Individual differences & cocaine effects on impulsive choice in rats: D3/5HT1B

个体差异

• 批准号: 9891993
• 负责人: Jane R Taylor
• 金额: $ 37.7万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891993
• 关键词: Abstinence; Addictive Behavior; Affinity; Agonist; Behavior; Behavioral; Brain; Brain region; Choice Behavior; Chronic; Clinical Research; Cocaine; Cocaine Dependence; Complement; Corpus striatum structure; Data; Decision Making; Development; Disease; Dopamine; Drug Addiction; Drug usage; Etiology; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Future; Human; Image; Impairment; Impulsive Behavior; Impulsivity; Individual; Individual Differences; Lead; Measurement; Measures; Mediating; Midbrain structure; Pathologic; Pharmaceutical Preparations; Pharmacology; Positron-Emission Tomography; Prefrontal Cortex; Procedures; Process; Rattus; Research; Rewards; Risk; Role; Self Administration; Serotonin; Signal Transduction; Structure; Symptoms; System; TIRAP gene; Testing; Tracer; Validation; Variant; Ventral Striatum; addiction; biobehavior; cocaine exposure; cocaine use; discount; discounting; flexibility; in vivo; longitudinal positron emission tomography; monoamine; multimodality; neurobiological mechanism; neurochemistry; neuroimaging; nonhuman primate; peer; pre-clinical research; receptor; receptor binding; receptor density; relating to nervous system

Although many people engage in occasional drug use, few become drug-dependent. The mechanisms by which addiction vulnerability and drug-induced pathological factors interact to increase the likelihood of drug dependence remain unknown. Mounting evidence suggests that drug dependence is strongly associated with dysfunctional impulsive decision-making processes in which individuals with cocaine-use disorder (CUD) undervalue (Le., discount) future rewards in favor of smaller, immediate rewards to a greater extent than their non-addicted peers. Thus, temporal discounting of reward, as measured by various intertemporal choice tasks, has been proposed as a behavioral marker of addiction, which may be due to aberrant dopamine (DA) and serotonin (5HT) signaling within midbrain regions and corticostriatal circuits including the ventromedial prefrontal cortex (vmPFC) and striatum. Studies in CUD show elevated D3 receptor availability in the midbrain, decreased 5HT1B availability in the vmPFC and heightened levels of impulsive choice. Furthermore, our pilot rat positron emission tomography (PET) data demonstrate increased striatal l1C-PHNO binding is positively correlated with subsequent cocaine self-administration and individual differences in choice behavior, which highlights the impact of vulnerability factors on cocaine use. We have also shown that D2I3 receptors modulate flexible decision-making but it is not known how these receptors impact impulsive choice or cocaine self- administration. Here we will use a delay discounting across various randomly presented delays procedure, which yields robust individual differences in rat temporal discounting, in combination with two PET tracers (11C- PHNO for D3 and 11C-P943 for 5HT18 receptors), receptor-specific pharmacology and cocaine self- administration to investigate these proposed biobehavioral markers of addiction. In Aim 1, we will investigate the relationship between individual differences in corticostriatal D3 and 5HT1B receptors and impulsive choice and cocaine self-administration. In Aim 2, we will assess the impact of cocaine self-administration on corticostriatal D3 and 5HT18 receptors and impulsive choice using longitudinal PET/behavioral analyses and ex vivo analyses. Finally, in Aim 3, we will determine the role of midbrain D3 and vmPFC 5HT18 receptor regulated signaling in cocaine-induced enhancements in impulsive choice. In accordance with pre-clinical and clinical research, we predict that individual differences in impulsive choice are mediated by vmPFC 5HT1Band that cocaine induced-changes of midbrain D3 receptors modulates this signaling, yielding enhancements in impulsivity. Our studies in rats will complement studies in CUD individuals through the use of longitudinal neuroimaging, pharmacological manipulation of brain targets, and ex vivo validation of PET imaging results, while maintaining the common behavioral metric of impulsive choice.

尽管许多人偶尔从事毒品使用，但很少有人会依赖毒品。机制 成瘾脆弱性和药物诱导的病理因素相互作用以增加药物的可能性 依赖性仍然未知。越来越多的证据表明，药物依赖性与 可卡因使用障碍的个体（CUD）的功能失调的冲动决策过程（CUD） 低估（LE。，折扣）将来的奖励，而支持较小，立即奖励的程度比其更大的奖励 非成瘾的同龄人。因此，通过各种跨期选择任务来衡量的奖励的时间折扣， 已被提出为成瘾的行为标志，这可能是由于异常多巴胺（DA）和 中脑区域内的5-羟色胺（5HT）信号传导，包括腹膜包括腹膜 前额叶皮层（VMPFC）和纹状体。对CUD的研究表明，中脑的D3受体的可用性升高， VMPFC中的5HT1B供应量降低，冲动选择的水平提高。此外，我们的飞行员 大鼠正电子发射断层扫描（PET）数据表明，纹状体L1C-PHNO结合的增加是积极的 与随后的可卡因自我管理和选择行为的个体差异相关， 突出了脆弱性因素对可卡因使用的影响。我们还显示D2I3受体调节 灵活的决策，但尚不知道这些受体如何影响冲动选择或可卡因自我 行政。在这里，我们将在各种随机提出的延迟过程中使用延迟折扣， 与两个宠物示踪剂相结合（11C- D3和11C-P943的PHNO，用于5HT18受体），受体特异性药理学和可卡因自我 管理这些成瘾的这些提出的生物行为标记。 在AIM 1中，我们将研究皮质纹状体D3和 5HT1B受体和冲动选择和可卡因自我管理。在AIM 2中，我们将评估 使用纵向的可卡因自我管理D3和5HT18受体以及冲动选择 宠物/行为分析和离体分析。最后，在AIM 3中，我们将确定中脑D3和 VMPFC 5HT18受体调节可卡因诱导的脉冲选择增强的信号传导。在 根据临床前和临床研究，我们预测，冲动选择的个体差异是 由VMPFC 5HT1带介导的可卡因诱导中脑D3受体变化可调节这一点 信号传导，产生冲动性的增强。我们在大鼠中的研究将补充CUD个体的研究 通过使用纵向神经影像学，大脑靶标的药理学操纵和离体 验证PET成像结果，同时保持冲动选择的共同行为度量。