Individual Differences & Cocaine Effects on Impulsive Choice in Rat

个体差异

基本信息

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
项目类别：
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

项目摘要

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.

可卡因的依赖性与影响影响的中脑功能失调的中脑皮层 - 纹状体电路决策过程并导致强迫性毒品行为的发展。我们的新和以前的资助期发布的数据表明，（1）强化学习机制预测可卡因的行为（例如，积极结果更新）与受到干扰的行为不同可卡因自我管理（例如，负面结果更新），（2）中脑D3 BPND可预测可卡因的行为和与积极成果更新有关的行为，但可卡因自我管理会破坏前额叶皮质（PFC）mglu5 bpnd，与负面结果更新有关，（3）结果更新由Amygdala项目控制到PFC，而负面结果更新为由PFC项目控制给伏隔核（NAC）。这些发现共同表明介导可卡因行为的脆弱性的生物行为机制与那些行为的行为不同被慢性可卡因暴露破坏，并识别中脑D3和皮质MGLU5受体作为关键可卡因使用的易感性和后果的介体。功能相关性与成瘾有关的神经活动中的中脑多巴胺D3和皮质mglu5 但是，行为尚不清楚。这里提出的研究将研究D3和MGLU5 BPND在大鼠决策和寻求药物行为的电路级机制。我们将使用极地排放用纤维光度法（PET）和钙成像确定D3和MGLU5 BPND的样子与可卡因自我管理之前和之后大鼠的电路级活动相关。在目标1中，我们将研究中脑多巴胺D3 BPND中的个体差异与动态中性之间的关系在决策过程中和随后的可卡因自我给药行为中，皮质膜电路的活性。在AIM 2中，我们将确定MGLU5谷氨酸能信号和神经活动中的破坏如何介导与成瘾相关（寻求/采取）行为，并在短期和长时间改变决策策略可卡因自我管理的禁欲。一起，我们的整合和新颖的方法 - 结合软化行为任务，计算分析，钙纤维的神经活动的体内记录光度法和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中的作用。