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: 10580692
• 负责人: Caitlin Anne Orsini
• 金额: $ 19.52万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580692
• 关键词: Abstinence; Affinity; Agonist; Attenuated; Behavior; Behavioral; Buprenorphine; Chronic; Data; Decision Making; Development; Drug Exposure; Drug usage; Exhibits; Female; Fentanyl; 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; Pharmacotherapy; Property; Punishment; Rattus; Relapse; Research; Rewards; Risk; Risk Reduction; Risk Taking; Rodent; Self Administration; Substance Use Disorder; Testing; Unsafe Sex; Withdrawal; Work; attenuation; behavioral impairment; cocaine exposure; cocaine self-administration; cost; design; drug craving; drug relapse; efficacy evaluation; experimental study; fentanyl self-administration; fentanyl use; illicit opioid; improved; insight; long term abstinence; maladaptive behavior; male; mu opioid receptors; mu receptors; neuromechanism; opioid use; opioid use disorder; opioid user; pharmacologic; pre-clinical research; programs; receptor; relapse prevention; remediation; restoration; sex; synthetic opioid; timeline

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.

项目概要： 决策失误和冒险行为显着增加可能导致持续吸毒和/或 这些行为障碍在慢性药物暴露后尤其明显。 患有阿片类药物使用障碍 (OUD) 的个体，在以下方面表现出明显的冒险行为： 迄今为止，大多数临床前研究都集中在实验室和现实环境中。 对奖励的过度敏感会导致不良决策和持续使用阿片类药物的机制； 然而，我们对阿片类药物引起的变化的机制只有初步的了解。 对惩罚风险的敏感性导致了这种异常和适应不良的行为。 R21 的目标是。 阐明 OUD 与冒险行为增加之间的因果关系，并通过以下方式确定机制： 该信息将提供关键的信息，以减少阿片类药物引起的冒险行为的增加。 R01 应用程序的初步数据，旨在了解阿片类药物背后的神经机制 为了实现这一目标，我们将使用风险承担模型（“风险决策”）。 “任务”）概括了现实生活中的决策，因为它包含了奖励和惩罚风险。 之前使用该模型的研究表明，长期接触可卡因会导致受惩罚风险持续增加 最近的初步数据表明，雄性和雌性大鼠之间存在类似的因果关系。 合成阿片类药物芬太尼的自我给药和男性冒险行为的增加。 将建立在这些发现的基础上并测试中心假设，即在 决策在阿片类药物使用的早期就发展起来，并持续到长期戒断。 假设是，由于其独特的药理学特性，长期服用长效 mu- 阿片受体激动剂将通过恢复对风险的敏感性来减少芬太尼引起的冒险行为升高 这些假设将使用行为药理学方法进行测试。 通过监测期间风险承担的变化来确定芬太尼引起的风险承担升高的轨迹 芬太尼的使用、戒断和长期戒断也将使我们能够确定是否像这样。 对于男性，芬太尼会导致女性的冒险行为增加，目标 2 将决定是否长期服用芬太尼。 美沙酮和丁丙诺啡，长效 mu-阿片受体激动剂，其药理学特性 不仅与非法阿片类药物不同，而且彼此之间也不同，可以减少芬太尼引起的冒险行为增加 通过恢复对惩罚风险的敏感性，这些发现将提供对影响的深入了解。 OUD 对决策过程中惩罚风险敏感性的研究，并揭示了可能的机制 用于改善风险承担缺陷并促进长期戒断阿片类药物的使用。