Inserm, U1216, Univ. Grenoble Alpes, Grenoble Institut Neurosciences, 38000, Grenoble, France.
Inserm, U1216, Univ. Grenoble Alpes, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38000, Grenoble, France.
Mol Psychiatry. 2023 Jan;28(1):463-474. doi: 10.1038/s41380-022-01848-5. Epub 2022 Nov 14.
The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.
强迫性酒精使用的神经生物学机制，即酒精使用障碍的主要特征，仍然难以捉摸。动机过程的关键调节剂多巴胺（DA）被怀疑在这种病理中起着重要作用，但它的确切作用仍有待确定。在这里，我们发现表现出强迫性酒精使用的大鼠，即作为惩罚抵抗性自我给药的操作性定义，表现出多巴胺水平的下降，仅限于纹状体的背外侧区域，这是黑质纹状体多巴胺通路的主要输出结构。然后，我们通过因果关系证明，该通路的化学遗传诱导选择性低多巴胺能导致原本具有弹性的大鼠出现强迫性酒精自我给药，同时出现酒精戒断样动机损伤（即对自然奖励的动机受损）。最后，使用先前报道可纠正低多巴胺能状态的单胺稳定剂 OSU6162，可使易感性大鼠的强迫性酒精自我给药短暂减少。这些结果表明，紧张性黑质纹状体低多巴胺能状态在酒精成瘾中可能起着关键作用，并为我们理解强迫性酒精使用的神经生物学机制提供了新的见解。
