Development Of New Approaches To Neuroimaging with PET and SPECT

开发 PET 和 SPECT 神经影像新方法

• 批准号: 7966775
• 负责人: ELLIOT A STEIN
• 金额: $ 59.1万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966775
• 关键词: Adolescent; Affect; Affinity; Animal Experimentation; Animals; Anterior; Anxiety; Arts; Autopsy; Binding; Biological; Biological Assay; Brain; Brain region; Cerebellum; Characteristics; Corpus Callosum; Dependence; Development; Disease; Dissociation; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug abuse; Early-life trauma; Female; Gated Ion Channel; Human; Human Volunteers; Image; In Vitro; Individual; Lead; Life Stress; Ligands; Literature; Macaca mulatta; Measures; Medial; Mediating; Mediation; Methodology; Methods; Midbrain structure; Modeling; Monkeys; Motivation; Neurobiology; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Panic Disorder; Perinatal; Pharmaceutical Preparations; Play; Pontine structure; Positron-Emission Tomography; Prefrontal Cortex; Property; Psychological reinforcement; Reinforcement Schedule; Rewards; Role; Saimiri; Sampling; Self-Administered; Serotonin; Smoke; Smoker; Smoking; Smoking Behavior; Stress; System; Thalamic structure; Tobacco smoke; Up-Regulation; Woman; base; brain tissue; cholinergic; cingulate cortex; density; depression; frontal lobe; in vivo; interest; male; method development; neuroimaging; neuropsychiatry; nicotine abuse; non-smoker; nonhuman primate; novel strategies; peer; preference; psychostimulant; putamen; receptor; receptor density; single photon emission computed tomography; smoking cessation; social; trait; transmission process

Part of this project determined if differences in nAChR density between smokers and non-smokers could be shown in vivo with PET and to determine the neuroanatomical extent of the difference. We used dynamic PET imaging with 2F-18F-A-85380 (2FA) to measure total volume of distribution (VT) in non-smokers and heavy smokers. Values for VT obtained by several modeling methods using a metabolite-corrected arterial input function for 2FA yielded similar results. The thalamus (TH), midbrain (MB), pons (P), cerebellum (CB), frontal cortex (FC), putamen (PUT) and corpus callosum (CC) were sampled. VT was significantly higher in smokers than in nonsmokers in CB, FC, MB, P and PUT. PET imaging of nAChRs suggests that it can be used to study the role of nicotine-induced upregulation of nAChRs in smoking behaviors and in smoking cessation. Low serotonin1A receptor (5-HT1AR) binding, measured by both in vivo positron emission tomography (PET) and in vitro binding assays of post mortem brain tissue, is found in individuals with several stress-related neuropsychiatric disorders, including depression, social anxiety and panic disorders. Low serotonin1A receptor density during development is proposed as a trait characteristic leading to increased vulnerability of stress-related neuropsychiatric disorders. To assess the relationship between early-life stress and alterations in serotonin system during development, we used positron emission tomography. We measured serotonin1A receptor availability, density and apparent dissociation constant in different brain regions of juvenile rhesus monkeys exposed to early-life stress in the form of peer-rearing. Compared with controls, serotonin1A receptor availability was elevated in peer-reared females in the dorsomedial prefrontal cortex, and decreased in peer-reared males in the anterior and medial cingulate cortex. We speculate that these changes were mainly driven by decreased serotonin levels (measured as changes in apparent dissociation constant), rather than changes in receptor density. In addition, lower serotonin levels were found in females compared to males independent of early-life stress exposure. Early-life stress differentially affects the serotonin system in juvenile male and female monkeys. The decrease in serotonin levels found in juvenile females and animals exposed to stress provides a biological basis for the increased vulnerability to stress-related neuropsychiatric disorders in women exposed to early-life trauma what can lead to drug abuse. Marked interindividual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain alpha4beta2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of interindividual differences in midbrain nAChR levels on motivation to self-administer nicotine. Baseline levels of alpha4beta2* nAChRs were measured using 2-(18)Ffluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio (PR) schedule of reinforcement. Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs. The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D(2) receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and nonhuman primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems.

该项目的一部分确定了吸烟者和非吸烟者之间nAChR密度的差异是否可以用PET在体内显示，并确定差异的神经解剖学程度。我们使用2F-18F-A-85380（2FA）进行动态PET成像，以测量非吸烟者和重度吸烟者的总分布容积（VT）。通过几种建模方法获得的VT值使用代谢物校正的动脉输入函数2FA产生了类似的结果。取丘脑（TH）、中脑（MB）、脑桥（P）、小脑（CB）、额叶皮质（FC）、壳核（PUT）和胼胝体（CC）。吸烟者的VT在CB、FC、MB、P和PUT上均显著高于非吸烟者。nAChRs的PET成像表明，它可用于研究尼古丁诱导的nAChRs上调在吸烟行为和戒烟中的作用。 通过体内正电子发射断层扫描（PET）和死后脑组织的体外结合试验测量，在患有几种与压力相关的神经精神障碍（包括抑郁症、社交焦虑和恐慌症）的个体中发现了低的降钙素1A受体（5-HT 1AR）结合。在发展过程中的低doponin 1A受体密度被认为是一种特质特征，导致与压力相关的神经精神疾病的脆弱性增加。为了评估早期生活压力与发育过程中血清素系统变化之间的关系，我们使用了正电子发射断层扫描。我们测量了幼年恒河猴暴露于同伴养育形式的早期生活压力下不同脑区的降钙素1A受体的可用性、密度和表观解离常数。与对照组相比，同龄女性背内侧前额叶皮质中的阿托宁1A受体的可用性升高，而同龄男性前扣带皮层和内侧扣带皮层中的阿托宁1A受体的可用性降低。我们推测，这些变化主要是由血清素水平下降（测量表观解离常数的变化），而不是受体密度的变化。此外，较低的血清素水平被发现在女性相比，男性独立的早期生活压力暴露。早期生活压力对幼年雄性和雌性猴子血清素系统的影响不同。在青少年女性和动物暴露于压力的血清素水平的下降提供了一个生物学基础上增加的脆弱性，以压力相关的神经精神疾病的妇女暴露于早期生活的创伤，这可能导致药物滥用。 尼古丁依赖的易感性存在明显的个体间差异，但这种差异背后的因素还没有得到很好的理解。烟碱乙酰胆碱受体（nAChR）的中脑α 4 β 2 * 亚型参与了尼古丁依赖性增强效应的介导。然而，尚未进行研究评估中脑nAChR水平的个体间差异对自我给予尼古丁的动机的影响。在5只松鼠猴中，使用2-（18）Ffluoro-A-85380（2-FA）和正电子发射断层扫描（PET）测量了α 4 β 2 * nAChR的基线水平。随后使用渐进比（PR）强化计划测量自我给予尼古丁的动机（压杆次数）。自我给予尼古丁的更大动机与中脑nAChR水平较低相关。结果表明，nAChRs的表达水平是尼古丁依赖发展的一个促成因素。类似地，先前已经表明，低水平的多巴胺D（2）受体（DRD 2）与人类和非人类灵长类动物对精神兴奋剂使用的更高偏好有关。总之，这些多巴胺能和烟碱胆碱能传递的PET研究结果表明，在不同的神经递质系统中，介导强化的受体的可用性与服用药物的动机之间存在反比关系。