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Chronic Social Isolation Stress during Peri-Adolescence Alters Presynaptic Dopamine Terminal Dynamics via Augmentation in Accumbal Dopamine Availability.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-10-16 , DOI: 10.1021/acschemneuro.8b00360 Anushree N Karkhanis 1 , Amy C Leach , Jordan T Yorgason 2 , Ayse Uneri , Samuel Barth , Farr Niere , Nancy J Alexander , Jeffrey L Weiner , Brian A McCool , Kimberly F Raab-Graham , Mark J Ferris , Sara R Jones
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-10-16 , DOI: 10.1021/acschemneuro.8b00360 Anushree N Karkhanis 1 , Amy C Leach , Jordan T Yorgason 2 , Ayse Uneri , Samuel Barth , Farr Niere , Nancy J Alexander , Jeffrey L Weiner , Brian A McCool , Kimberly F Raab-Graham , Mark J Ferris , Sara R Jones
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Chronic peri-adolescent stress in humans increases risk to develop a substance use disorder during adulthood. Rats reared in social isolation during peri-adolescence (aSI; 1 rat/cage) period show greater ethanol and cocaine intake compared to group housed (aGH; 4 rats/cage) rats. In addition, aSI rats have a heightened dopamine response in the nucleus accumbens (NAc) to rewarding and aversive stimuli. Furthermore, single pulse electrical stimulation in slices containing NAc core elicits greater dopamine release in aSI rats. Here, we further investigated dopamine release kinetics and machinery following aSI. Dopamine release, across a wide range of stimulation intensities and frequencies, was significantly greater in aSI rats. Interestingly, subthreshold intensity stimulations also resulted in measurable dopamine release in accumbal slices from aSI but not aGH rats. Extracellular [Ca2+] manipulations revealed augmented calcium sensitivity of dopamine release in aSI rats. The readily releasable pools of dopamine, examined by bath application of Ro-04-1284/000, a vesicular monoamine transporter 2 (VMAT2) inhibitor, were depleted faster in aGH rats. Western blot analysis of release machinery proteins (VMAT2, Synaptogyrin-3, Syntaxin-1, and Munc13-3) showed no difference between the two groups. Tyrosine hydroxylase (TH) protein expression levels, however, were elevated in aSI rats. The greater dopamine release could potentially be explained by higher levels of TH, the rate-limiting step for dopamine synthesis. This augmented responsivity of the dopamine system and heightened dopamine availability post-aSI may lead to an increased risk of addiction vulnerability.
中文翻译：
青春期周围的慢性社会隔离压力通过累积多巴胺的可利用性来改变突触前多巴胺的终末动态。
人类的长期青少年期应激会增加成年期发生物质使用障碍的风险。与成年圈养（aGH; 4只大鼠/笼）大鼠相比，在青春期（aSI; 1只大鼠/笼）期间处于社会隔离状态饲养的大鼠显示出更多的乙醇和可卡因摄入。此外，aSI大鼠在伏伏核（NAc）中对奖励和厌恶刺激的多巴胺反应增强。此外，在包含NAc核心的切片中单脉冲电刺激会引起aSI大鼠更大的多巴胺释放。在这里，我们进一步研究了aSI后的多巴胺释放动力学和机理。在广泛的刺激强度和频率范围内，多巴胺释放在aSI大鼠中明显更高。有趣的是，亚阈值强度刺激还导致可测量的aSI而非aGH大鼠的伏隔片中的多巴胺释放。细胞外[Ca2 +]操纵显示aSI大鼠多巴胺释放的钙敏感性增强。通过沐浴应用Ro-04-1284 / 000（一种水泡单胺转运蛋白2（VMAT2）抑制剂）检查的多巴胺易于释放池在aGH大鼠中耗竭更快。释放机制蛋白（VMAT2，Synaptogyrin-3，Syntaxin-1和Munc13-3）的蛋白质印迹分析表明，两组之间没有差异。然而，酪氨酸羟化酶（TH）蛋白表达水平在aSI大鼠中升高。多巴胺释放更多可能是由较高水平的TH（多巴胺合成的限速步骤）解释的。
更新日期：2018-10-04
中文翻译：
青春期周围的慢性社会隔离压力通过累积多巴胺的可利用性来改变突触前多巴胺的终末动态。
人类的长期青少年期应激会增加成年期发生物质使用障碍的风险。与成年圈养（aGH; 4只大鼠/笼）大鼠相比，在青春期（aSI; 1只大鼠/笼）期间处于社会隔离状态饲养的大鼠显示出更多的乙醇和可卡因摄入。此外，aSI大鼠在伏伏核（NAc）中对奖励和厌恶刺激的多巴胺反应增强。此外，在包含NAc核心的切片中单脉冲电刺激会引起aSI大鼠更大的多巴胺释放。在这里，我们进一步研究了aSI后的多巴胺释放动力学和机理。在广泛的刺激强度和频率范围内，多巴胺释放在aSI大鼠中明显更高。有趣的是，亚阈值强度刺激还导致可测量的aSI而非aGH大鼠的伏隔片中的多巴胺释放。细胞外[Ca2 +]操纵显示aSI大鼠多巴胺释放的钙敏感性增强。通过沐浴应用Ro-04-1284 / 000（一种水泡单胺转运蛋白2（VMAT2）抑制剂）检查的多巴胺易于释放池在aGH大鼠中耗竭更快。释放机制蛋白（VMAT2，Synaptogyrin-3，Syntaxin-1和Munc13-3）的蛋白质印迹分析表明，两组之间没有差异。然而，酪氨酸羟化酶（TH）蛋白表达水平在aSI大鼠中升高。多巴胺释放更多可能是由较高水平的TH（多巴胺合成的限速步骤）解释的。
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