DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking
DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking
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DOI：
10.1097/01.alc.0000125270.30501.08
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发表时间：
2004-05-01
影响因子：
3.2
通讯作者：
Volkow, ND
中科院分区：
文献类型：
--
作者：
Thanos, PK;Taintor, NB;Volkow, ND
背景：使用腺病毒载体在伏隔核（NAc）中短暂过表达多巴胺D2受体（DRD2）基因与Sprague Dawley大鼠酒精摄入量的显著减少有关。在两瓶选择范式中，DRD2的过度表达减少了酒精消耗，并支持了高水平DRD2可能对酒精滥用有保护作用的观点。方法：采用有限通道（1小时）两瓶选择（水与10%乙醇）饮用模式，我们检测了DRD2载体对遗传近亲繁殖的酒精偏好(P)和非偏好（NP）大鼠酒精摄入的影响。此外，在研究结束时，使用微正电子发射断层成像来评估乙醇暴露对两组之间DRD2水平的体内慢性（7周）影响。结果：用DRD2载体（在NAc中）处理的P大鼠的酒精偏好（减少37%）和摄入量（减少48%）显著降低，这些措施在第20天恢复到预处理水平。在NP大鼠中观察到类似的行为模式（酒精饮用的衰减）。慢性（7周）暴露于乙醇后的[C-11]氯氯pride微正电子发射断层扫描数据分析显示，11和NP大鼠之间的DRD2结合存在明显差异。与NP大鼠相比，P大鼠纹状体中[C-11]raclopride特异性结合降低16%。结论：这些发现进一步支持了我们的假设，即高水平的DRD2与饮酒减少有因果关系，并可能作为防止酒精中毒的保护因素。这种效应在P大鼠身上被发现，P大鼠本来就有酒精摄入的倾向，这表明它们甚至对那些遗传上有高酒精摄入倾向的人也有保护作用。值得注意的是，增加DRD2可显著减少酒精摄入量，但并不能完全消除它，这表明高DRD2水平可能会特别干扰大量酒精的摄入。7周后，NP大鼠的DRD2浓度明显高于P大鼠，因此可以解释低酒精摄入量的原因。
Background: Transient overexpression of the dopamine D2 receptor (DRD2) gene in the nucleus accumbens (NAc) using an adenoviral vector has been associated with a significant decrease in alcohol intake in Sprague Dawley rats. This overexpression of DRD2 reduced alcohol consumption in a two-bottle-choice paradigm and supported the view that high levels of DRD2 may be protective against alcohol abuse.Methods: Using a limited access (1 hr) two-bottle-choice (water versus 10% ethanol) drinking paradigm, we examined the effects of the DRD2 vector in alcohol intake in the genetically inbred alcohol-preferring (P) and -nonpreferring (NP) rats. In addition, micro-positron emission tomography imaging was used at the completion of the study to assess in vivo the chronic (7 weeks) effects of ethanol exposure on DRD2 levels between the two groups.Results: P rats that were treated with the DRD2 vector (in the NAc) significantly attenuated their alcohol preference (37% decrease) and intake (48% decrease), and these measures returned to pretreatment levels by day 20. A similar pattern of behavior (attenuation of ethanol drinking) was observed in NP rats. Analysis of the [C-11]raclopride micro-positron emission tomography data after chronic (7 weeks) exposure to ethanol revealed clear DRD2 binding differences between the 11 and NP rats. P rats showed 16% lower [C-11]raclopride specific binding in striatum than the NP rats.Conclusions: These findings further support our hypothesis that high levels of DRD2 are causally associated with a reduction in alcohol consumption and may serve as a protective factor against alcoholism. That this effect was seen in P rats, which are predisposed to alcohol intake, suggests that they are protective even in those who are genetically predisposed to high alcohol intake. It is noteworthy that increasing DRD2 significantly decreased alcohol intake but did not abolish it, suggesting that high DRD2 levels may specifically interfere with the administration of large quantities of alcohol. The significantly higher DRD2 concentration in NP than P rats after 7 weeks of ethanol therefore could account for low alcohol intake.