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

项目概要： 决策不当和冒险行为增加可能会显著导致继续使用药物和/或 促进慢性药物暴露后的复发。这些行为障碍在以下人群中尤为明显： 阿片类药物使用障碍（OUD）的个体，他们在两个方面都表现出明显的风险升高， 在实验室和现实世界中。迄今为止，大多数临床前研究都集中在 对奖励的超敏反应促进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， 对惩罚风险敏感导致了这种反常和适应不良的行为。R21的目标是 阐明OUD和风险承担增加之间的因果关系，并通过以下方式确定机制： 阿片类药物引起的风险增加可以减少。这些信息将提供关键的 R 01应用程序的初步数据旨在了解阿片类药物的神经机制 对风险承担的影响。为了实现这一目标，我们将使用一个风险承担的大鼠模型（“风险决策 任务”），它概括了现实生活中的决策，因为它包含了奖励和惩罚的风险。 先前使用该模型的研究表明，长期接触可卡因会导致惩罚风险的持续增加 在雄性和雌性大鼠中。最近的初步数据表明， 自我管理的合成阿片类芬太尼和男性的风险增加。拟议的实验 将建立在这些发现和测试的中心假设，不敏感的惩罚风险期间， 决策能力在阿片类药物使用的早期发展，并持续到长期戒断。我们的次要 假设是，由于其独特的药理学性质，长期施用长效μ- 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诱导的风险承担升高 惩罚。这些假设将使用行为药理学方法进行检验。目标1将 通过监测风险承担的变化，确定芬太尼诱导的风险承担升高的轨迹， 芬太尼的使用，戒断和长期禁欲。这一目标也将使我们能够确定，如 芬太尼会导致女性冒险行为的增加。目标2将确定长期给药是否 美沙酮和丁丙诺啡，长效μ-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，而且彼此不同， 通过恢复对惩罚风险的敏感性。总的来说，这些发现将提供深入了解的影响， OUD对决策过程中惩罚风险的敏感性，并揭示可能 利用这些手段来改善风险承担赤字，并促进长期戒断阿片类药物的使用。

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.