Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration.
Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration.
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DOI：
10.1016/j.biopsych.2019.10.019
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发表时间：
2020-06-01
影响因子：
10.6
通讯作者：
Lobo MK
中科院分区：
文献类型：
--
作者：
Engeln M;Mitra S;Chandra R;Gyawali U;Fox ME;Dietz DM;Lobo MK
我们以前发现，可卡因暴露24小时后，转录因子早期生长反应3(Egr3)在伏核(NAC)细胞亚型中被反向调控，并双向调节雄性啮齿类动物的可卡因相关行为。在药物暴露前，在含有D2受体的中棘神经元(D2-MSN)中过表达Egr3会减少可卡因的奖赏和精神运动敏化效应。然而，目前尚不清楚Egr3是否在NAC的长期神经适应和对可卡因寻求的复发中发挥作用。我们测定了10周龄SD大鼠和C57BL/6小鼠在强制静脉注射可卡因20天后NAC中EGR3蛋白的水平。在8-10周龄的A2a-Cre小鼠中，我们利用病毒介导的Egr3在NAC D2-MSN中过表达，以测试Egr3在寻找、消退和药物诱导的可卡因自我给药恢复过程中对操作反应的作用。为了评估Egr3是否是导致可卡因复发的性别差异的原因，我们在雄性和雌性啮齿动物身上进行了这些程序。我们发现，只有在强制禁欲20天后，EGR3的表达才会在女性中减少。此外，我们还表明，我们在小鼠身上的自我给药范例概括了人类和大鼠在可卡因摄入量和复发方面的性别差异。最后，虽然强制禁欲期间D2-MSN中Egr3的过度表达促进了雌性小鼠的灭绝和钝化药物诱导的恢复，但在雄性小鼠中却有相反的效果。我们表明，即刻早期基因Egr3对药物相关行为具有长期影响。我们的工作表明，D2-MSN中Egr3表达的变化有助于可卡因复发的性别差异。
We previously showed the transcription factor Early Growth Response 3 (Egr3) is oppositely regulated in nucleus accumbens (NAc) cell subtypes 24 hours following cocaine exposure and bidirectionally mediates cocaine-related behaviors in male rodents. Overexpressing Egr3 in D2 receptor-containing medium spiny neurons (D2-MSNs) prior to drug exposure reduces the rewarding and psychomotor sensitization effects of cocaine. However, it is unknown if Egr3 plays a role in long-term neuroadaptations in the NAc and relapse to cocaine seeking. We measured EGR3 protein levels in the NAc following 20 days of forced abstinence from intravenous cocaine self-administration in 10 week-old Sprague-Dawley rats and C57BL/6 mice. In 8–10 week-old A2A-Cre mice, we used virally mediated Egr3 overexpression in NAc D2-MSNs to test the role of Egr3 on operant responding during seeking, extinction and drug-induced reinstatement of cocaine self-administration. To evaluate if Egr3 contributed to sex-differences to cocaine relapse, we conducted these procedures in both male and female rodents. We found that EGR3 expression was reduced only in females after 20 days of forced abstinence. Additionally, we showed that our self-administration paradigm in mice recapitulates the sex-differences in cocaine intake and relapse demonstrated in humans and rats. Finally, while Egr3 overexpression in D2-MSNs during forced abstinence facilitated extinction and blunted drug-induced reinstatement in females, it had the opposite effect in male mice. We show that the immediate early gene Egr3 has long-term effects on drug-related behaviors. Our work suggests that changes in Egr3 expression in D2-MSNs contributes to sex-differences in cocaine relapse.
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影响因子：
11
作者：
Francis TC;Chandra R;Gaynor A;Konkalmatt P;Metzbower SR;Evans B;Engeln M;Blanpied TA;Lobo MK
通讯作者：
Lobo MK
影响因子：
11
作者：
Fox ME;Chandra R;Menken MS;Larkin EJ;Nam H;Engeln M;Francis TC;Lobo MK
通讯作者：
Lobo MK
影响因子：
3.5
作者：
Li, Lin;Yun, Sung Hwan;Tourtellotte, Warren G.
通讯作者：
Tourtellotte, Warren G.
影响因子：
4
作者：
Kumbrink, Joerg;Kirsch, Kathrin H.;Johnson, Judith P.
通讯作者：
Johnson, Judith P.
影响因子：
1.7
作者：
Greenfield, Shelly F.;Back, Sudie E.;Lawson, Katie;Brady, Kathleen T.
通讯作者：
Brady, Kathleen T.