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.

项目概要阿片类药物使用障碍 (OUD) 通常与其他药物使用共存，而酒精是最常见的共存药物之一。然而，目前 OUD 的大部分基础研究都是在单一药物使用模型中进行的。 FDA 批准的 OUD 治疗方法直接针对内源性阿片类药物系统，或者作为替代疗法（例如丁丙诺啡、美沙酮）或对抗阿片类药物作用的拮抗剂（例如纳曲酮、纳洛酮）。治疗将 mu 阿片受体 (MOR) 确立为 OUD 的主要治疗靶点。与酒精使用障碍 (AUD) 的病理生理学有关，纳曲酮用于治疗这两种 OUD 和 AUD，进一步强调了这些疾病之间的重叠机制。功能方面，前额叶皮层在抑制药物渴望和复吸方面发挥着不可或缺的作用。患有物质使用障碍（SUD）的人类前额叶皮层表现出结构和功能变化，伴随认知功能缺陷，因此，前额叶皮层可能是阿片类药物诱发的关键部位。我的实验室已经确定了啮齿类动物边缘下（IL）前额叶皮层投射的适应性。伏核壳 (ILNAshell) 作为 IL 皮质内海洛因寻找的重要限制器，中间神经元表达 MOR，第 5 层锥体神经元（产生 NAshell 投影）表达此外，我们最近证明了 5-HT2A 激动剂能够减少阿片类药物的使用。和酗酒（在单一药物使用模型中），并且这些影响在单次治疗后是持久的。因此，5-HT2A 激动剂是 OUD 和 AUD 的一类新兴疗法，它们可能作用于该提案旨在检查这两种受体系统，在多药海洛因和酒精使用的临床前模型中，重点关注前额皮质。包括慢性共病酒精暴露，在海洛因自我给药之前开始并持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 受体在海洛因和酒精共病自我给药后寻求药物中的作用，以确定其作用 ILNAshell 电路在多种药物使用后寻找药物中的作用，并确定多种药物暴露如何改变内在边缘下皮层不同神经元群的兴奋性以及神经元兴奋性的调节 5-HT2A 和 MOR 这些受体的作用是调节皮质子回路的兴奋性。预计最终会增加 ILNAshell 输出，从而增加对药物的抑制控制从该项目中获得的信息将有助于了解海洛因和酒精等多种毒品的使用情况。会引起皮质子回路中的神经适应，这些神经适应是对立的、相加的或其他不同的。揭示了这些电路如何受 5-HT2A 和 MOR 调节，这两者都是可药物靶点总的来说，这将为 SUD 的已知或新兴治疗应用奠定基础。了解如何最好地针对阿片类药物和酒精使用共病的个体制定治疗方案。