The protective effect of volitional social interaction on drug addiction

项目摘要 尽管在理解成瘾的电路和分子机制方面取得了进展， 基本保持不变。这种僵局至少部分是由于结构和预测的局限性 成瘾动物模型的有效性，很少纳入社会因素。在人类和实验室中 动物、不良的社会交往和社会隔离促进了药物自我给药和复发， 社会互动往往是保护性的。我最近开发了一个可操作的老鼠模型 和社会互动，并显示了后者对成瘾的深刻保护作用。我的研究 揭示了两个主要的发现：（1）大鼠强烈喜欢操作性社会互动超过药物，（2）社会选择- 诱导自愿禁欲防止甲基苯丙胺（甲基）渴望的孵化。这种保护作用 与中央杏仁核外侧部（CeL）PKCδ的激活有关（通过双标记 Fos与PKCδ）。相反，在家庭强制禁欲后，渴望的孵化与 选择性募集细胞生长抑素（SOM）神经元。因此，本建议的目的是研究（1） 社会奖励对甲基苯丙胺渴求孵化的保护作用的电路机制，以及（2） 社会互动与冰毒选择的神经编码机制。在K99阶段，我将 探讨了社会奖励对甲基苯丙胺渴求潜伏期保护作用的细胞学机制。这将 使用shRNAs病毒构建体来选择性地敲低PKCδ或SOM， 合作者梅辛博士此外，在Schoenbaum博士（我的共同导师）的指导下，我将使用 单单位记录调查的神经基板的偏好社会奖励超过甲基。 我将重点讨论眶额皮层，因为它在联想学习和决策中起着关键作用。 在R 00阶段，我将使用我在博士后培训和K99期间学到的技术 阶段，以进一步表征社会互动对孵化的保护作用的电路机制 对药物的渴望和选择拟议的培训将使我能够发展未来的独立研究 该计划旨在确定社会因素在吸毒成瘾中的作用机制。

Project Summary Despite strides towards understanding circuit and molecular mechanisms of addiction, treatment options remain largely unchanged. This impasse is at least partly due to limitations in the construct and predictive validity of animal models of addiction, which rarely incorporate social factors. In both humans and laboratory animals, adverse social interactions and social isolation promote drug self-administration and relapse, while social interactions tend to be protective. I recently developed an operant rat model of choice between drugs and social interaction and showed the profound protective effects of the latter on addiction. My research revealed two major findings: (1) rats strongly prefer operant social interaction over drugs, and (2) social choice- induced voluntary abstinence prevents incubation of methamphetamine (Meth) craving. This protective effect was associated with activation of PKCδ in central amygdala lateral part (CeL) (assessed by double-labeling of Fos with PKCδ). In contrast, after homecage forced abstinence, incubation of craving was associated with selective recruitment of CeL-somatostatin (SOM) neurons. Therefore, the aim of this proposal is to study (1) the circuit mechanisms underlying the protective effect of social reward on incubation of Meth craving, and (2) the neural encoding mechanisms of the social interaction versus Meth choice. During the K99 phase, I will investigate a CeL mechanism of the protective effect of social reward on incubation of Meth craving. This will be achieved using shRNAs viral constructs to selectively knockdown PKCδ or SOM recently developed by my collaborator Dr. Messing. Additionally, under the guidance of Dr. Schoenbaum (my co-mentor), I will use single-unit recording to investigate the neural substrates underlying the preference for social reward over Meth. I will focus on the orbitofrontal cortex because of its critical role in associative learning and decision-making. During the R00 phase, I will use the techniques I have learned during my post-doctoral training and the K99 phase to further characterize the circuit mechanisms of the protective effect of social interaction on incubation of drug craving and drug choice. The proposed training will allow me to develop a future independent research program geared towards identifying mechanisms underlying the role of social factors in drug addiction.