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Trans-generational effects of nicotine self-administration

尼古丁自我给药的跨代效应

基本信息

批准号：
9242612
负责人：
HEATH D SCHMIDT
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242612
关键词：
Adolescent Affect Animal Model Behavior Behavioral Behavioral Paradigm Brain Brain region Candidate Disease Gene ChIP-seq Child Chronic Chronic lung disease Clinical Cohort Effect Coupled DNA DNA Methylation Data Development Electrophysiology (science)Environment Epidemiology Epigenetic Process Event Exploratory/Developmental Grant Exposure to Female Future Future Generations Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Transcription Goals Heart Diseases Heritability High-Throughput Nucleotide Sequencing Human Immunoprecipitation Incidence Inherited Literature Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Mediating Modeling Molecular Molecular Profiling Molecular Target Nicotine Nicotine Dependence Nucleus Accumbens Opioid Parents Pharmaceutical Preparations Phenotype Pilot Projects Play Predisposition Psychological reinforcement Rattus Research Risk Rodent Model Role Saline Self Administration Self-Administered Smoke Smoking Smoking Behavior Sucrose Tobacco smoke Tobacco smoking addiction behavior influence behavioral plasticity body system chromatin immunoprecipitation chromatin remodeling drug discovery drug of abuse early onset epidemiology study experience experimental study genome-wide high risk intergenerational male methylation pattern novel offspring programs psychostimulant public health relevance reinforced behavior reinforcer smoking cessation transmission process

项目摘要

DESCRIPTION (provided by applicant): Tobacco smoking results in the development of variable illness ranging from chronic lung and heart disease to cancer of multiple organ systems. Recent evidence indicates that paternal smoking is associated with nicotine dependence and increased incidence of childhood cancer in offspring. These findings indicate that tobacco smoke is capable of affecting behavioral phenotypes in future generations. Here, we describe a novel rodent model developed in order to delineate a heritable phenotype resulting from the self-administration of nicotine. We found that both male and female offspring of nicotine-experienced sires had increased nicotine self- administration when compared to the offspring of yoked saline controls. These exciting and provocative results are consistent with human epidemiological studies and suggest that nicotine-experienced sires confer increased/enhanced susceptibility to nicotine dependence in their offspring. The proposed research utilizes this animal model to further characterize the trans-generational effects of paternal nicotine self-administration. The experiments outlined in Aim 1 will evaluate the acquisition and maintenance of nicotine self-administration in the offspring (F1) and grandoffspring (F2) of male rats that self-administered nicotine. Parallel studies of sucrose self-administration will also be conducted in nicotine-sired and saline-sired F1 and F2 generations in order to determine whether the effects of paternal nicotine self-administration are reinforcer-specific. While genetic factors contribute significantly to the risk of nicotine dependence in humans, the potential role of epigenetic influences on nicotine-associated heritable phenotypes remains unclear. Epigenetics is a key mechanism by which the environment can influence and interact with genes to influence behavior. Epigenetic mechanisms have been shown to underlie drug-induced behavioral plasticity by coordinating expression of gene networks in the brain. Thus, one direct mechanism by which nicotine may influence genetic events involved in the development of nicotine addiction as well as its heritability in future generations is epigenetics. However, the epigenetic mechanisms by which paternal nicotine exposure influences smoking behavior in subsequent generations have not been identified. Therefore, Aim 2 focuses on identifying potential molecular targets and epigenetic mechanisms that are associated with this heritable phenotype. We will use microarrays and chromatin immunoprecipitation coupled to ultra high-throughput sequencing (ChIP-seq) to identify genome-wide changes in total RNA expression profiles and DNA methylation patterns in the nucleus accumbens, a brain region that plays a critical role in nicotine reinforcement, of F1 and F2 nicotine-sired rats. Results from these studies will allow us to identify gene networks and epigenetic marks that regulate patrilineal transmission of increased susceptibility to nicotine reinforcement and thereby inform drug discovery programs aimed at developing novel smoking cessation medications in generations that are high risk for chronic smoking behavior.