Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release.
Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release.
复制标题
DOI：
10.7554/elife.80747
复制
发表时间：
2022-08-22
期刊：
影响因子：
7.7
通讯作者：
Liu, Qing-song
中科院分区：
文献类型：
--
作者：
Liu, Xiaojie;Vickstrom, Casey R.;Yu, Hao;Liu, Shuai;Snarrenberg, Shana Terai;Friedman, Vladislav;Mu, Lianwei;Chen, Bixuan;Kelly, Thomas J.;Baker, David A.;Liu, Qing-song
反复暴露于药物滥用导致中脑边缘多巴胺系统cAMP信号上调，这一分子适应被认为在药物依赖的发展中起关键作用。由cAMP直接激活的交换蛋白（Epac2）是cAMP在大脑中大量表达的主要效应蛋白。然而，尚不清楚Epac2是否有助于可卡因强化。在这里，我们报告了中边缘多巴胺系统中的Epac2通过增强多巴胺释放来促进可卡因强化。从中脑多巴胺神经元（Epac2- cko）中有条件敲除Epac2和选择性Epac2抑制剂ESI-05，在固定比例和渐进比例强化计划下以及在大范围的可卡因剂量下，小鼠的可卡因自我给药减少。此外，Epac2- cko导致诱发多巴胺释放减少，而Epac2激动作用在体外增强伏隔核多巴胺释放。该机制是Epac2破坏行为影响的核心，因为通过去氯氯氮平（DCZ）诱导Gs-DREADD激活的腹侧被盖区（VTA）多巴胺神经元的化学发生刺激增加了多巴胺释放，逆转了Epac2- cko小鼠可卡因自我给药的损害。相反，Gi-DREADD对VTA多巴胺神经元的化学发生抑制减少了野生型小鼠的多巴胺释放和可卡因自我给药。因此，epac2介导的多巴胺释放增强可能代表了一种有助于可卡因强化的新颖而强大的机制。
Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.
影响因子：
2.5
作者：
Chen R;McIntosh S;Hemby SE;Sun H;Sexton T;Martin TJ;Childers SR
通讯作者：
Childers SR