Neuromodulatory mechanisms mediating escalation of drug consumption

介导药物消耗升级的神经调节机制

• 批准号: 10335740
• 负责人: Ryan D Farero
• 金额: $ 2.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-16 至 2021-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335740
• 关键词: Affect; Anatomy; Animals; Area; Attenuated; Behavior; Behavioral Assay; Bilateral; Biological; Brain Diseases; Brain region; Characteristics; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Consumption; Contralateral; Corpus striatum structure; Corticotropin-Releasing Hormone Receptors; Cues; Data; Detection; Development; Dopamine; Dorsal; Drug Addiction; Drug Targeting; Drug abuse; Drug usage; Dynorphins; Genes; Genetic; Goals; Harm Reduction; Implant; Individual; Intake; Intervention; Ipsilateral; Knock-out; Knowledge; Levodopa; Medial; Mediating; Mediator of activation protein; Mental disorders; Microelectrodes; Microinjections; Modeling; Neuromodulator; Neuropeptides; Nucleus Accumbens; Overdose; Pathway interactions; Pattern; Periodicity; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Relapse; Research; Role; Satiation; Scanning; Self Administration; Signal Transduction; Site; Substance Use Disorder; System; Techniques; Testing; United States; Ventral Striatum; Ventral Tegmental Area; Viral; Work; addiction; anterior commissure; attenuation; carbon fiber; cocaine self-administration; combinatorial; design; drug addiction therapy; drug maintenance; drug of abuse; experience; experimental study; interest; kappa opioid receptors; multidrug abuse; neuromechanism; neuroregulation; novel; optogenetics; overdose death; phase change; prevent; receptor; response; substance use treatment; theories; tool; trait; transmission process

PROJECT SUMMARY Alterations in dopamine transmission are implicated in most contemporary theories of drug addiction. One of the leading theories ascribes dopamine transmission within the nucleus accumbens core (NAcc) responsible for the loss of control in regulating drug consumption, a hallmark of addiction. Consistent with this theory dopamine within the NAcc has been demonstrated to be involved in producing drug-satiety, and thus regulating drug-intake. Recent work in our lab has revealed that phasic dopamine signals, elicited by response- contingent drug associated cues, are attenuated in animals that have transitioned into excessive or escalated drug consumption. Administration of L-DOPA, or stimulated release of dopamine through the use of optogenetics within the NAcc, decreased the amount of cocaine consumed in animals that had escalated their daily drug intake. These causal data indicate that attenuated phasic dopamine signals promote escalated cocaine consumption. However, the mechanisms mediating the reduction of phasic dopamine signaling are unresolved. Antagonism of either the kappa opioid receptor (KOR) or the corticotrophin releasing hormone receptor-1 (CRHR1) alters escalated drug consumption. Given the necessity of dopamine attenuation in the development of escalated cocaine intake, and that antagonists of both KOR and CRHR1 affect this behavior, I hypothesize that activation of KOR and CRHR1 promote escalation of drug consumption by mediating the attenuation of phasic dopamine release. In order to test this hypothesis, I have developed two separate aims to investigate neuropeptide action on both the progression of escalated drug-intake and dopamine signaling within the nucleus accumbens core. Animals will receive local NAcc delivery of pharmacological agents to manipulate either KOR or CRHR1 receptors during extended self-administration behavioral assays. I will utilize chronically implanted fast-scan cyclic voltammetry carbon fiber microelectrodes to detect phasic changes in dopamine transmission to drug-associated cues following the administration of the KOR and CRHR1 targeted pharmacological agents. I will implement a double disassociation manipulation technique to examine if KOR inactivation and dopamine replacement techniques alter escalated drug consumption through converging or indepedent mechanisms. Furthermore, to better our understanding in the role CRHR1 in the NAcc has in producing escalated drug consumption I will use a cre-depedent, viral-mediated CRISPR/SaCas9 system to knock-out the CRHR1 gene in a pathway specific manner. Revealing these mechanisms will provide potential pharmacological targets for drug addiction therapy, and increase our knowledge and understanding in modulation of aberrant dopamine transmission, which is implicated in many psychiatric disorders.

项目总结 大多数当代的药物成瘾理论都涉及多巴胺传递的改变。 一种主要的理论认为多巴胺在伏隔核(NAcc)内的传递。 对药物消费失去控制负有责任，这是上瘾的一个标志。与此一致 理论上，NAcc内的多巴胺已被证明与产生药物满足感有关，因此 控制药物摄入量。我们实验室最近的研究表明，由反应引发的相性多巴胺信号- 与药物有关的偶发线索，在转变为过度或升级的动物中减弱 毒品消费。服用L多巴，或通过使用 NAcc内的光遗传学减少了动物体内可卡因的消耗量，这些动物已经升级了他们的 每天的药物摄入量。这些因果数据表明，时相性多巴胺信号的减弱促进了 吸食可卡因。然而，调节时相多巴胺信号减少的机制是 悬而未决。Kappa阿片受体(KOR)或促肾上腺皮质激素释放激素的拮抗作用 受体-1(CRHR1)改变不断增加的药物消耗。鉴于多巴胺在脑组织中衰减的必要性 可卡因摄入量增加的发展，以及KOR和CRHR1的拮抗剂影响这一行为，我 假设KOR和CRHR1的激活通过调节 时相性多巴胺释放的衰减。为了验证这一假设，我制定了两个不同的目标 探讨神经肽在药物摄取增加和多巴胺信号转导中的作用 在伏隔核的核心内。动物将收到当地NACC递送的药理药物 在延长的自我给药行为分析期间操纵KOR或CRHR1受体。我会利用 慢性植入快速扫描循环伏安法碳纤维微电极检测 KOR和CRHR1靶向给药后多巴胺向药物相关线索的传递 药理制剂。我将实施一种双重分离操作技术来检查KOR 灭活和多巴胺替代技术通过汇聚或 独立的机制。此外，为了更好地理解CRHR1在NACC中的作用 产生不断上升的药物消耗我将使用一种不依赖病毒的CRISPR/SaCas9系统来 以途径特异性的方式敲除CRHR1基因。揭示这些机制将提供潜在的 药物成瘾治疗的药理学靶点，增加我们对药物成瘾治疗的认识和理解 调节异常的多巴胺传递，这与许多精神疾病有关。