A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors
A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors
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DOI：
10.1016/j.celrep.2019.09.059
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发表时间：
2019-10-29
期刊：
影响因子：
8.8
通讯作者：
Alvarez, Veronica A.
中科院分区：
文献类型：
--
作者：
Bocarsly, Miriam E.;da Silva e Silva, Daniel;Alvarez, Veronica A.
酒精对人类和啮齿动物产生兴奋和镇静作用。在人类中，酒精滥用障碍与对酒精的较高兴奋反应和较低镇静反应有关。在这里，我们证明这种关联在小鼠中是保守的，并证明了与另一个责任因素的因果关系：纹状体多巴胺 D2 受体 (D2R) 的低表达。使用转基因小鼠品系，我们发现纹状体中型多棘神经元上 D2R 的选择性丢失增强了对乙醇刺激的敏感性，并产生了对乙醇镇静的抵抗力。这些小鼠还表现出更高的乙醇饮用偏好和升级，尽管出现了不良后果，但这种情况仍在继续。我们发现纹状体 D1R 激活是乙醇刺激所必需的，并且这种信号在纹状体 D2R 较低的小鼠中得到增强。这些数据证明了酗酒的两个脆弱因素之间的联系，并为低纹状体 D2R 触发 D1R 超敏性，最终导致强迫性饮酒的机制提供了证据。
Alcohol produces both stimulant and sedative effects in humans and rodents. In humans, alcohol abuse disorder is associated with a higher stimulant and lower sedative responses to alcohol. Here, we show that this association is conserved in mice and demonstrate a causal link with another liability factor: low expression of striatal dopamine D2 receptors (D2Rs). Using transgenic mouse lines, we find that the selective loss of D2Rs on striatal medium spiny neurons enhances sensitivity to ethanol stimulation and generates resilience to ethanol sedation. These mice also display higher preference and escalation of ethanol drinking, which continues despite adverse outcomes. We find that striatal D1R activation is required for ethanol stimulation and that this signaling is enhanced in mice with low striatal D2Rs. These data demonstrate a link between two vulnerability factors for alcohol abuse and offer evidence for a mechanism in which low striatal D2Rs trigger D1R hypersensitivity, ultimately leading to compulsive-like drinking.