Possible Significance of Cholinergic Influence in ADHD

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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.