Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence
Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence
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DOI：
10.1073/pnas.1506012113
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发表时间：
2016-03-15
影响因子：
11.1
通讯作者：
Hansson, Anita C.
中科院分区：
文献类型：
--
作者：
Hirth, Natalie;Meinhardt, Marcus W.;Hansson, Anita C.
成瘾研究中的一个主要假设是，酒精诱导中脑边缘多巴胺（DA）系统的神经适应，这些神经适应是强迫性药物使用和复发的关键神经化学事件。这些神经适应是否会导致戒断过程中多巴胺能水平低下或过高，这是成瘾研究人员之间长期存在的未解决的争论。这个答案对于理解成瘾行为的神经生物学机制至关重要。本研究旨在系统研究酒精依赖患者和大鼠在成瘾周期中DA系统的神经适应性变化。在人类酗酒者的死后大脑样本中，我们发现D1受体和DA转运蛋白（DAT）结合位点的强烈下调，但D2样受体结合不受影响。为了深入了解这些神经适应的时间过程，我们将人类数据与戒酒期间几个时间点的酒精依赖大鼠的数据进行了比较。在戒断3周内，D_1和DAT呈动态变化。第三周后，大鼠的数据反映了我们的人类数据。这个时间点的特点是细胞外DA水平升高，缺乏对D1刺激的突触反应，和增强的运动活动。进一步的功能性证据是由多巴胺能亢进的遗传大鼠模型提供的，该模型类似于长期戒酒期间酒精依赖大鼠的表型。总之，我们提供了一个新的动态模型的禁欲相关的变化在纹状体DA系统，在这个模型中，高多巴胺能状态在长期禁欲与复发的脆弱性。
A major hypothesis in addiction research is that alcohol induces neuroadaptations in the mesolimbic dopamine (DA) system and that these neuroadaptations represent a key neurochemical event in compulsive drug use and relapse. Whether these neuroadaptations lead to a hypo-or hyperdopaminergic state during abstinence is a long-standing, unresolved debate among addiction researchers. The answer is of critical importance for understanding the neurobiological mechanism of addictive behavior. Here we set out to study systematically the neuroadaptive changes in the DA system during the addiction cycle in alcohol-dependent patients and rats. In postmortem brain samples from human alcoholics we found a strong down-regulation of the D1 receptor-and DA transporter (DAT)-binding sites, but D2-like receptor binding was unaffected. To gain insight into the time course of these neuroadaptations, we compared the human data with that from alcohol-dependent rats at several time points during abstinence. We found a dynamic regulation of D1 and DAT during 3 wk of abstinence. After the third week the rat data mirrored our human data. This time point was characterized by elevated extracellular DA levels, lack of synaptic response to D1 stimulation, and augmented motor activity. Further functional evidence is given by a genetic rat model for hyperdopaminergia that resembles a phenocopy of alcohol-dependent rats during protracted abstinence. In summary, we provide a new dynamic model of abstinence-related changes in the striatal DA system; in this model a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse.