Possible Significance of Cholinergic Influence in ADHD

描述(由申请者提供)：注意缺陷障碍(ADD)与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，并在需要集中注意力的时候渴望吸烟。目前，人们正在研究尼古丁类药物以增强患有ADD的受试者的认知能力。这项建议使用动物模型从认知和成瘾的角度评估尼古丁和ADD之间的联系。我们开发了一项技术，可以使用功能磁共振成像(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，这使得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个机会。青少年自发性高血压大鼠(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中更有回报，并更增强认知功能；(2)在与认知和自我评价相关的脾后皮质，尼古丁对SHR表现出更大的神经元激活和22个尼古丁亚单位的表达；(3)尼古丁在SHR的皮质区域(脾后皮质和前额叶皮质)与杏仁核和腹侧纹状体之间产生功能性连接；(4)与尼古丁配对的感觉线索的呈现在SHR的脾后皮质和海马区产生了比对照组更大的神经活性。患有ADD的吸烟者更强的线索反应性可能会导致复发。我们的成像研究将与行为研究(成瘾和认知评估)和分子研究(激活的大脑区域中蛋白质和尼古丁亚单位的表达)协调进行。我们的目标是(1)识别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，以及(3)证明可以在清醒的动物中测量大脑对条件性药物线索的反应。这项研究具有新颖性和重要意义，因为它采用了跨学科的方法，使用了一种新的技术，评估了以前未确定的感兴趣脑区之间的功能连接的可能性，并在ADD动物模型中检查了尼古丁的治疗潜力。我们研究的一个目标是能够在人类和动物身上进行同样的实验，使用功能磁共振成像来研究成瘾和成瘾。考虑到吸烟对青少年的公共健康影响，特别是在患有ADD的青少年中，拟议的研究具有重要意义，因为他们通常很难戒烟。 公共卫生相关性：目前的提案将通过探索尼古丁暴露对ADA动物模型中认知和成瘾指标的影响来解决吸烟和ADD之间的联系，ADAS动物模型通过行为、大脑激活和尼古丁受体亚单位基因表达的变化来表现。据我们所知，这项拟议的研究将首次在ADD动物模型中评估大脑激活和烟碱亚单位对奖励线索和认知线索的反应。这项拟议的研究可能有助于更好地了解选择性尼古丁类药物作为治疗ADD的一类新药物的潜在疗效。由于ADD是一个终生的挑战，这些结果可能对许多个人和家庭有用。

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.