Chronic Nicotine Effects on Receptor Subtypes

尼古丁对受体亚型的慢性影响

• 批准号: 8290471
• 负责人: DAVID C PERRY
• 金额: $ 33.81万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290471
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Age; Animals; Antibodies; Autoradiography; Behavior; Biological Assay; Birth; Brain; Brain region; Candidate Disease Gene; Cholinergic Receptors; Chronic; Cigarette; Dependence; Development; Drug Addiction; Exposure to; Gene Expression; Goals; Health; Immunoprecipitation; Individual; Knowledge; Length; Measures; Mediating; Methods; Microarray Analysis; Modeling; Morphology; Mothers; Neurons; Neurotransmitters; Nicotine; Nicotine Dependence; Pattern; Pharmacology; Phenotype; Pregnancy; Preparation; Quantitative Autoradiography; Rattus; Receptor Gene; Regimen; Regulation; Research Design; Rubidium; Saline; Smoke; Smoker; Staging; Structure; Testing; Tobacco; Vertebral column; Work; cholinergic; critical period; density; desensitization; drug of abuse; fetal tobacco exposure; functional status; in utero; mature animal; neurochemistry; neurodevelopment; neurophysiology; neurotransmitter release; offspring; postnatal; pregnant; prenatal; prenatal exposure; receptor; receptor expression; receptor function; research study; response; Acute; Address; Adolescence; Adolescent; Adult; Age; Animals; Antibodies; Autoradiography; Behavior; Biological Assay; Birth; Brain; Brain region; Candidate Disease Gene; Cholinergic Receptors; Chronic; Cigarette; Dependence; Development; Drug Addiction; Exposure to; Gene Expression; Goals; Health; Immunoprecipitation; Individual; Knowledge; Length; Measures; Mediating; Methods; Microarray Analysis; Modeling; Morphology; Mothers; Neurons; Neurotransmitters; Nicotine; Nicotine Dependence; Pattern; Pharmacology; Phenotype; Pregnancy; Preparation; Quantitative Autoradiography; Rattus; Receptor Gene; Regimen; Regulation; Research Design; Rubidium; Saline; Smoke; Smoker; Staging; Structure; Testing; Tobacco; Vertebral column; Work; cholinergic; critical period; density; desensitization; drug of abuse; fetal tobacco exposure; functional status; in utero; mature animal; neurochemistry; neurodevelopment; neurophysiology; neurotransmitter release; offspring; postnatal; pregnant; prenatal; prenatal exposure; receptor; receptor expression; receptor function; research study; response

DESCRIPTION (provided by applicant): The CNS effects of nicotine are mediated by multiple subtypes of neuronal nicotinic cholinergic receptors (nAChRs). The effects of nicotine after chronic administration differ from those after acute administration, and nicotine effects also vary at different stages of development. Our previous work characterized the effects of chronic nicotine on expression and function of different subtypes of nAChRs. Knowledge of the shifting expression pattern of these receptors during nicotine use is critical for understanding cholinergic neurophysiology as well as nicotine pharmacology. Chronic nicotine is associated with dependence, changes in gene expression and behavior, and altered neural development. This latter effect is of critical importance given the widespread exposure to nicotine that occurs during periods of critical neural development, particularly due to prenatal exposure from mothers who smoke or use NRT products, and adolescents who are beginning to experiment with tobacco. Prenatal nicotine exposure can have profound effects upon subsequent development and behavior of offspring. Adolescent exposure to nicotine is associated with higher rates of adult dependence, both to nicotine and to other drugs of abuse. Thus these represent uniquely vulnerable periods for nicotine exposure. The overarching goal of the present proposal is to compare the effects of chronic nicotine exposure at three critical ages: prenatal, adolescence and adult. We will employ rat models to study the overlapping effects of chronic nicotine exposure on nAChR expression and function, neuronal morphology and gene expression; we will focus on receptors, genes and brain regions associated with nicotine dependence. In particular, we will examine for persistent effects of nicotine exposure on these parameters. These studies will test the general hypothesis that nicotine's effects on these parameters differ at different developmental stages of exposure. In particular, Aim 4 will test the hypothesis that prenatal nicotine exposure inhibits the response of adolescents to subsequent nicotine challenge, increasing the number of cigarettes smoked and thus the likelihood of subsequent dependence. For each of the following Specific Aims, we will test for both the short-term and persistent effects of chronic nicotine exposure on expression (using autoradiography and immunoprecipitation) and function (using rubidium efflux and neurotransmitter release) of nAChR subtypes, alteration of neuronal morphology (measuring dendritic length and spine density), and changes in global gene expression (using microarrays and rtPCR) in brain regions associated with nicotine dependence. Differential developmental effects will be determined by comparison across aims. SPECIFIC AIMS 1. Determine the immediate and the persistent direct effects of prenatal chronic nicotine exposure. 2. Determine the immediate and the persistent direct effects of adolescent chronic nicotine exposure. 3. Determine the immediate and the persistent direct effects of adult nicotine exposure. 4. Determine the persistent indirect effects of prenatal nicotine exposure by determining how prenatal nicotine exposure alters the ability of the adolescent to respond to a new nicotine exposure PUBLIC HEALTH RELEVANCE: This work will address hypotheses critical for understanding how chronic exposure to nicotine, such as occurs in tobacco smokers and NRT users, can alter receptor expression and function, neuronal structure, and gene expression. The work will measure nicotine's effects on these parameters caused by prenatal exposure in rats, and compare them to those effects from exposure during adolescence and adulthood. These studies should help to better understand the unique age-specific effects underlying vulnerability to nicotine's effects at these younger ages.

