Investigation of non-canonical opioid signaling in the prefrontal cortex of alcohol-dependent rats

酒精依赖大鼠前额叶皮层非典型阿片类药物信号传导的研究

• 批准号: 10811444
• 负责人: LUIS ALBERTO NATIVIDAD
• 金额: $ 22.78万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-26 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10811444
• 关键词: Abstinence; Address; Adherence; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Area; Automobile Driving; Behavior; Behavioral; Behavioral Model; Binding; Brain; Chronic; Clinic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive Therapy; Complex; Consumption; Data; Dependence; Development; Elements; Enkephalins; Environment; Ethanol; Family; Foundations; Functional disorder; Goals; Human; Impairment; Individual; Infusion procedures; Investigation; Knowledge; Laboratories; Leucine Enkephalin; Ligands; Mass Spectrum Analysis; Medial; Mediating; Methionine Enkephalin; Microdialysis; Modeling; Molecular; Monitor; Motivation; Naltrexone; Neuropeptides; Opioid; Opioid Antagonist; Opioid Peptide; Opioid Receptor; Pathology; Patients; Pattern; Peptides; Performance; Pharmaceutical Preparations; Pharmacy (field); Phosphorylation; Phosphorylation Site; Play; Prefrontal Cortex; Prevention; Process; Production; Property; Protein Precursors; Proteome; Rattus; Receptor Signaling; Recovery; Relapse; Research; Rewards; Rodent; Role; Short-Term Memory; Signal Transduction; Symptoms; Time; Work; addiction; advanced analytics; alcohol abuse therapy; alcohol misuse; alcohol use disorder; antagonist; clinical efficacy; cognitive function; cognitive performance; cognitive recovery; cognitive testing; craving; density; desensitization; druggable target; endogenous opioids; flexibility; frontal lobe; improved; in vivo; insight; long term abstinence; non-opioid analgesic; novel; preclinical study; preference; proenkephalin; protein aminoacid sequence; response; success; treatment adherence; vapor

Project Abstract Current treatments of Alcohol Use Disorder (AUD) have shown moderate success in reducing heavy alcohol drinking but are marred with the problem of treatment adherence. In the clinic, opiate receptor pharmaceutics are often combined with cognitive behavioral therapies to improve long-term abstinence. These findings suggest an important relation between endogenous opioid signaling and cognitive factors in the treatment of AUD; however, lapses in treatment can quickly reinstate alcohol drinking, highlighting a knowledge gap in our understanding of how these mechanisms may influence long-term misuse. In this regard, alcohol consumption stimulates the release of endogenous opioids, including enkephalins that bind to mu-type opioid receptors (MOR) commonly found in limbic areas of the brain. The manipulation of MOR signaling alters the rewarding properties of alcohol, with agonists facilitating reward and consumption, and antagonists blocking these responses. The shared relation between opioidergic responses that underlie motivation and cognition are not well understood but present a focal point for addressing complex pathologies that may underlie alcohol-related sensitivities. In this regard, MORs are found in frontal cortical regions that modulate cognitive function, such as the medial prefrontal cortex (mPFC). Preclinical studies in our laboratory demonstrate that alcohol dependence in rats decreases the phosphorylation of MOR in the mPFC, and increases expression of the neuropeptide precursor, proenkephalin (PENK). This pattern of changes overlaps with clinical observations of MOR desensitization in AUD patients. The findings suggest that dependence may dysregulate opioidergic signaling in the mPFC, although the extent to which such conditions surmise changes in the endogenous ligands is unclear. A better understanding is warranted given that adherence to opiate antagonists diminishes over protracted abstinence and may be undermined by molecular intermediates in the processing of small-opioid peptides. Here, we will explore the central hypothesis that non-canonical PENK signaling in the mPFC plays a pivotal role in dysregulating cognitive function during abstinence. Towards this goal, discovery-based and quantitative mass spectrometry approaches will be combined with in vivo microdialysis to broadly capture PENK-mediated signaling in alcohol-dependent rats undergoing abstinence (Aim 1). We will then explore the functional relevance of non-canonical PENK signaling in an operant model of cognitive flexibility, and further determine whether similar dysfunctions in dependence are modulated by mPFC MOR (Aim 2). The results are expected to provide insight into druggable targets that extend beyond conventional opioidergic signaling processes and will lay the foundation for mechanistic studies exploring the role of non-canonical PENK signaling in driving vulnerability to addiction behavior.

项目摘要 目前对酒精使用障碍的治疗（AUD）在减少沉重的酒精方面表现出了适度的成功 喝酒，但由于治疗依从性而受到伤害。在诊所，阿片类药物药物 通常与认知行为疗法相结合，以改善长期禁欲。这些发现表明 内源性阿片类药物信号传导与认知因素在AUD治疗中的重要关系； 但是，治疗的失误可以迅速恢复饮酒，突出我们的知识差距 了解这些机制如何影响长期滥用。在这方面，饮酒 刺激内源性阿片类药物的释放，包括与MU型阿片受体（MOR）结合的Enkephalins 通常在大脑的边缘区域发现。 MOR信号的操纵改变了奖励性能 酒精，激动剂促进奖励和消费，对抗者阻止了这些反应。这 基于动力和认知的基础的阿片类反应之间的共同关系尚未得到很好的理解 但提出了解决与酒精相关敏感性基础的复杂病理的焦点。在 这方面，在调节认知功能的额叶皮质区域中发现了MOR，例如内侧 前额叶皮层（MPFC）。我们实验室中的临床前研究表明，大鼠的酒精依赖性 降低MPFC中MOR的磷酸化，并增加神经肽前体的表达， Proenkephalin（Penk）。这种变化的模式与MOR脱敏的临床观察结果重叠 aud患者。研究结果表明，依赖性可能会使MPFC中的阿片类信号失调。 尽管这种条件在多大程度上推测内源配体的变化尚不清楚。更好 鉴于依从性鸦片拮抗剂的坚持减少了持久的禁欲，因此有必要理解。 并且可能会在小阿片类肽的加工中被分子中间体破坏。在这里，我们会的 探索中心假设，即MPFC中的非典型PENK信号传导在 戒酒期间的认知功能失调。朝着这个目标，基于发现的和定量的质量 光谱方法将与体内微透析结合使用，以广泛捕获PENK介导的 依赖酒精依赖大鼠的信号传导（AIM 1）。然后，我们将探索功能相关性 在认知灵活性的操作模型中，非经典的PENK信号传导，并进一步确定是否是否 MPFC MOR调节了类似的依赖功能（AIM 2）。结果预计将提供 深入了解可药物的目标，这些目标范围超出了常规的阿片类信号传导过程，并将放置 机械研究基金会探讨了非规范penk信号在推动脆弱性中的作用 成瘾行为。