Possible Significance of Cholinergic Influence in ADHD

描述（由申请人提供）：注意缺陷障碍（ADD）和青少年吸烟之间有很强的联系。我们的研究表明，患有注意力缺陷多动症的青少年吸烟者在需要集中注意力的时候更容易对尼古丁上瘾，更渴望吸烟。目前，人们正在研究尼古丁制剂以提高ADD受试者的认知表现。本提案通过动物模型评估尼古丁与ADD在认知和成瘾方面的联系。我们已经开发了一种技术，利用功能磁共振成像（fMRI）和功能连接来测量全意识大鼠的大脑活动。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接，使研究清醒动物的认知和成瘾相关事件成为可能。这一创新为评估清醒动物对条件药物相关刺激的大脑激活提供了第一次机会。青少年自发性高血压大鼠（SHR）是一种胆碱能功能不足的ADD动物模型。我们的初步研究表明(1)尼古丁在SHR中比亲本品系更有回报，更能增强认知功能；(2)在尼古丁暴露的情况下，SHR在与认知和自我评价相关的脾后皮层中表现出更大的神经元激活和22个尼古丁亚基的更多表达。(3)尼古丁在SHR皮层区域（脾后和前额叶皮层）与杏仁核和腹侧纹状体之间产生功能连接；(4)在SHR中，先前与尼古丁配对的感觉线索的呈现在脾后皮层和海马中产生比对照组更大的神经反应性。adhd吸烟者更强的线索反应性可能导致复发。我们的影像学研究将与行为（成瘾和认知评估）和分子研究（激活脑区的蛋白质和尼古丁亚基表达）一起进行。我们的目标是：(1)确定在SHR中伴随ADD和尼古丁奖励增加的神经元激活的差异，(2)评估尼古丁如何改变大脑回路，(3)证明大脑对条件药物线索的反应可以在清醒的动物中测量。这项研究是新颖而重要的，因为它采用了跨学科的方法，使用了一种新技术，有可能评估以前未识别的大脑区域之间的功能连接，并在动物模型中检查尼古丁的治疗潜力。我们的研究目标是能够在人类和动物中使用fMRI进行相同的实验来研究ADD和成瘾。考虑到青少年吸烟对公共健康的影响，尤其是对那些通常很难戒烟的多动症青少年来说，拟议的研究具有重要意义。

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.