描述（由申请人提供）：尼古丁的CNS效应是由神经元烟碱胆碱能受体（NACHRS）的多种亚型介导的。长期给药后尼古丁的作用与急性给药后的尼古丁不同，而尼古丁的影响在不同的发育阶段也有所不同。我们以前的工作表征了慢性尼古丁对NACHRS不同亚型表达和功能的影响。在使用尼古丁期间，这些受体的转移表达模式的知识对于理解胆碱能神经生理学以及尼古丁药理学至关重要。慢性尼古丁与依赖性，基因表达和行为的变化以及神经发育改变有关。鉴于在关键神经发育期间发生的尼古丁的广泛暴露，特别是由于吸烟或使用NRT产品的母亲以及开始尝试烟草的青少年，这是至关重要的。产前尼古丁暴露会对后代的后续发展和行为产生深远的影响。青少年接触尼古丁与尼古丁和其他滥用药物的成人依赖率更高。因此，这些代表了尼古丁暴露的独特脆弱时期。本提案的总体目标是比较三个关键时代的慢性尼古丁暴露的影响：产前，青春期和成人。我们将采用大鼠模型来研究慢性尼古丁暴露对NACHR表达和功能，神经元形态和基因表达的重叠影响。我们将专注于与尼古丁依赖性相关的受体，基因和大脑区域。特别是，我们将研究尼古丁暴露对这些参数的持续影响。这些研究将检验一个总体假设，即在暴露的不同发育阶段，尼古丁对这些参数的影响有所不同。特别是，AIM 4将检验以下假设：产前尼古丁暴露抑制青少年对随后的尼古丁挑战的反应，从而增加吸烟的香烟数量，从而增加随后的依赖性。 For each of the following Specific Aims, we will test for both the short-term and persistent effects of chronic nicotine exposure on expression (using autoradiography and immunoprecipitation) and function (using rubidium efflux and neurotransmitter release) of nAChR subtypes, alteration of neuronal morphology (measuring dendritic length and spine density), and changes in global gene expression (using microarrays and rtpcr）在与尼古丁依赖性相关的大脑区域中。差异发育效果将通过对目标进行比较来确定。具体目的1。确定产前慢性尼古丁暴露的直接和持续直接影响。 2。确定青少年慢性尼古丁暴露的直接和持续直接影响。 3。确定成年尼古丁暴露的直接和持续直接影响。 4. Determine the persistent indirect effects of prenatal nicotine exposure by determining how prenatal nicotine exposure alters the ability of the adolescent to respond to a new nicotine exposure PUBLIC HEALTH RELEVANCE: This work will address hypotheses critical for understanding how chronic exposure to nicotine, such as occurs in tobacco smokers and NRT users, can alter receptor expression and function, neuronal structure, and gene expression.这项工作将测量尼古丁对大鼠产前暴露引起的这些参数的影响，并将其与青春期和成年期暴露的影响进行比较。这些研究应有助于更好地理解这些年轻年龄段尼古丁影响的独特特异性影响。