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

项目总结： 糟糕的决策和更高的风险承担可能会极大地导致持续使用毒品和/或 在慢性药物暴露后促进复发。这些行为障碍在以下方面尤为明显 患有阿片类药物使用障碍(OUD)的人，他们在风险承担方面表现出明显的上升，在 在实验室和真实世界的环境中。到目前为止，大多数临床前研究都集中在 对奖励的高敏感性促进糟糕的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一个初步的了解。 对惩罚风险的敏感导致了这种反常和不适应的行为。这款R21的目标是 阐明OUD和风险增加之间的因果关系，并通过以下方式确定机制 哪些阿片类药物引起的冒险行为升高可以减少。该信息将提供关键的 用于了解阿片类药物潜在神经机制的R01应用程序的初步数据 对冒险行为的影响。为了实现这一目标，我们将使用风险承担的老鼠模型(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。 使用这一模型的先前研究表明，长期接触可卡因会导致受罚风险的持久增加 接收雄鼠和雌鼠。最近的初步数据表明， 合成阿片类芬太尼的自我给药和男性风险增加。拟议中的实验 将建立在这些发现的基础上，并测试对惩罚风险不敏感的中心假设 决策形成在阿片类药物使用的早期，并持续到长期戒断。我们的次要 假说是，由于其独特的药理特性，长期给药长效的小鼠。 阿片受体激动剂将通过恢复对风险的敏感性来降低芬太尼诱导的风险承担增加 关于惩罚的问题。这些假说将使用行为药理学方法进行测试。目标1将 通过监测以下过程中风险承担的变化来确定芬太尼诱导的风险承担升高的轨迹 芬太尼的使用、停用和长期戒断。这一目标还将使我们能够确定是否像 男性，芬太尼会增加女性的风险。目标2将决定慢性给药是否 美沙酮和丁丙诺啡，长效阿片受体激动剂，其药理学特性 不仅不同于非法阿片类药物，而且彼此不同，减少芬太尼诱导的风险增加 通过恢复对惩罚风险的敏感性。总而言之，这些发现将提供对影响的洞察 关于决策过程中对惩罚风险的敏感性，并揭示了可以 用来改善风险承担不足，促进长期戒除阿片类药物的使用。

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.