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

描述（由申请人提供）：皮质-基底神经节系统是一个涉及动机和奖励的复杂网络。纹状体内的中棘投射神经元（msn）是该回路的主要中继站，并通过两条不同的通路指导行为输出。含有神经肽dynorphin （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enkephalin （ENK）的纹状体神经元是间接通路的一部分。反复滥用药物会导致皮质-基底神经节回路失调，部分原因是皮层下结构（如纹状体）的可塑性异常，以及谷氨酸传入系统自上而下控制的丧失。直接和间接纹状体msn最近被证明在精神兴奋剂产生的行为中起着重要但不同的作用。然而，对于这些不同的细胞群，以及它们的传入连接，在产生成瘾特征的强迫性吸毒和寻求药物模式的模型中所起的作用，例如长期获得药物自我给药，所知甚少。此外，这些纹状体细胞群的信号活动如何在强迫性行为后发生变化

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.