Individual Differences & Cocaine Effects on Impulsive Choice in Rat

个体差异

• 批准号: 10361717
• 负责人: Jane R Taylor
• 金额: $ 51.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361717
• 关键词: Abstinence; Affect; Amygdaloid structure; Behavior; Behavioral; Binding; Biological Markers; Calcium; Chronic; Cocaine; Cocaine Dependence; Cocaine use disorder; Computer Analysis; Corpus striatum structure; Data; Decision Making; Development; Dopamine; Drug Exposure; Drug usage; Fiber; Funding; Future; GRM5 gene; Human; Image; Impairment; Impulsivity; Individual; Individual Differences; Lead; Learning; Link; Mediating; Mediator of activation protein; Midbrain structure; Modeling; Neurobiology; Nucleus Accumbens; Outcome; Pathology; Pharmaceutical Preparations; Photometry; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Process; Psychological reinforcement; Publishing; Rattus; Relapse; Reporting; Reversal Learning; Rewards; Role; Signal Transduction; Testing; Transgenic Organisms; Tyrosine 3-Monooxygenase; Up-Regulation; Update; Variant; addiction; base; biobehavior; cocaine exposure; cocaine self-administration; cocaine use; cortico-limbic circuits; dopamine D3 receptor; drug seeking behavior; drug testing; glutamatergic signaling; in vivo; metabotropic glutamate receptor 5; neural circuit; neurobiological mechanism; neuroimaging; novel strategies; receptor; relating to nervous system

Cocaine dependence is associated with dysfunctional midbrain cortico-limbic-striatal circuits that impact decision-making processes and lead to the development of compulsive drug-seeking behaviors. Our new and published data from the prior funding period show that (1) that the reinforcement-learning mechanisms that predict cocaine-taking behaviors (e.g., positive-outcome updating) differ from those that are disrupted following cocaine self-administration (e.g., negative-outcome updating), (2) that midbrain D3 BPND is predictive of cocaine-taking behaviors and related to positive-outcome updating, but cocaine self-administration disrupts prefrontal cortical (PFC) mGlu5 BPND and is related to negative-outcome updating, and (3) that positive- outcome updating is controlled by amygdala projections to the PFC whereas negative-outcome updating is controlled by PFC projections to the nucleus accumbens (NAc). These findings, collectively, indicate that the biobehavioral mechanisms that mediate vulnerability to cocaine-taking behaviors differ from those that are disrupted by chronic cocaine exposure and identify midbrain D3 and cortical mGlu5 receptors as critical mediators of susceptibility to and consequence of cocaine use, respectively. The functional relevance of midbrain dopamine D3 and cortical mGlu5 BPND on the neural activity associated with addiction-relevant behaviors, however, is not known. The studies proposed here will investigate the role of D3 and mGlu5 BPND in circuit-level mechanisms of decision-making and drug-seeking behaviors in rats. We will use positron emission tomography (PET) and calcium imaging with fiber photometry to determine how D3 and mGlu5 BPND are associated with circuit-level activity in rats before and after cocaine self-administration. In Aim 1 we will investigate the relationship between individual differences in midbrain dopamine D3 BPND and dynamic neural activity in cortico-limbic circuits during decision making and subsequent cocaine self-administration behaviors. In Aim 2 we will determine how disruptions in mGlu5 glutamatergic signaling and neural activity mediate addiction-relevant (seeking/taking) behaviors and alter decision-making strategies after short and long periods of abstinence from cocaine self-administration. Together, our integrative and novel approach – combining sophisticated behavioral tasks, computational analyses, in vivo recordings of neural activity with calcium fiber photometry, and PET imaging – will determine the functional impact and neurobiological mechanisms of decision-making circuits and their role in addiction vulnerability and pathology.

皮质醇依赖与中脑皮质-边缘-纹状体回路功能障碍有关， 决策过程，并导致强迫性寻求药物行为的发展。我们的新的和 上一个资助期公布的数据表明，（1） 预测可卡因服用行为（例如，积极结果更新）不同于那些被破坏的， 可卡因自我给药（例如，负结果更新），（2）中脑D3 BPND预测 可卡因服用行为和积极的结果更新相关，但可卡因自我管理破坏 前额叶皮层（PFC）mGlu 5 BPND，并与消极结果更新，（3）积极- 结果更新是由杏仁核投射到PFC控制的，而消极结果更新是由杏仁核投射到PFC控制的。 由PFC投射到延髓核（NAc）控制。这些发现总体上表明， 介导可卡因服用行为脆弱性的生物行为机制与那些 并确定中脑D3和皮质mGlu 5受体是关键的 介质的易感性和可卡因使用的后果。的功能相关性 中脑多巴胺D3和皮质mGlu 5 BPND对成瘾相关神经活动的影响 然而，行为是未知的。本文提出的研究将调查D3和mGlu 5 BPND在 大鼠决策和药物寻求行为的回路水平机制。我们将使用正电子发射 断层扫描（PET）和钙成像与纤维光度测定，以确定如何D3和mGlu 5 BPND 与可卡因自我给药前后大鼠的回路水平活动相关。在目标1中， 探讨中脑多巴胺D3 BPND的个体差异与动态神经功能缺损的关系 在决策过程中皮质边缘回路的活动和随后的可卡因自我管理行为。 在目标2中，我们将确定mGlu 5介导的信号传导和神经活动的中断如何介导 成瘾相关（寻求/服用）行为，并在短期和长期后改变决策策略 自我注射可卡因的禁忌总之，我们的综合性和新颖的方法-结合 复杂的行为任务，计算分析，用钙纤维记录神经活动 光度测定和PET成像-将确定功能的影响和神经生物学机制， 决策电路及其在成瘾脆弱性和病理学中的作用。