Possible Significance of Cholinergic Influence in ADHD

胆碱能影响对多动症的可能意义

• 批准号: 8050094
• 负责人: JEAN A KING
• 金额: $ 36.44万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050094
• 关键词: Acute; Address; Adolescence; Adolescent; Amygdaloid structure; Animal Model; Animals; Area; Attention; Attention Deficit Disorder; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Brain region; Childhood; Chronic; Cigarette; Cognition; Cognitive; Conscious; Control Animal; Cues; Data; Disease; Dose; Emotions; Event; Exhibits; Exposure to; Family; Food; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Goals; Hippocampus (Brain); Human; Image; Inbred SHR Rats; Individual; Link; Maps; Measures; Messenger RNA; Methods; Modeling; Molecular; Neurons; Nicotine; Nicotinic Agents; Nicotinic Receptors; Nootropic Agents; Parents; Patients; Performance; Pharmaceutical Preparations; Pilot Projects; Prefrontal Cortex; Process; Proteins; Public Health; Rattus; Recruitment Activity; Relapse; Reporting; Research; Research Design; Rewards; Role; Sensory; Smoke; Smoker; Smoking; Stimulus; System; Technology; Therapeutic; Time; Translating; Ventral Striatum; Work; addiction; adolescent smoking; awake; base; behavior measurement; behavioral sensitization; cholinergic; cigarette smoking; cognitive function; craving; cue reactivity; drug reward; innovation; interest; neuronal patterning; new technology; nicotine craving; novel; preference; prenatal exposure; public health relevance; relating to nervous system; research study; response; smoking prevalence

DESCRIPTION (provided by applicant): There is a strong link between Attention Deficit Disorder (ADD) and adolescent smoking. Our studies demonstrate that adolescent smokers with ADD are more addicted to nicotine and crave cigarettes when they need to concentrate. Presently, nicotinic agents are being studied to enhance cognitive performance in subjects with ADD. This proposal evaluates the connections between nicotine and ADD in terms of cognition and addiction using an animal model. We have developed the technology to measure brain activity in fully conscious rats using functional MRI (fMRI) and functional connectivity. We can measure neuronal activation and functional connectivity between any two brain regions, making it possible to study cognitive and addiction-related events in awake animals. This innovation provides the first opportunity to evaluate brain activation in response to conditioned drug- related stimuli in awake animals. The adolescent Spontaneously Hypertensive Rat (SHR) is an animal model of ADD that has deficiencies in cholinergic function. Our pilot studies suggest (1) nicotine is more rewarding, and enhances cognitive function more in the SHR compared to its parent strain, (2) the SHR exhibits greater neuronal activation and greater expression of 22 nicotinic subunits in response to nicotine exposure in the retrosplenial cortex, a region that is associated with cognition and self-appraisal, (3) nicotine produces functional connectivity between cortical areas (retrosplenial and the prefrontal cortices) and the amygdala and ventral striatum in the SHR, and (4) the presentation of a sensory-cue previously paired with nicotine produces greater neural reactivity in the retrosplenial cortex and hippocampus in the SHR than in controls. Greater cue-reactivity in smokers with ADD may contribute to relapse. Our imaging studies will be performed in concert with behavioral (addiction and cognitive assessments) and molecular studies (protein and nicotinic subunit expression in activated brain regions). Our goals are (1) to identify differences in neuronal activation that accompany ADD and heightened nicotine reward in the SHR, (2) to evaluate how nicotine alters brain circuits, and (3) to demonstrate that brain responses to conditioned drug-cues can be measured in awake animals. This study is novel and significant due to its transdisciplinary approach, the use of a novel technology, the potential of assessing functional connectivity between previously unidentified brain regions of interest and an examination of the therapeutic potential of nicotine in an animal model of ADD. A goal of our research is to be able to conduct the same experiments using fMRI in humans and animals to study both ADD and addiction. The proposed studies are of significance given the public health impact of cigarette smoking in adolescence and particularly in adolescents with ADD who generally have a harder time quitting. PUBLIC HEALTH RELEVANCE: The current proposal will address the connection between smoking and ADD by exploring the impact of nicotine exposure on measures of cognition and addiction in an animal model of ADD as manifested through changes in behavior, brain activation, and nicotinic receptor subunit gene expression. To our knowledge, the proposed study will be the first to evaluate brain activation and nicotinic subunit expression in response to reward cues, and cognitive cues in an animal model of ADD. The proposed study has the potential to facilitate better understanding of the potential efficacy of selective nicotinic agents as a new class of drugs in the treatment of ADD. Since ADD is a lifelong challenge these results can be potentially of use to many individuals and families.

描述（由申请人提供）：注意力缺陷障碍（ADD）和青少年吸烟之间存在牢固的联系。我们的研究表明，在需要集中精力时，添加的青春期吸烟者更沉迷于尼古丁和渴望香烟。目前，正在研究烟碱剂，以增强ADD受试者的认知性能。该提案使用动物模型评估了尼古丁与添加的联系之间的联系。我们已经开发了使用功能性MRI（fMRI）和功能连接性来测量完全意识大鼠大脑活动的技术。我们可以测量任何两个大脑区域之间的神经元激活和功能连通性，从而可以研究清醒动物的认知和成瘾相关事件。这项创新为响应有条件药物与药物相关的动物的刺激提供了第一个评估大脑激活的机会。青少年自发性高血压大鼠（SHR）是胆碱能功能缺乏的添加动物模型。我们的试点研究表明（1）尼古丁更有意义，与父母的菌株相比，SHR的认知功能更加增强，（2）SHR表现出更大的神经元激活和22个烟碱亚基的表达，以响应于肾上腺皮质的尼古丁暴露，与后脑皮质（与认知和自我apprapriention and actiention and coptienty and coptienty and coptienty and coptiention and Cockrention and Cockrention and Cockrention and Cockrention and Cockrientiation（3）相关的区域（3）尼古丁的表达。 SHR中的前额叶皮层）和杏仁核和腹纹状体，（4）先前与尼古丁搭配的感觉 - 呈现在SHR中与对照组相比，在SHR中与尼古丁的呈现产生更大的神经反应性。吸烟者的提示反应较高可能有助于复发。我们的成像研究将与行为（成瘾和认知评估）和分子研究（激活脑区域中的蛋白质和烟碱亚基表达）一起进行。我们的目标是（1）确定伴随SHR添加和增强尼古丁奖励的神经元激活的差异，（2）评估尼古丁如何改变脑电路，（3）证明可以在清醒动物中测量对条件药物的脑反应。这项研究是新颖的，并且由于其跨学科方法，新技术的使用，评估先前未识别的感兴趣的大脑区域之间的功能连通性以及在ADD动物模型中检查尼古丁的治疗潜力的潜力。我们研究的目的是能够在人类和动物中使用fMRI进行相同的实验，以研究添加和成瘾。鉴于青春期吸烟的公共卫生影响，尤其是在添加时间通常很难戒烟的青少年中，拟议的研究具有重要意义。 公共卫生相关性：当前的提案将通过探索尼古丁暴露对ADD动物模型中认知和成瘾的影响来解决吸烟与添加之间的联系，这是通过行为，脑激活和烟碱受体亚基基因表达的变化所表现出来的。据我们所知，拟议的研究将是第一个评估大脑激活和烟碱亚基的表达，以响应奖励提示，以及在ADD动物模型中的认知提示。拟议的研究有可能更好地理解选择性烟碱剂的潜在功效，这是一类新的药物在ADD治疗中。由于添加是终生的挑战，因此这些结果可能对许多个人和家庭有可能使用。