Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors
Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors
复制标题
DOI：
10.1016/s0014-2999(03)01564-4
复制
发表时间：
2003-04-25
影响因子：
5
通讯作者：
Söderpalm, B
中科院分区：
文献类型：
--
作者：
Ericson, M;Molander, A;Söderpalm, B
先前已证明，灌注在腹侧被盖区（VTA）的中枢烟碱乙酰胆碱受体拮抗剂美加明抵消了全身乙醇后，通过体内微透析测定的丘脑核细胞外多巴胺水平的升高。在本研究中，我们研究了不同浓度的乙醇局部灌注在腹侧被盖区或延髓核细胞外多巴胺水平的影响。在腹侧被盖区灌注乙醇（10 - 1000 mM）不影响延髓核的多巴胺输出。然而，乙醇（300 mM）灌注在丘脑核增加多巴胺水平，以大约相同的程度（30%）后观察到全身乙醇，而乙醇（1000 mM）减少多巴胺输出约50%。其次，假设内源性乙酰胆碱是必需的增加多巴胺水平乙醇后受到挑战。结果表明，在用vesamicol（一种囊泡乙酰胆碱储存的有效抑制剂）预处理的动物中，延髓核中的乙醇（300 mM）未能提高细胞外多巴胺水平。同样，在动物的腹侧被盖区灌注美加明，但在丘脑核中没有，丘脑核中的乙醇（300 mM）未能增加丘脑多巴胺水平。然而，尽管在VTA中灌注二氢-p-赤藓定（烟碱受体亚型α 4 β 2的拮抗剂）阻止了全身尼古丁后多巴胺的增加，但拮抗剂无法阻止乙醇的多巴胺升高作用。最后，为了研究美加明是否通过与NMDA受体MK-801的相互作用对乙醇诱导的伏隔多巴胺水平发挥拮抗作用，检查了原型NMDA受体拮抗剂的作用，并与美加明的作用进行了比较。在VTA中灌注后，MK-801自身增强了多巴胺水平，但不拮抗乙醇的增强作用。目前的一组实验表明，中脑边缘多巴胺激活乙醇的影响可能是由于一个间接的，而不是直接激活腹侧被盖烟碱乙酰胆碱受体的亚型组成不同的α 4 β 2。乙醇升高多巴胺的主要作用部位可能位于丘脑外侧核或其附近区域。(C)出版社：Elsevier Science B.V.
It was previously demonstrated that the central nicotinic acetylcholine receptor antagonist mecamylamine perfused in the ventral tegmental area (VTA) counteracts the elevation of extracellular dopamine levels in the nucleus accumbens after systemic ethanol, as measured by in vivo microdialysis. In the present study we investigated the effect of different concentrations of ethanol perfused locally in the VTA or in the nucleus accumbens on extracellular accumbal dopamine levels. Ethanol (10-1000 mM) perfused in the VTA did not influence dopamine output in the nucleus accumbens. However, ethanol (300 mM) perfused in the nucleus accumbens increased accumbal dopamine levels to approximately the same extent (30%) as observed after systemic ethanol, whereas ethanol (1000 mm) decreased the dopamine output by approximately 50%. Next, the hypothesis that endogenous acetylcholine is required for the increased accumbal dopamine levels after ethanol was challenged. It was shown that in animals pre-treated with vesamicol, a potent inhibitor of vesicular acetylcholine storage, ethanol (300 mM) in the nucleus accumbens failed to elevate extracellular accumbal dopamine levels. Similarly, in animals perfused with mecamylamine in the VTA, but not in the nucleus accumbens, ethanol in the nucleus accumbens (300 mM) failed to increase accumbal dopamine levels. However, whereas dihydro-p-erythroidine (antagonist for the nicotinic receptor subtype alpha4beta2) perfused in the VTA prevented the increase in accumbal dopamine after systemic nicotine, the antagonist was unable to prevent the dopamine elevating effects of ethanol. Finally, to investigate whether mecamylamine exerts its antagonizing effect of ethanol induced accumbal dopamine levels through an interaction with the NMDA receptor MK-801, the effects of the prototypic NMDA receptor antagonist were examined and compared to those of mecamylamine. After perfusion in the VTA, MK-801 enhanced accumbal dopamine levels by itself but did not antagonize the enhancing effect of ethanol. The present set of experiments indicate that the mesolimbic dopamine activating effects of ethanol may be due to an indirect rather than direct activation of ventral tegmental nicotinic acetylcholine receptors of a subtype composition different from the alpha4beta2. Furthermore, it is argued that the primary site of action of ethanol in its accumbal dopamine elevating effect may be located to the nucleus accumbens or nearby regions. (C) 2003 Published by Elsevier Science B.V.