Neural circuits and mechanisms underlying maladaptive risk-taking following cocaine self-administration

可卡因自我给药后适应不良冒险的神经回路和机制

• 批准号: 9986142
• 负责人: Caitlin Anne Orsini
• 金额: $ 24.66万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986142
• 关键词: Abstinence; Address; Affect; Agonist; Amygdaloid structure; Attenuated; Behavior; Behavioral; Brain; Characteristics; Chronic; Cocaine; Cocaine Dependence; Cocaine Users; Communication; Coupled; Cues; Data; Decision Making; Development; Disease; Dopamine D2 Receptor; Drug Addiction; Drug usage; Electrophysiology (science); Exhibits; Female; Foundations; Functional disorder; Goals; Human; Hypersensitivity; Impairment; Insula of Reil; Knowledge; Laboratories; Learning; Life; Mediating; Mental disorders; Modeling; Monitor; Neurobiology; Neurons; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Probability; Process; Punishment; Rattus; Recording of previous events; Relapse; Research; Rewards; Risk; Risk-Taking; Rodent; Role; Self Administration; Sex Differences; Structure; Testing; Time; Training; addiction; cocaine use; cost; drug of abuse; experimental study; in vivo; information processing; insight; male; neural circuit; neuromechanism; novel; novel therapeutics; optogenetics; pre-clinical research; prevent; programs; real time monitoring; receptor function; relating to nervous system; sex; substance abuser; targeted treatment; time use

Project Summary: Drug addiction is associated with poor decision-making and elevated risk-taking, which can persist well into abstinence and contribute to relapse. These adverse behavioral changes are particularly evident in cocaine users, 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 drug use; however, we have only a rudimentary understanding of the brain circuits that encode the risk of punishment associated with these maladaptive choices. The long term goal of this project is to elucidate the neurobiology of drug-induced maladaptive decision-making involving punishment and, thereby, identify neural targets for therapeutically attenuating risk-taking in substance abusers. Relevant to this goal, our laboratory has established a rat model of risk-taking (the “Risky Decision-Making Task”; RDT) that recapitulates real-life decision-making in that it incorporates both reward and risk of punishment. Using this model, our lab showed that chronic cocaine self- administration causes lasting increases in punished risk-taking behavior and that dopamine D2 receptor (D2R) function in the nucleus accumbens (NAc) plays a critical role in this behavior. Further, preliminary data reveal unique roles in punishment-related decision-making for the basolateral amygdala (BLA) and insular cortex (INS), both of which project to the NAc and are impacted by drugs of abuse. The proposed experiments will build on these findings and test the central hypothesis that cocaine-induced insensitivity to risk of punishment is mediated both by attenuated D2R function in the NAc and by disrupted communication between the NAc and afferent structures that convey essential information regarding anticipation and probability of punishment. This hypothesis will be tested using a combination of in vivo electrophysiology and optogenetics to allow both in vivo manipulation and real-time monitoring of neural activity during decision-making behavior. Aim 1 will determine whether alterations in NAc D2R function mediate cocaine-induced insensitivity to risk of punishment by first testing whether a D2R agonist restores altered neural activity in the NAc during decision-making in rats with a history of cocaine self-administration. In a second experiment, D2R-expressing neurons in the NAc will be optogenetically manipulated during decision-making to test whether inhibition of these neurons reverses cocaine-induced increases in risk-taking. Aim 2 will determine whether dysfunction in the BLA and INS afferents to the NAc contributes to cocaine-induced insensitivity to risk of punishment. These experiments will determine how activation or silencing of these circuits affects risk-taking and neural encoding of risk of punishment following cocaine self-administration. Collectively, these findings will provide insight into how the neural circuitry underlying risk-taking may become compromised by drugs of abuse and, thus, reveal brain targets that could be modulated to reduce maladaptive risk-taking associated with drug addiction.

项目概述：药物成瘾与决策能力差和冒险行为增加有关，这可能 坚持到禁欲，并有助于复发。这些不良的行为变化， 这在可卡因使用者中很明显，他们在实验室和真实的环境中都表现出明显的冒险精神。 世界设置。迄今为止，大多数临床前研究都集中在以下机制上： 对奖励的超敏反应会促进不良决策和继续使用药物;然而，我们只有一个 对大脑回路的初步了解，这些回路编码了与这些相关的惩罚风险， 不适应的选择该项目的长期目标是阐明药物诱导的神经生物学 涉及惩罚的适应不良决策，从而确定治疗的神经靶点 减少药物滥用者的冒险行为。与此相关，我们实验室建立了大鼠模型， 风险决策任务（Risky Decision-Making Task，RDT），它概括了现实生活中的决策过程， 同时包含了奖励和惩罚的风险。使用这个模型，我们的实验室表明，慢性可卡因自我- 给药会导致惩罚性冒险行为的持续增加，多巴胺D2受体（D2 R） 在这种行为中，丘脑核（NAc）的功能起着关键作用。初步数据显示， 基底外侧杏仁核（BLA）和岛叶皮质在惩罚相关决策中的独特作用 (INS)，两者都投射到NAc，并受到滥用药物的影响。拟议的实验将 在这些发现的基础上，检验可卡因引起的对惩罚风险不敏感的中心假设， 是由NAc中减弱的D2 R功能和NAc之间中断的通讯介导的。 以及传递关于预期和惩罚可能性的基本信息的传入结构。 将使用体内电生理学和光遗传学的组合来测试这一假设， 在决策行为过程中对神经活动的体内操纵和实时监测。目标1将 确定NAc D2 R功能的改变是否介导可卡因诱导的对惩罚风险的不敏感性 首先测试D2 R激动剂是否能恢复大鼠在决策过程中NAc中改变的神经活动， 有服用可卡因的前科在第二个实验中，NAc中表达D2 R的神经元将 在决策过程中进行光遗传学操作，以测试这些神经元的抑制是否会逆转 可卡因导致的冒险行为增加目标2将确定BLA和INS功能障碍是否 NAc的传入纤维有助于可卡因诱导的对惩罚风险的不敏感性。这些实验将 确定这些回路的激活或沉默如何影响冒险和神经编码的风险， 可卡因自我管理后的惩罚。总的来说，这些发现将提供有关如何 神经回路潜在的冒险可能会受到滥用药物的损害，从而揭示大脑 这些目标可以被调节，以减少与药物成瘾相关的适应不良风险。