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: 10004014
• 负责人: Caitlin Anne Orsini
• 金额: $ 24.9万
• 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/10004014
• 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.

项目摘要：吸毒成瘾与决策不良和冒险升高有关，这可以 坚持禁欲，并有助于退休。这些不利的行为改变尤其是 可卡因使用者的证据，他们在实验室和实际情况下都暴露了高程 世界环境。迄今为止，大多数临床前研究都集中在该机制上 超敏反应促进决策不良和继续使用毒品；但是，我们只有一个 对编码与这些惩罚风险的大脑电路的基本理解 适应不良的选择。该项目的长期目标是阐明药物诱导的神经生物学 适应不良的决策涉及惩罚，从而确定治疗的神经目标 削弱滥用药物的冒险。与这个目标相关，我们的实验室已经建立了老鼠模型 冒险（“冒险决策任务”； RDT）概括了现实生活中的决策 包括奖励和惩罚风险。使用此模型，我们的实验室表明慢性可卡因自我 管理导致持续增加的惩罚冒险行为和多巴胺D2受体（D2R） 伏隔核（NAC）的功能在这种行为中起着关键作用。此外，初步数据揭示了 基底外侧杏仁核（BLA）和Insular Cortex在与惩罚相关的决策中的独特角色 （ins），这两者都向NAC投射，并受到滥用药物的影响。提出的实验将 基于这些发现并检验了可卡因引起的对惩罚风险的不敏感性的中心假设 通过NAC中的D2R功能和NAC之间的通信破坏来介导D2R功能。 以及传达有关预期和惩罚可能性的基本信息的情感结构。 该假设将使用体内电生理学和光遗传学的组合进行检验 在决策行为期间，体内操纵和实时监测神经活动。目标1意志 确定NAC D2R功能的改变是否介导可卡因引起的对惩罚风险的不敏感性 通过首先测试D2R激动剂是否恢复大鼠决策过程中NAC中的神经活动 具有可卡因自我管理的历史。在第二个实验中，NAC中表达D2R的神经元将 在决策过程中可以通过光源操纵，以测试抑制这些神经元是否反向 可卡因引起的冒险增加。 AIM 2将确定BLA和INS中的功能障碍是否 NAC的传入有助于可卡因引起的对惩罚风险的不敏感性。这些实验会 确定这些电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。这些发现总的来说将提供有关如何 潜在冒险的神经电路可能会因滥用药物而受到损害，因此揭示了大脑 可以调节以减少与吸毒相关的适应不良冒险的目标。