Prefrontal mechanisms underlying polydrug heroin and alcohol use

多种药物海洛因和酒精使用的前额叶机制

基本信息

批准号：
10739702
负责人：
JAMIE PETERS
金额：
$ 49.77万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739702
关键词：
Acute Addictive Behavior Agonist Alcohol consumption Alcohols Animals Basic Science Brain Buprenorphine Chronic Clinical Research Cues Data Decision Making Disease Drug usage Electrophysiology (science)Exhibits Extinction FDA approved Frequencies Functional disorder Genetic Goals HTR2A gene Heroin Home Human Individual Interneurons Light Measures Medial Methadone Modeling Motivation Naloxone Naltrexone Neurons Nucleus Accumbens Opioid Opioid Receptor Opioid Rotation Outcome Measure Output Pathway interactions Patients Pharmaceutical Preparations Physiological Adaptation Play Population Positioning Attribute Pre-Clinical Model Prefrontal Cortex Public Health Publishing Recording of previous events Regulation Relapse Reporting Research Rodent Role Self Administration Serotonin Serotonin Receptor 5-HT2A Severities Site Slice Substance Use Disorder System Testing Therapeutic Treatment Efficacy United States alcohol comorbidity alcohol exposure alcohol seeking behavior alcohol use disorder antagonist cell type chronic alcohol ingestion cocaine seeking cognitive function comorbidity drug craving drug relapse druggable target endogenous opioids executive function heroin use hippocampal pyramidal neuron innovation insight mu opioid receptors multiple drug use neuroadaptation neuronal excitability neurophysiology novel opioid exposure opioid use opioid use disorder opioid withdrawal polysubstance use preclinical study receptor stimulant use therapeutic evaluation therapeutic opioid therapeutic target treatment strategy

项目摘要

PROJECT SUMMARY Opioid use disorder (OUD) is often comorbid with other drug use, and alcohol is one of the most commonly co- used drugs. Yet most of the basic research on OUD has been conducted in single-drug use models. Current FDA-approved treatments for OUD target the endogenous opioid system directly, either as substitution therapies (e.g. buprenorphine, methadone) or antagonists that oppose opioid effects (e.g. naltrexone, naloxone). These treatments establish the mu opioid receptor (MOR) as a major therapeutic target for OUD. Similarly, opioids have been implicated in the pathophysiology of alcohol use disorder (AUD), and naltrexone is used to treat both OUD and AUD, further underscoring the overlapping mechanisms between these disorders. As the seat of executive function, the prefrontal cortex plays an integral role in the inhibitory control over drug craving and relapse. Humans with substance use disorders (SUDs) exhibit structural and functional changes in the prefrontal cortex, accompanied by deficits in cognitive function. Thus, the prefrontal cortex may be a key locus for opioid-induced adaptations that impact SUD severity. My lab has identified the rodent infralimbic (IL) prefrontal cortex projection to the nucleus accumbens shell (ILNAshell) as an important limiter of heroin seeking. Within the IL cortex, interneurons express MORs, and layer 5 pyramidal neurons (which give rise to the NAshell projection) express 5-HT2A receptors. Furthermore, we have recently demonstrated the ability of a 5-HT2A agonist to reduce opioid and alcohol seeking (in single-drug use models), and these effects were long-lasting after a single treatment. Thus, 5-HT2A agonists are an emerging class of therapeutics for OUD and AUD, and they may act upon prefrontal cortex microcircuits to elicit these effects. This proposal aims to examine these two receptor systems, with a focus on the prefrontal cortex, in a preclinical model of polydrug heroin and alcohol use. This model incorporates chronic comorbid alcohol exposure, initiated prior to heroin self-administration and continuing throughout the period of opioid exposure. The overarching objectives of this project are to identify the role of 5- HT2A receptors in drug seeking after comorbid heroin and alcohol self-administration, to define the role of the ILNAshell circuit in drug seeking after polydrug use, and to determine how polydrug exposure alters intrinsic excitability of different neuronal populations in the infralimbic cortex and the regulation of neuronal excitability by 5-HT2A and MOR. These receptors are positioned to regulate excitability of cortical sub-circuits, with each predicted to culminate in increased ILNAshell output, and therefore increased inhibitory control over drug seeking. Information gained from this project will provide insight into whether heroin and alcohol polydrug use elicits neuroadaptations in cortical sub-circuits that are oppositional, additive, or otherwise distinct. It will also shed light onto how these circuits are regulated by 5-HT2A and MOR, both of which are druggable targets with known or emerging therapeutic applications for SUDs. Collectively, this will provide the groundwork for understanding how treatments can best be tailored to individuals with comorbid opioid and alcohol use.

项目摘要阿片类药物使用障碍（OUD）通常与其他药物使用合并，酒精是最常见的共同使用之一二手药物。然而，关于OUD的大多数基础研究都是在单药使用模型中进行的。当前的 FDA批准的OUD治疗直接靶向内源性阿片类药物系统，要么作为替代疗法（例如，丁丙诺啡，Metagadone）或反对阿片类药物作用的拮抗剂（例如纳曲酮，纳洛酮）。这些治疗将MU阿片受体（MOR）确定为OUD的主要治疗靶点。同样，阿片类药物也有与酒精使用障碍（AUD）的病理生理有关，纳曲酮用于治疗两种OUD 和AUD，进一步强调了这些疾病之间的重叠机制。作为行政的所在地功能，前额叶皮层在对药物渴望和继电器的抑制控制中起着不可或缺的作用。患有药物使用障碍（SUD）的人类暴露于前额叶皮层中的结构和功能变化，伴随着定义的认知功能。那就是，前额叶皮层可能是阿片类药物引起的关键基因座影响SUD严重程度的适应。我的实验室已经确定了啮齿动物插头（IL）前额叶皮层投影对伏隔核（ILNashell）作为寻求海洛因的重要限制。在IL皮质中，中间神经元表达MOR和5层锥体神经元（引起Nashell投影）表达 5-HT2A受体。此外，我们最近证明了5-HT2A激动剂减少Ooid的能力和寻求酒精（在单药使用模型中），并且在一次治疗后，这些作用是长期的。那是5-HT2A激动剂是Oud和Aud的新兴治疗类别，他们可能会采取行动前额叶皮层微电路会引起这些作用。该建议旨在检查这两个受体系统，即重点是前额叶皮层，以多药海洛因和酒精使用的临床前模型。这个模型纳入慢性合并酒精暴露，在海洛因自我管理之前启动并继续在整个阿片类药物暴露期间。该项目的总体目标是确定5-的作用 HT2A在合并海洛因和酒精自我管理后寻求药物中的受体，以定义 iL在使用多药物后寻求药物的纳赛尔电路，并确定多药暴露如何改变固有的在输卵管皮质中不同神经元种群的兴奋性和神经元令人兴奋的调节 5-HT2A和MOR。这些受体定位可调节皮质亚电路的刺激性预计最终导致IL nashell输出增加，因此对药物的抑制作用增加寻求。从该项目中获得的信息将提供有关海洛因和酒精多药的使用的见解引起对立，添加剂或其他不同的皮质亚电路的神经加热。它也会阐明了这些电路如何受到5-HT2A和MOR调节的方式，这两个都是可吸毒的目标已知或新兴的SUD治疗应用。总的来说，这将为了解如何最好地针对合并症阿片类药物和饮酒的人量身定制治疗方法。