Abstract

Stress during adolescence has profound effects on the onset and severity of substance use later in life. However, not everyone with adverse experiences during this period will go on to develop a substance use disorder in adulthood, and the factors that alter susceptibility to substance use remain unknown. Here, we investigated individual differences in response to stress and drugs of abuse using our selectively bred high-responder (bHR) and low-responder (bLR) rats. These animals model extremes of temperamental tendencies and differ dramatically in both stress responsiveness and addiction-related traits. The present study investigated how environmental interventions in the form of a chronic variable stress (CVS) regimen in early adolescence interact with the bHR/bLR phenotype to alter behavioral sensitization to cocaine in adulthood. We also determined whether accumbal dopamine signaling is involved in the interaction of stress history and cocaine by assessing the mRNA levels of dopamine D1 (D1R) and D2 (D2R) receptors. Our results showed that CVS history alone had enduring and phenotype-specific effects on accumbal dopamine signaling. Importantly, adolescent stress had opposing effects in the two lines- decreasing the locomotor response to cocaine challenge in bHRs but increasing this measure in bLRs. Moreover, these opposing effects on cocaine sensitivity following adolescent CVS were accompanied by parallel effects in the accumbal dopamine system, with prior stress and cocaine exposure interacting to decrease D2R mRNA in bHRs but increase it in bLRs. Overall, these findings indicate that environmental challenges encountered in adolescence interact with genetic background to alter vulnerability to cocaine later in life.

• Lay Summary

• Stress experienced during adolescence affects the onset and severity of drug dependence later in life. However, not everyone with adverse experiences during this period will go on to develop SUD in adulthood. Using a rat model of innate differences in emotional reactivity, this study shows that the interplay between individual temperament and previous experience of adolescent stress/trauma determines whether an individual will be vulnerable or resilient to develop SUDs later in life. In addition, the present study shows that the dopamine D2 receptor in the brain’s reward center, nucleus accumbens, may be implicated in this interplay.

摘要

青春期的压力对以后生活中物质使用的发生和严重程度有深远的影响。然而，并非所有在此期间有不良经历的人都会在成年后继续发展为物质使用障碍，并且改变对物质使用易感性的因素仍然未知。在这里，我们使用选择性繁殖的高反应者 (bHR) 和低反应者 (bLR) 大鼠调查了个体对压力和滥用药物反应的差异。这些动物模仿极端的气质倾向，并且在压力反应和成瘾相关特征方面存在显着差异。本研究调查了青春期早期慢性可变应激 (CVS) 方案形式的环境干预如何与 bHR/bLR 表型相互作用，从而改变成年期对可卡因的行为敏感性。我们还通过评估多巴胺 D1 (D1R) 和 D2 (D2R) 受体的 mRNA 水平来确定累积多巴胺信号传导是否参与应激史和可卡因的相互作用。我们的结果表明，单独的 CVS 病史对 accumbal 多巴胺信号传导具有持久和表型特异性的影响。重要的是，青春期压力在两条线中有相反的影响——降低 bHRs 中对可卡因挑战的运动反应，但增加 bLRs 中的这种措施。此外，这些对青少年 CVS 后可卡因敏感性的相反影响伴随着累积多巴胺系统的平行效应，先前的压力和可卡因暴露相互作用以减少 bHRs 中的 D2R mRNA，但增加 bLRs 中的 D2R mRNA。全面的，

• 外行摘要

• 青春期经历的压力会影响日后药物依赖的发生和严重程度。然而，并非所有在此期间有过不良经历的人都会在成年后继续发展 SUD。本研究使用情绪反应先天差异的大鼠模型，表明个体气质与以前的青春期压力/创伤经历之间的相互作用决定了个体在以后的生活中是否容易或有弹性地发展成 SUD。此外，本研究表明大脑奖赏中心伏隔核中的多巴胺 D2 受体可能与这种相互作用有关。