Neural mechanisms regulating cocaine consumption

摘要 可卡因滥用仍然是公共卫生的主要负担，大量过量死亡 每年。这项拟议中的工作描述了作为药物增加基础的神经回路。 一些人在长期吸毒后进行的消费。此应用程序利用 以前的工作表明促肾上腺皮质激素释放因子(CRF)、强啡肽和多巴胺 信号可以单独影响药物的摄取，这些系统中的每一个都会随着慢性疾病的改变而改变 可卡因的使用。具体地说，拟议的实验询问这三个神经调节系统是如何 在规范药品消费中相互作用。工作假说是，升级 慢性药物使用后的药物摄入量是通过一系列途径发生的，其中CRF升高 水平会导致强啡肽的增加，从而减少多巴胺的释放，产生 升级。然而，这些实验旨在系统地测试功能连接 在这些结节之间的可卡因摄入量的调节，并在这样做，辨别之间的八个 相互作用的竞争模型。因此，无论结果是否与工作相匹配 不管是否假设，这些实验将对这些系统之间的相互作用产生新的见解。 这一信息将为控制药物滥用者摄入量的潜在治疗目标提供信息，并 从而减少伤害。

Abstract Cocaine abuse remains a major burden on public health with significant numbers of overdose deaths each year. The proposed work characterizes a neural circuit that underlies the increased drug consumption that takes place by some individuals following chronic drug use. This application leverages previous work demonstrating that corticotropin releasing factor (CRF), dynorphin and dopamine signaling can individually impact drug intake and that each of these systems changes with chronic cocaine use. Specifically, the proposed experiments ask how these three neuromodulatory systems interact with each other in the regulation drug consumption. The working hypothesis is that escalation of drug intake following chronic drug use, comes about through a serial pathway where elevated CRF levels causes an increase in dynorphin which consequently reduces dopamine release, producing escalation. However, the experiments are designed to systematically test the functional connections between each of these nodes in the regulation of cocaine intake and, in doing so, discern between eight competing models of the interactions. Therefore, regardless, of whether the results match the working hypothesis or not, the experiments will yield new insight into the interactions between these systems. This information will inform potential treatment targets for moderating intake in substance abusers and thereby reducing harm.