Examination of fentanyl-induced insensitivity to risk of punishment during decision making and the potential use of methadone and buprenorphine in attenuating risk-taking deficits

检查决策过程中芬太尼引起的对惩罚风险的不敏感性以及美沙酮和丁丙诺啡在减轻风险承担缺陷方面的潜在用途

• 批准号: 10373348
• 负责人: Caitlin Anne Orsini
• 金额: $ 23.51万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373348
• 关键词: Abstinence; Address; Affinity; Agonist; Attenuated; Buprenorphine; Chronic; Data; Decision Making; Development; Drug Exposure; Drug usage; Exhibits; Female; Fentanyl; Foundations; Goals; Half-Life; Human; Hypersensitivity; Impaired cognition; Impairment; Individual; Knowledge; Laboratories; Life; Mediating; Methadone; Modeling; Monitor; Neurobiology; Neurophysiology - biologic function; Opioid; Opioid agonist; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Property; Punishment; Rattus; Relapse; Research; Rewards; Risk; Risk-Taking; Rodent; Self Administration; Substance Use Disorder; Testing; Time; TimeLine; Unsafe Sex; Withdrawal; Work; attenuation; behavioral impairment; behavioral pharmacology; cocaine exposure; cocaine self-administration; cost; design; experimental study; illicit opioid; improved; insight; maladaptive behavior; male; mu opioid receptors; mu receptors; neuromechanism; opioid use; opioid use disorder; opioid user; pre-clinical research; prevent; programs; receptor; restoration; sex; synthetic opioid

Project Summary: Poor decision making and elevated risk taking can significantly contribute to continued drug use and/or promote relapse after chronic drug exposure. These behavioral impairments are particularly evident in individuals with opioid use disorder (OUD), who exhibit pronounced elevations in risk taking both in the laboratory and in real-world settings. The majority of preclinical research to date has focused on the mechanisms by which hypersensitivity to reward promotes poor decision making and continued opioid use; however, we have only a rudimentary understanding of the mechanisms by which opioid-induced changes in sensitivity to risk of punishment contribute to such aberrant and maladaptive behavior. The goal of this R21 is to elucidate the causal relationship between OUD and increased risk taking and to identify mechanisms by which opioid-induced elevations in risk taking can be reduced. This information will provide critical preliminary data for a R01 application designed to understand the neural mechanisms underlying opioid’s impact on risk taking. To achieve this goal, we will use a rat model of risk taking (the “Risky Decision-Making Task”) that recapitulates real-life decision making in that it incorporates both reward and risk of punishment. Prior work using this model showed chronic exposure to cocaine causes lasting increases in punished risk taking in male and female rats. More recent preliminary data demonstrate a similar causal relationship between self-administration of the synthetic opioid fentanyl and elevated risk taking in males. The proposed experiments will build on these findings and test the central hypothesis that insensitivity to risk of punishment during decision making develops early in opioid use and persists into long-term abstinence. Our secondary hypothesis is that, due to their distinct pharmacological properties, chronic administration of long-acting mu- opioid receptor agonists will reduce fentanyl-induced elevations in risk taking via restoration of sensitivity to risk of punishment. These hypotheses will be tested using a behavioral pharmacological approach. Aim 1 will determine the trajectory of fentanyl-induced elevations in risk taking by monitoring changes in risk taking during fentanyl use, withdrawal and protracted abstinence. This Aim will also allow us to determine whether, like males, fentanyl causes elevations in risk taking in females. Aim 2 will determine whether chronic administration of methadone and buprenorphine, long-acting mu-opioid receptor agonists whose pharmacological properties not only differ from illicit opioids but also differ from each other, reduce fentanyl-induced increases in risk taking via restoration of sensitivity to risk of punishment. Collectively, these findings will provide insight into the impact of OUD on sensitivity to risk of punishment during decision making and reveal mechanisms that could be leveraged to ameliorate risk-taking deficits and promote long-lasting abstinence from opioid use.

项目摘要： 决策不良和冒险升高可能会大大导致继续使用毒品和/或 慢性药物暴露后促进缓解。这些行为障碍是尤其是证据 患有阿片类药物使用障碍（OUD）的人，他们暴露了同时承担风险的高程 实验室和现实环境。迄今为止，大多数临床前研究都集中在 高敏性奖励的机制促进了不良的决策和持续使用阿片类药物； 但是，我们只对阿片类药物诱导的变化的机制有基本的理解 对惩罚风险的敏感性会导致这种异常和适应不良的行为。 R21的目标是 阐明OUD与增加风险的因果关系，并通过 可以降低阿片类药物引起的风险升高。这些信息将提供关键 R01应用程序的初步数据，旨在了解阿片类药物的神经机制 对冒险的影响。为了实现这一目标，我们将使用冒险的大鼠模型（“风险决策” 任务”）概括了现实生活中的决策，因为它既包含奖励和惩罚风险。 使用此模型的先前工作显示可卡因的长期暴露会导致持久的惩罚风险增加 接纳男性和雌性老鼠。最新的初步数据表明 合成阿片类药物芬太尼和男性风险升高的自我管理。提出的实验 将基于这些发现并检验中心假设，即对惩罚风险不敏感 决策在阿片类药物的使用早期发展，并持续长期禁欲。我们的次要 假设是，由于其独特的药物特性，长期施用了长效Mu- 阿片类药物受体激动剂将通过恢复对风险的敏感性来降低芬太尼引起的风险的海拔 惩罚。这些假设将通过行为药物方法进行检验。目标1意志 通过监视冒险的变化在 芬太尼使用，戒断和持久的禁欲。这个目标还将使我们能够确定是否喜欢 雄性，芬太尼会导致女性服用风险升高。 AIM 2将决定是否长期管理 Metagadone和丁丙诺啡，长效的MU阿片受体激动剂，其药物特性 不仅不同于非法阿片类药物，而且彼此不同，减少了芬太尼引起的风险增加 通过恢复对惩罚风险的敏感性。总的来说，这些发现将提供对影响的见解 对决策和揭示可能是惩罚风险的敏感性的敏感性 杠杆化可以改善冒险定义并促进使用阿片类药物的长期禁欲。