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

特定皮质基底神经节通路在成瘾动物模型中的作用

• 批准号: 8814194
• 负责人: Susan Marie Ferguson
• 金额: $ 41.45万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814194
• 关键词: Addictive Behavior; Amygdaloid structure; Animal Model; Basal Ganglia; Behavior; Behavioral; Cells; Characteristics; Cocaine; Complex; Corpus striatum structure; Coupled; Designer Drugs; Dopamine D2 Receptor; Drug Addiction; Drug Receptors; Drug abuse; Drug usage; Dynorphins; Engineering; Enkephalins; Equilibrium; Exhibits; Exposure to; GTP-Binding Proteins; Glutamates; Health; Individual; MAP Kinase Gene; Measures; Medical; Modeling; Modification; Motivation; Neurons; Neuropeptides; Nucleus Accumbens; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Play; Population; Public Health; Punishment; Rattus; Reinforcement Schedule; Relapse; Research; Rewards; Role; Self Administration; Shock; Signal Transduction; Social Impacts; Societies; Structure; Substance P; System; Testing; Thalamic structure; Viral Vector; Work; addiction; cocaine use; drug of abuse; drug seeking behavior; economic impact; foot; novel; novel therapeutic intervention; promoter; protective effect; psychostimulant; receptor; recombinase; research study; selective expression; tool

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.

描述（由申请人提供）：皮质基底神经节系统是一个复杂的网络，涉及动机和奖励。纹状体内的中型多刺投射神经元（MSN）作为该回路的主要中继站，并通过两个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是直接途径的一部分，而含有神经肽脑啡肽（ENK）的纹状体神经元是间接途径的一部分。重复暴露于滥用药物可在皮质-基底神经节回路中产生失调，部分原因是通过皮质下结构（如纹状体）的异常可塑性，以及通过多巴胺能传入系统自上而下控制的丧失。直接和间接的纹状体MSNs最近被证明在精神兴奋剂药物产生的行为中发挥重要但不同的作用。然而，关于这些不同的细胞群的作用以及它们的传入连接，在产生成瘾特征的强迫性吸毒和药物寻求模式的模型中，如长期获得药物自我管理，知之甚少。此外，这些纹状体细胞群中的信号活动如何在强迫性行为后发生变化， 药物使用，以及调节成瘾样行为是不是很清楚。所提出的实验的总体目标是使用表达工程化DREADD（由设计者药物独家激活的设计者受体）受体的新型病毒载体来定义直接和间接途径MSN以及多巴胺能传入在强迫性吸毒和寻求药物行为中的作用。此外，如何强迫模式的药物使用改变纹状体细胞群的细胞内信号转导活动将进行检查。该建议的中心假设是，重复使用药物在一个子集的个体中对纹状体中的G蛋白依赖性信号级联产生谷氨酸依赖性修饰，导致强迫性成瘾样行为（定义为服用药物的高动机，以及在药物不可用期间和惩罚期间寻求药物）。具体来说，我们提出ERK/MAPK信号级联在直接途径MSNs中增强，在间接途径MSNs中抑制，这将这些途径的平衡转向“去”驱动，从而增加药物服用和药物寻求。这项工作有可能确定新的治疗靶点（即，特定的细胞群或传入投射）以及可能逆转成瘾行为的新型治疗，如DREADD受体调节细胞内信号级联。