Role of specific cortico-basal ganglia pathways in animal models of addiction

描述(申请人提供)：皮质-基底节系统是一个复杂的网络，涉及动机和奖励。纹状体内的中棘投射神经元(MSN)是该环路的主要中继站，通过两条不同的通路引导行为输出。含有神经肽强啡肽(Dyn)和P物质的纹状体MSN是直接通路的一部分，而含有神经肽脑啡肽(ENK)的纹状体神经元是间接通路的一部分。反复接触滥用药物可导致皮质-基底神经节回路的失调，部分原因是皮质下结构(如纹状体)的异常可塑性，以及谷氨酸能传入系统自上而下的控制丧失。直接和间接纹状体MSN最近被证明在精神刺激药物产生的行为中发挥着重要但不同的作用。然而，对于这些不同的细胞群体以及它们的传入联系在产生以成瘾为特征的强迫吸毒和寻求毒品模式的模型中所起的作用，人们知之甚少，例如长期接触药物自我给药。此外，这些纹状体细胞群中的信号活动如何在强迫症后发生变化 药物使用以及对类似成瘾行为的监管还没有被很好地理解。本实验的总体目标是使用新型病毒载体表达DREADD(Designer Reptor，由Designer Drug独占激活)受体，以确定直接和间接途径MSN以及谷氨酸能传入在强迫服药和寻找药物行为中的作用。此外，药物使用的强迫模式如何改变纹状体细胞群体中的细胞内信号活动也将被研究。这一建议的中心假设是，重复使用药物会对一部分人的纹状体G蛋白依赖信号级联产生谷氨酸依赖的修饰，导致强迫性、成瘾性行为(定义为吸毒的高动机，以及在无法获得药物期间和惩罚期间的寻求药物)。具体地说，我们认为ERK/MAPK信号级联在直接途径MSN中被增强，在间接途径MSN中被抑制，从而使这些途径的平衡向GO驱动转移，从而增加药物的摄取和寻找。这项工作有可能确定新的治疗靶点(即特定的细胞群体或传入投射)，以及可能逆转成瘾行为的新类型的治疗，例如DREADD受体对细胞内信号级联的调节。

DESCRIPTION (provided by applicant): The cortico-basal ganglia system is a complex network involved in motivation and reward. Medium spiny projection neurons (MSNs) within the striatum serve as the primary relay station of this circuit, and guide behavioral output through two divergent pathways. Striatal MSNs that contain the neuropeptides dynorphin (DYN) and substance P are part of the direct pathway whereas striatal neurons that contain the neuropeptide enkephalin (ENK) are part of the indirect pathway. Repeated exposure to drugs of abuse can produce dysregulation in the cortico-basal ganglia circuit, in part through aberrant plasticity at sub-cortical structures, such as the striatum, as well as through a loss of top-down control from glutamatergic afferent systems. Direct and indirect striatal MSNs have recently been shown to play important, but distinct, roles in behaviors produced by psychostimulant drugs. However, little is known regarding the roles of these distinct cell populations, as well as their afferent connections, in models that produce patterns of compulsive drug-taking and drug-seeking that are characteristic of addiction, such as prolonged access drug self-administration. In addition, how signaling activity in these striatal cell populations changes following compulsive drug use, as well as regulates addiction-like behavior is not well understood. The overall aim of the proposed experiments is to use novel viral vectors expressing engineered DREADD (Designer Receptor Exclusively Activated by Designer Drug) receptors to define the role of direct and indirect pathway MSNs, as well as glutamatergic afferents, in compulsive drug-taking and drug-seeking behaviors. In addition, how compulsive patterns of drug use alter intracellular signaling activity in striatal cell populations will be examined. The central hypothesis of this proposal is that repeated drug use produces glutamate-dependent modifications to G-protein dependent signaling cascades in the striatum in a subset of individuals, leading to compulsive, addiction-like behavior (defined by high motivation to take drugs, and drug-seeking during periods of drug unavailability and during punishment). Specifically, we propose that ERK/MAPK signaling cascades are enhanced in direct pathway MSNs and suppressed in indirect pathway MSNs, which shifts the balance of these pathways towards the 'go' drive, thereby increase drug-taking and drug-seeking. This work has the potential to identify new targets for treatment (i.e., specific cell populations or afferent projections) as well as new types of treatments that may reverse addictive behaviors, such as DREADD receptor modulation of intracellular signaling cascades.