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.

虽然许多人偶尔使用毒品，但很少有人成为毒品依赖者。的机制 成瘾脆弱性和药物引起的病理因素相互作用，增加药物滥用的可能性， 依赖性仍然未知。越来越多的证据表明，药物依赖与 可卡因使用障碍（CUD）患者的冲动决策过程功能障碍， 低估（即，折扣）未来的奖励，有利于较小的，即时的奖励，在更大程度上比他们的 不上瘾的同龄人因此，奖励的时间折扣，通过各种跨期选择任务来测量， 已被提出作为成瘾的行为标志物，这可能是由于异常的多巴胺（DA）， 中脑区域和皮质纹状体回路内的5-羟色胺（5-HT）信号传导，包括腹内侧 前额叶皮层（vmPFC）和纹状体。对CUD的研究显示中脑中D3受体的可用性升高， VMPFC中5HT1B可用性降低，冲动选择水平升高。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结合的增加是阳性的， 与随后的可卡因自我管理和选择行为的个体差异相关， 强调了脆弱性因素对可卡因使用的影响。我们还表明，D2I3受体调节 灵活的决策，但目前还不知道这些受体如何影响冲动的选择或可卡因自我， 局在这里，我们将使用各种随机呈现的延迟过程的延迟折扣， 其在大鼠时间折扣中产生稳健的个体差异，结合两种PET示踪剂（11C-11D）， PHNO用于D3和11C-P943用于5HT 18受体）、受体特异性药理学和可卡因自身 管理调查这些建议的成瘾生物行为标志物。 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 可卡因自身给药对皮质纹状体D3和5HT18受体的影响以及使用纵向 PET/行为分析和离体分析。最后，在目标3中，我们将确定中脑D3的作用， 在可卡因诱导的冲动选择增强中，vmPFC 5HT18受体调节信号传导在 根据临床前和临床研究，我们预测冲动选择的个体差异是 可卡因诱导的中脑D3受体的变化调节了这一过程 信号，产生冲动的增强。我们对大鼠的研究将补充对CUD个体的研究 通过使用纵向神经成像、脑靶的药理学操作和离体 验证PET成像结果，同时保持冲动选择的常见行为度量。