Vengeliene Valentina, Leonardi-Essmann Fernando, Perreau-Lenz Stephanie, Gebicke-Haerter Peter, Drescher Karla, Gross Gerhard, Spanagel Rainer
Department of Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany.
FASEB J. 2006 Nov;20(13):2223-33. doi: 10.1096/fj.06-6110com.
Our study aimed to identify new candidate genes, which might be involved in alcohol craving and relapse. To find changes in gene expression after long-term alcohol consumption, we studied gene expression profiles in the striatal dopamine system by using DNA microarrays of two different alcohol-preferring rat lines (HAD and P). Our data revealed an up-regulation of the dopamine D3 receptor (D3R) after 1 yr of voluntary alcohol consumption in the striatum of alcohol preferring rats that was confirmed by qRT-polymerase chain reaction. This finding was further supported by the finding of up-regulated striatal D3R mRNA in nonselected Wistar rats after long-term alcohol consumption when compared with age-matched control animals. We further examined the role of the D3R in mediating alcohol relapse behavior using the alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats and the model of cue-induced reinstatement of alcohol-seeking behavior using the selective D3R antagonist SB-277011-A (0, 1, 3, and 10 mg/kg) and the partial agonist BP 897 (0, 0.1, 1, and 3 mg/kg). Both treatments caused a dose-dependent reduction of relapse-like drinking in the ADE model as well as a decrease in cue-induced ethanol-seeking behavior. We conclude that long-term alcohol consumption leads to an up-regulation of the dopamine D3R that may contribute to alcohol-seeking and relapse. We therefore suggest that selective antagonists of this pharmacological target provide a specific treatment approach to reduce alcohol craving and relapse behavior.
我们的研究旨在识别可能与酒精渴望和复发有关的新候选基因。为了发现长期饮酒后基因表达的变化，我们通过使用两种不同的嗜酒大鼠品系（HAD和P）的DNA微阵列，研究了纹状体多巴胺系统中的基因表达谱。我们的数据显示，在自愿饮酒1年后，嗜酒大鼠纹状体中的多巴胺D3受体（D3R）上调，这一结果通过定量逆转录聚合酶链反应得到证实。与年龄匹配的对照动物相比，长期饮酒后的非选择Wistar大鼠纹状体中D3R mRNA上调的发现进一步支持了这一结果。我们进一步使用长期饮酒的Wistar大鼠的酒精剥夺效应（ADE）模型以及使用选择性D3R拮抗剂SB-277011-A（0、1、3和10 mg/kg）和部分激动剂BP 897（0、0.1、1和3 mg/kg）的线索诱导的酒精觅求行为恢复模型，研究了D3R在介导酒精复发行为中的作用。两种处理均导致ADE模型中复发样饮酒的剂量依赖性减少以及线索诱导的乙醇觅求行为的减少。我们得出结论，长期饮酒导致多巴胺D3R上调，这可能有助于酒精觅求和复发。因此，我们建议针对这一药理学靶点的选择性拮抗剂提供一种减少酒精渴望和复发行为的特异性治疗方法。
