The protective effect of volitional social interaction on drug addiction

项目摘要 尽管在了解成瘾的回路和分子机制方面取得了很大进展，但治疗方案 基本保持不变。这一僵局至少部分是由于结构和预测性方面的限制。 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、不利的社会交往和社会隔离促进了药物自我管理和复发，而 社交互动往往具有保护性。我最近开发了一种可操作的大鼠模型，可以在药物之间进行选择 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 揭示了两个主要发现：(1)与毒品相比，大鼠更喜欢操作性社交；(2)社交选择-- 诱导的自愿禁欲可以防止对甲基苯丙胺(Meth)的渴望。这种保护作用 与中央杏仁核外侧部(CEL)蛋白激酶Cδ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，这项建议的目的是研究(1) 社会奖励对蛋氨酸渴求孵化保护作用的环路机制 社会互动与Meth选择的神经编码机制。在K99阶段，我将 探讨社会回报对蛋氨酸渴求孵化的保护作用机制。这将是 使用shRNA病毒构建物选择性地击倒pkcδ或我最近开发的sOM来实现 合作者梅辛博士。此外，在勋鲍姆博士(我的共同导师)的指导下，我将使用 单单位记录，以调查社会奖赏偏好的神经基础。 我将重点介绍眶前叶皮质，因为它在联想学习和决策中起着关键作用。 在R00阶段，我将使用我在博士后培训期间学到的技术和K99 进一步描述社会相互作用对孵化的保护作用的回路机制 对毒品的渴望和毒品的选择。拟议的培训将使我能够发展未来的独立研究 旨在确定社会因素在吸毒成瘾中作用的潜在机制的计划。

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.