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.

尽管许多人偶尔吸毒，但很少有人对毒品上瘾。其作用机制 成瘾易感性和药物诱导的病理因素相互作用从而增加吸毒的可能性 依存度仍然未知。越来越多的证据表明，药物依赖与 可卡因使用障碍(CUD)患者的功能障碍冲动决策过程 低估(勒.，贴现)未来的回报，倾向于更小的，即时的回报，在更大程度上超过他们 没有上瘾的同龄人。因此，通过各种跨期选择任务来衡量奖励的时间折扣， 已被认为是成瘾的行为标志，这可能是由于异常的多巴胺(DA)和 5-羟色胺(5-羟色胺)在中脑区和包括腹内侧区在内的皮质纹状体回路中的信号传递 前额叶皮质(VmPFC)和纹状体。CUD的研究表明，D3受体在中脑的可用性增加， 降低vmPFC中5HT1b的可用性，并提高冲动选择的水平。此外，我们的飞行员 大鼠正电子发射断层扫描(PET)数据显示纹状体L1C-PHNO结合增加是正的 与随后的可卡因自我管理和选择行为的个体差异相关，这 强调脆弱性因素对可卡因使用的影响。我们还发现，D2I3受体可以调节 灵活的决策，但尚不清楚这些受体如何影响冲动选择或可卡因自身 行政管理。这里我们将使用跨各种随机呈现的延迟的延迟折扣过程， 结合两种PET示踪剂(11C-1)，可以在大鼠的时间折扣中产生强大的个体差异。 D3的PHNO和5HT18受体的11C-P943)、受体特异性药理学和可卡因自身 对这些被提出的成瘾生物行为标志物进行调查。 在目标1中，我们将研究皮质纹状体D3的个体差异与 5HT1b受体与冲动选择和可卡因自我给药。在目标2中，我们将评估 可卡因在皮质纹状体D3和5HT18受体上的自我给药和纵向冲动选择 PET/行为分析和体外分析。最后，在目标3中，我们将确定中脑D3和 VmPFC 5HT18受体在可卡因诱导的冲动选择增强中调节信号。在……里面 根据临床前和临床研究，我们预测冲动选择的个体差异是 VmPFC 5HT1Band和可卡因诱导的中脑D3受体改变对此的调节作用 发出信号，增强冲动。我们在大鼠身上的研究将补充对Cud个体的研究。 通过使用纵向神经成像，大脑靶点的药物操纵，以及体外 验证PET成像结果，同时保持冲动选择的常见行为指标。