水平。这些变化与从观察到的酪氨酸羟化酶（TH）表达增加推断出的VTA神经元激活状态增加一致。这些结果表明，长期乙醇暴露会导致中脑边缘多巴胺系统出现几种生化适应性变化，这可能是与酒精滥用和酒精中毒相关的这条神经通路在结构和功能特性上显著变化的基础。
