Cellular and Circuit Mechanisms Responsible for Dynorphin Actions in mPFC

负责 mPFC 中强啡肽作用的细胞和电路机制

基本信息

批准号：
10547071
负责人：
Charles Chavkin
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547071
关键词：
Abstinence Acute Addictive Behavior Address Adverse effects Agonist Amphetamines Amygdaloid structure Antibodies Anxiety Award Behavior Behavioral Brain Brain region Calcium Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cognition Cognitive Corpus striatum structure Coupled Development Disease Dorsal Drug Addiction Drug usage Dynorphins Emotional Ethanol Excision Female Fiber Foundations Genetic Genus Mentha Glutamates Goals Heroin Human Impaired cognition Individual Label Lead Ligands Light LoxP-flanked allele MAP Kinase Gene Medial Mediating Mental Depression Molecular Mood Disorders Morphine Motivation Mus Naloxone Neurons Neuropeptides Neurophysiology - biologic function Nicotine Nucleus Accumbens Opioid Opioid Antagonist Opioid agonist Pain Pathway interactions Performance Pharmaceutical Preparations Pharmacology Phenotype Photometry Physiological Prefrontal Cortex Proteins Receptor Activation Regulation Relapse Reporting Research Resolution Rewards Risk Rodent Role Salvia Self Administration Serotonin Site Source Stimulus Stress Stressful Event Substance Use Disorder Substance abuse problem Syndrome System Therapeutic Ventral Striatum Ventral Tegmental Area Viral Withdrawal antagonist anxiety-like behavior chronic pain management conditioned place preference dopaminergic neuron dorsal raphe nucleus drug of abuse drug seeking behavior dysphoria in vivo insight kappa opioid receptors kappa receptors male motivated behavior neural circuit neurochemistry neuronal circuitry neuronal excitability novel novel therapeutic intervention optogenetics p38 Mitogen Activated Protein Kinase postsynaptic pre-clinical recreational drug use response sensor stress resilience symptom treatment therapeutically effective tool

项目摘要

Project Summary: Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of dysphoria and cognitive disruption. KOR activation in rodents by agonists or by stress-evoked dynorphin release has been shown to produce aversion, increase anxiety-like behaviors, increase the rewarding effects of drugs of abuse (e.g. cocaine, amphetamine, heroin, ethanol & nicotine), increase addictive drug self-administration, and reinstate extinguished drug-seeking behaviors. The cellular and molecular mechanisms responsible for these dynorphin-dependent, pro-addictive behaviors are not fully understood, and a better understanding may suggest new therapeutic approaches to the treatment of stress-related diseases including relapse to drug use. Prior studies supported by this award demonstrated that KOR activation in the dorsal raphe, ventral tegmentum and ventral striatum by stress-induced release of dynorphin or pharmacological KOR agonist administration produces aversion in mice and potentiates cocaine conditioned place preference by activating p38 MAPK in serotonergic and dopaminergic neurons to regulate excitability and serotonin transport. Recent studies supported by this award continued to define the molecular and cellular sites of dynorphin action in the medial prefrontal cortex (mPFC) and mechanisms of KOR regulation of neuronal circuit function at each of these sites in brain. Studies proposed in the present application will continue to build on this strong foundation by characterizing cellular and molecular mechanisms responsible for dynorphin / KOR induced cognitive disruption in the mPFC. We propose to address three questions: What are the individual contributions of pre- and postsynaptic KORs in the mPFC in controlling behavior in an operant delayed alternation task? What are the behavioral stimuli required to evoke dynorphin release in mPFC? What are the effects of dynorphin release and KOR activation on excitability of mPFC neurons? Our background studies establish that pharmacological KOR activation disrupts performance in the delayed alternation operant task, and this effect can be blocked by local KOR inactivation by a KOR antagonist (norBNI) or by virally-mediated genetic excision of PFC KORs (AAV-Cre in the PFC of floxed KOR male mice). The effects of KOR activation on delayed alternation performance in females are not yet known. Stress-induced release of endogenous dynorphins in PFC also disrupt performance in the delayed alternation task, but the efficacy of different forms of behavioral stress have not yet been established. KOR is expressed on both pre- and postsynaptic components of the PFC circuit, but the respective contributions to controlling delayed alternation performance are not yet understood. Preliminary results demonstrate that naloxone precipitated withdrawal in morphine dependent male mice evokes dynorphin release in mPFC, and this suggests that dynorphin-mediated disruption of cognition may be a component of the opioid abstinent state. The proposed studies would further advance our understanding of the therapeutic potential of kappa selective ligands in the treatment of chronic pain and drug addiction.

项目摘要：人类 kappa 阿片受体 (KOR) 的药理学激活引发了以下报告：激动剂或压力诱发的强啡肽释放导致啮齿动物的烦躁和认知破坏。已被证明会产生厌恶感，增加类似焦虑的行为，增加药物的奖赏效果滥用（例如可卡因、安非他明、海洛因、乙醇和尼古丁），增加成瘾药物的自我给药，以及恢复已消失的药物寻求行为。强啡肽依赖的、促成瘾的行为尚未完全理解，更好的理解可能表明治疗压力相关疾病（包括吸毒复发）的新方法。该奖项支持的研究表明，中缝背侧、腹侧被盖和腹侧被盖中的 KOR 激活腹侧纹状体通过应激诱导释放强啡肽或药理学 KOR 激动剂给药产生小鼠厌恶并通过激活血清素能中的 p38 MAPK 增强可卡因条件性位置偏好和多巴胺能神经元调节兴奋性和血清素运输。该奖项继续定义了内侧前额皮质中强啡肽作用的分子和细胞位点 (mPFC) 以及 KOR 在大脑研究中每个部位神经回路功能的调节机制。本申请中提出的方法将继续通过表征细胞和我们提出强啡肽/KOR 诱导 mPFC 认知破坏的分子机制。解决三个问题： mPFC 中突触前和突触后 KOR 的单独贡献是什么？在操作性延迟交替任务中控制行为需要哪些行为刺激？ mPFC 中的强啡肽释放和 KOR 激活对兴奋性有何影响？ mPFC 神经元？我们的背景研究证实药理学 KOR 激活会破坏性能在延迟交替操作任务中，这种效果可以通过 KOR 的局部 KOR 失活来阻止拮抗剂（norBNI）或通过病毒介导的 PFC KOR 基因切除（floxed KOR 的 PFC 中的 AAV-Cre） KOR 激活对雌性延迟交替性能的影响尚不清楚。压力诱导的 PFC 中内源性强啡肽的释放也会破坏延迟交替中的表现任务，但不同形式的行为压力的功效尚未确定。 PFC 电路的突触前和突触后组件，但各自对控制延迟的贡献初步结果表明纳洛酮会沉淀。吗啡依赖的雄性小鼠戒断会引起 mPFC 中的强啡肽释放，这表明强啡肽介导的认知破坏可能是阿片类药物缺失状态的一个组成部分。研究将进一步加深我们对 kappa 选择性配体治疗潜力的理解治疗慢性疼痛和毒瘾。