Possible Significance of Cholinergic Influence in ADHD

描述（由申请人提供）：注意力缺陷障碍（ADD）和青少年吸烟之间有很强的联系。我们的研究表明，患有ADD的青少年吸烟者更容易对尼古丁上瘾，并且在需要集中注意力时渴望吸烟。目前，烟碱类药物正在研究，以提高认知能力的主体与ADD。本建议评估尼古丁和ADD之间的联系，在认知和成瘾使用动物模型。我们已经开发出了使用功能性MRI（fMRI）和功能连接来测量完全清醒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。这一创新提供了第一次机会来评估清醒动物对条件性药物相关刺激的大脑激活反应。青春期自发性高血压大鼠（SHR）是一种胆碱能功能缺陷的ADD动物模型。我们的初步研究表明：（1）与其亲本品系相比，尼古丁在SHR中更具奖励性，并且更多地增强了认知功能，（2）SHR表现出更大的神经元激活和更大的22个烟碱亚基表达，以响应压后皮质中的尼古丁暴露，压后皮质是与认知和自我评价相关的区域，（3）尼古丁产生皮质区域之间的功能连接（压后和前额叶皮质）和杏仁核和腹侧纹状体的SHR，（4）预先与尼古丁配对的感觉线索的呈现在SHR的压后皮质和海马中产生比对照组更大的神经反应性。更大的提示反应性吸烟者与添加可能有助于复发。我们的成像研究将与行为（成瘾和认知评估）和分子研究（激活脑区的蛋白质和烟碱亚基表达）一起进行。我们的目标是（1）确定SHR中伴随ADD和尼古丁奖赏增强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提示的反应可以在清醒动物中测量。这项研究是新颖的和重要的，由于其跨学科的方法，使用一种新的技术，以前未识别的大脑区域的利益和尼古丁的治疗潜力的检查之间的功能连接评估的潜力在ADD的动物模型。我们的研究的一个目标是能够进行相同的实验，使用功能磁共振成像在人类和动物研究ADD和成瘾。考虑到青少年吸烟对公共健康的影响，特别是在患有ADD的青少年中，他们通常很难戒烟，因此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.