Ericson M, Blomqvist O, Engel J A, Söderpalm B
Department of Pharmacology, Göteborg University, Sweden.
Eur J Pharmacol. 1998 Oct 9;358(3):189-96. doi: 10.1016/s0014-2999(98)00602-5.
The mesocorticolimbic dopamine system is believed to be involved in mediating the positive reinforcing effects of drugs of abuse, including ethanol. The nicotinic acetylcholine receptor antagonist mecamylamine perfused via reversed microdialysis in the ventral tegmental area antagonizes the increase of accumbal extracellular dopamine levels after systemic ethanol, and, after systemic injection, lowers ethanol intake in the rat. In the present study the effect of ventral tegmental mecamylamine on ethanol intake and preference, as well as on extracellular accumbal dopamine levels, was investigated in the same animal. To this end, in vivo microdialysis using a double probe approach (one in the nucleus accumbens and one in the ventral tegmental area) was combined with an ethanol preference model invoking a free choice between a bottle of water and a bottle of ethanol 6% (v/v) solution. Wistar rats drinking more than 60% of their total daily fluid intake from the ethanol solution (ethanol high-preferring animals) were selected during a screening period and used for the experiments. The animals received vehicle or mecamylamine (100 microM) in the ventral tegmental area and were then presented with a choice between water and ethanol in a limited access paradigm to which they previously had been adapted. On the next day the rats that received vehicle day 1 now received mecamylamine, and vice versa. When treated with vehicle, ethanol intake and preference were unaltered, as compared to baseline behavior, and accumbal dopamine levels increased significantly to approximately 130% of the pre-drug baseline level. When receiving mecamylamine, ethanol intake and preference were reduced markedly and dopamine levels were unaltered, as compared to pre-drug baseline levels. The present results further indicate that nicotinic acetylcholine receptors in the ventral tegmental area are involved in the positive reinforcing effects of ethanol. Thus, mecamylamine or other antagonists specifically aimed at ventral tegmental nicotinic acetylcholine receptors could represent a new pharmacological treatment principle against alcohol abuse, the efficacy of which should be explored in high-scale alcohol consumers or alcoholics.
中脑皮质边缘多巴胺系统被认为参与介导包括乙醇在内的滥用药物的正性强化作用。通过反向微透析灌注到腹侧被盖区的烟碱型乙酰胆碱受体拮抗剂美加明，可拮抗全身给予乙醇后伏隔核细胞外多巴胺水平的升高，并且在全身注射后可降低大鼠的乙醇摄入量。在本研究中，在同一动物身上研究了腹侧被盖区美加明对乙醇摄入量和偏好以及伏隔核细胞外多巴胺水平的影响。为此，采用双探针方法（一个置于伏隔核，一个置于腹侧被盖区）进行体内微透析，并结合乙醇偏好模型，该模型允许动物在一瓶水和一瓶6%（v/v）乙醇溶液之间自由选择。在筛选期选择每日总液体摄入量超过60%来自乙醇溶液的Wistar大鼠（乙醇高偏好动物）用于实验。动物在腹侧被盖区接受载体或美加明（100 microM），然后在它们先前已适应的有限接触范式中在水和乙醇之间进行选择。第二天，第1天接受载体的大鼠现在接受美加明，反之亦然。与基线行为相比，给予载体时，乙醇摄入量和偏好未改变，伏隔核多巴胺水平显著增加至给药前基线水平的约130%。与给药前基线水平相比，接受美加明时，乙醇摄入量和偏好明显降低，多巴胺水平未改变。目前的结果进一步表明，腹侧被盖区的烟碱型乙酰胆碱受体参与了乙醇的正性强化作用。因此，美加明或其他专门针对腹侧被盖区烟碱型乙酰胆碱受体的拮抗剂可能代表一种针对酒精滥用的新药理学治疗原则，其疗效应在大量饮酒者或酗酒者中进行探索。
