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.

可卡因依赖与功能失调的中脑皮质-边缘-纹状体回路有关，影响 决策过程并导致强迫性寻求药物行为的发展。我们的新和 先前资助期公布的数据表明（1）强化学习机制 预测可卡因吸食行为（例如，积极结果更新）与以下被破坏的行为不同 可卡因自我给药（例如，阴性结果更新），(2) 中脑 D3 BPND 可以预测 可卡因服用行为并与积极结果更新相关，但可卡因自我管理会扰乱 前额皮质 (PFC) mGlu5 BPND 与消极结果更新相关，并且 (3) 积极- 结果更新由杏仁核对 PFC 的投射控制，而负结果更新则由杏仁核投射到 PFC 控制。 由 PFC 投射到伏隔核 (NAc) 控制。这些发现总的来说表明 调节可卡因吸食行为脆弱性的生物行为机制不同于那些 因长期接触可卡因而受到干扰，并确定中脑 D3 和皮质 mGlu5 受体至关重要 分别是可卡因使用的易感性和后果的中介因素。功能相关性 中脑多巴胺 D3 和皮质 mGlu5 BPND 对成瘾相关神经活动的影响 然而，行为尚不清楚。这里提出的研究将调查 D3 和 mGlu5 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) 和钙成像与光纤光度测定法，以确定 D3 和 mGlu5 BPND 的情况 与大鼠自我施用可卡因之前和之后的电路水平活动相关。在目标 1 中，我们将 探讨中脑多巴胺D3 BPND个体差异与动态神经元的关系 决策过程中皮质边缘回路的活动以及随后的可卡因自我给药行为。 在目标 2 中，我们将确定 mGlu5 谷氨酸信号传导和神经活动的破坏如何介导 与成瘾相关的（寻求/接受）行为并在短期和长期后改变决策策略 戒断自我服用可卡因。总之，我们的综合和新颖的方法 – 结合 复杂的行为任务、计算分析、钙纤维神经活动的体内记录 光度测定和 PET 成像——将确定功能影响和神经生物学机制 决策回路及其在成瘾脆弱性和病理学中的作用。