Prefrontal mechanisms underlying polydrug heroin and alcohol use

项目总结 阿片类药物使用障碍(OUD)经常与其他药物使用并存，而酒精是最常见的共用药物之一 吸毒。然而，大多数关于OUD的基础研究都是在单一药物使用模型中进行的。当前 FDA批准的OUD治疗直接针对内源性阿片系统，或者作为替代疗法 (如丁丙诺啡、美沙酮)或对抗阿片类药物作用的拮抗剂(如纳曲酮、纳洛酮)。这些 治疗确立了Mu阿片受体(MOR)作为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)的病理生理学有关，纳曲酮用于治疗这两种疾病 和AUD，进一步强调了这些疾病之间的重叠机制。作为执行机构的所在地 前额叶皮质在抑制药物渴求和复发方面起着不可或缺的作用。 患有物质使用障碍(SODS)的人表现出前额叶皮质的结构和功能变化， 伴随着认知功能的缺陷。因此，前额叶皮质可能是阿片类药物诱导的关键部位。 影响SUD严重程度的适应。我的实验室已经确定了啮齿动物的下缘(IL)前额叶皮质投射 伏隔核壳(IL--NAShell)是海洛因寻找的重要限制因子。在白介素皮层内， 中间神经元表达MORS，第5层锥体神经元(产生NAshell投射)表达 5-HT2a受体。此外，我们最近展示了5-HT2A激动剂减少阿片类药物的能力 和酗酒(在单一药物使用模型中)，这些影响在单一治疗后长期存在。 因此，5-HT2a激动剂是一类新兴的治疗OUD和AUD的药物，它们可能对 前额叶皮质微回路来诱导这些效应。这项建议旨在研究这两个受体系统， 重点放在前额叶皮质，在多药海洛因和酒精使用的临床前模型中。这款车 合并慢性共病酒精暴露，开始于海洛因自我给药之前，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- HT2a受体在海洛因和酒精共患给药后寻找药物中的作用 IL-NAshell环路在多药滥用后寻找药物中的作用，并确定多药暴露如何改变内在的 下缘皮质不同神经元群的兴奋性及其对神经元兴奋性的调节 5-HT2A和MOR。这些受体的定位是调节大脑皮层亚回路的兴奋性，每个受体 预计最终将导致IL-NAShell产量增加，从而加强对药物的抑制控制 寻找。从该项目获得的信息将提供关于海洛因和酒精多药使用情况的见解 在对抗性、相加性或其他截然不同的皮质亚循环中引起神经适应。它还将 阐明这些电路是如何受到5-HT2A和MOR的调节的，这两种物质都是 已知的或正在出现的肥皂水治疗应用。总体而言，这将为 了解如何最好地为同时使用阿片类药物和酒精的人量身定做治疗方法。

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.