Investigating corticostriatal pathways relevant to cocaine addiction with DREADDs

使用 DREADD 研究与可卡因成瘾相关的皮质纹状体通路

• 批准号: 8680020
• 负责人: Kerry Ann Kerstetter
• 金额: $ 5.33万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680020
• 关键词: Address; Agreement; Amygdaloid structure; Area; Basal Ganglia; Behavior; Behavioral; Brain region; Cells; Chronic; Clozapine; Cocaine; Cocaine Dependence; Complex; Corpus striatum structure; Coupled; Critical Pathways; Cues; Designer Drugs; Development; Disease; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug Sensitization; Dynorphins; Enkephalins; Excision; Extinction (Psychology); Fiber; Gene Expression; Glutamates; Goals; Intake; Investigation; Knowledge; Lead; Learning; Ligands; Measures; Modeling; Motivation; Nature; Neurons; Neuropeptide Receptor; Nucleus Accumbens; Optics; Oxides; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Population; Prefrontal Cortex; Process; Property; Rattus; Reinforcement Schedule; Relapse; Reporting; Rewards; Rodent Model; Role; Schedule; Self Administration; Signal Transduction; Stimulus; Substance P; System; Techniques; Technology; Testing; Thalamic structure; Training; Ventral Tegmental Area; Viral Vector; Work; addiction; behavior test; behavioral sensitization; cocaine use; combinatorial; drug of abuse; drug reward; effective therapy; improved; motivated behavior; neural circuit; neuropsychiatry; novel; optogenetics; post-doctoral training; preference; promoter; public health relevance; receptor; receptor expression; recombinase; research study; response; therapy development; training project; vector

DESCRIPTION (provided by applicant): Cocaine addiction is a neuropsychiatric disorder characterized by an uncontrollable motivation to seek cocaine. At present, no effective treatment exists for cocaine addiction and this is in part due to our lack of understanding of the circuitry involved in the disorder. The prefrontal cortex (PFC) and the nucleus accumbens (NAC) have both been implicated in the rewarding properties of drugs of abuse. However it is still unclear how neural circuitry within and between these regions regulates behavior relevant to drug addiction. Medium spiny neurons (MSNs) within the NAC can be divided into two populations by their projection targets and gene expression, commonly known as the 'direct' and 'indirect' pathways. Previous reports have indicated that 'direct' and 'indirect' pathway neurons play differential roles in drug reward and sensitization, however it has yet to be examined how these pathways in the NAC influence cocaine taking and cocaine seeking within a self-administration model. Thus, my first goal is to examine the role of the direct and indirect pathways within the NAC using DREADDs selective for the direct and indirect pathways in cocaine self-administration measures modeling drug motivation and relapse. Further, it has been suggested that a loss of top-down control from the PFC to the basal ganglia is related to the chronic nature of drug addiction. The PFC sends a major glutamatergic input to the NAC, however the NAC also receives input from the amygdala and thalamus and it is unknown if the input from the PFC to the NAC is the critical pathway for regulating addiction processes. Thus, our second goal is to examine the role of the input from the PFC to the NAC in regulating operant behavior for cocaine. To selectively activate this circuit, I will utilize Cre-recombinase dependent Gi/o DREADD FLEX vector technology to express DREADDs only in mPFC neurons that project to the NAC. Transient activation of these designer receptors during operant behavior will reveal the role of the mPFC-NAC pathway in motivation for cocaine. These experiments will help to elucidate the role of the direct and indirect NAC cell populations in the control of motivation for drugs of abuse, as well as how loss of top down control from cortical inputs into the NAC contributes to these behaviors that underlie a transition to addiction. By unraveling this complex circuitry, this work could help steer the development of treatments of drug addiction toward novel therapies that selectively target subcomponents of the cortico-basal ganglia system.

描述（由申请人提供）：可卡因成瘾是一种神经精神障碍，其特征是无法控制的寻求可卡因的动机。目前，没有有效的治疗可卡因成瘾的方法，这部分是由于我们缺乏对这种疾病所涉及的电路的了解。前额叶皮层（PFC）和脑桥核（NAC）都与滥用药物的奖励特性有关。然而，目前还不清楚这些区域内部和之间的神经回路如何调节与药物成瘾相关的行为。NAC内的中型多刺神经元（MSNs）可根据其投射靶点和基因表达分为两个群体，通常称为“直接”和“间接”途径。以前的报告表明，“直接”和“间接”通路神经元在药物奖励和致敏中发挥不同的作用，但尚未研究NAC中的这些通路如何影响自我给药模型中的可卡因服用和可卡因寻求。因此，我的第一个目标是检查的作用，直接和间接途径内的NAC使用DREADD选择性的直接和间接途径，在可卡因自我管理措施建模药物的动机和复发。此外，有人认为，从PFC到基底神经节的自上而下控制的丧失与药物成瘾的慢性性质有关。PFC向NAC发送主要的神经元能输入，然而NAC也接收来自杏仁核和丘脑的输入，并且尚不清楚从PFC到NAC的输入是否是调节成瘾过程的关键途径。因此，我们的第二个目标是研究从PFC到NAC的输入在调节可卡因操作行为中的作用。为了选择性地激活该回路，我将利用Cre重组酶依赖性Gi/o DREADD FLEX载体技术，仅在投射到NAC的mPFC神经元中表达DREADD。在操作行为过程中这些设计受体的瞬时激活将揭示mPFC-NAC通路在可卡因动机中的作用。这些实验将有助于阐明直接和间接NAC细胞群在控制药物滥用动机中的作用，以及从皮层输入到NAC的自上而下控制的丧失如何促成这些行为，这些行为是成瘾转变的基础。通过解开这个复杂的电路，这项工作可以帮助指导药物成瘾治疗的发展，选择性地靶向皮质基底神经节系统的子成分。