Nicotinic Acetylcholine Receptors and Inhibitory Behavior

烟碱乙酰胆碱受体和抑制行为

• 批准号: 8144922
• 负责人: David J Bucci
• 金额: $ 22.99万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144922
• 关键词: Acetylcholine; Adolescence; Adolescent; Adult; Affect; Age; Agonist; Animal Model; Animals; Antismoking; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Binding Sites; Brain; Cardiovascular Diseases; Cessation of life; Child; Cigarette Smoker; Clinical; Cues; Data; Denervation; Development; Disease; Dose; Exhibits; Female; Functional disorder; Hippocampus (Brain); Human; Immunoglobulin G; Immunotoxins; Impaired cognition; Impairment; Impulsivity; Inbred SHR Rats; Injection of therapeutic agent; Learning; Left; Lesion; Link; Literature; Lung diseases; Malignant Neoplasms; Measures; Medial; Mediating; Memory; Mental disorders; Methylphenidate; Modeling; Nicotine; Nicotine Dependence; Nicotinic Receptors; Performance; Persons; Population; Prefrontal Cortex; Primates; Procedures; Rat Strains; Rattus; Reporting; Research; Rest; Rewards; Rodent; Role; Schizophrenia; Sex Characteristics; Signal Transduction; Smoke; Smoking; Statutes and Laws; Stimulus; Structure; System; Techniques; Testing; Training; Treatment Protocols; United States; Withholding Treatment; Work; addiction; basal forebrain; base; brain behavior; cholinergic; cigarette smoking; experience; improved; insight; male; neuromechanism; neurotoxic; nicotine abuse; nicotine replacement; public health relevance; research study; response; smoking cessation; success; theories; young adult

DESCRIPTION (provided by applicant): Although recent anti-smoking campaigns and legislation have achieved success in reducing the number of adult cigarette smokers, other populations have been not so positively affected. For instance, there continues to be high rates of nicotine use in adolescents as well as in various clinical populations, including those with schizophrenia or Attention- Deficit/Hyperactivity Disorder (ADHD). Despite substantial research, it remains unclear why nicotine use is high in these groups. Various theories have been proposed, including the notion that nicotine is used to alleviate dysfunctional reward systems and that nicotine is used to self-medicate for cognitive impairment. Nicotine has beneficial effects on functions such as attention and memory, lending support to the latter theory. However, little is known about the effects of nicotine and the role of nicotinic acetylcholine receptors in regulating inhibitory behavior. Deficits in inhibition are considered among the core impairments in ADHD and are also associated with schizophrenia. Likewise, normal adolescence is often characterized by impulsivity and inhibitory deficits. To fill this gap in the literature, the proposed experiments will determine how nicotine effects inhibition using an animal model of response inhibition that is analogous to inhibition tasks commonly used in research with humans. Our preliminary data indicate that nicotine specifically enhances the ability of rats to withhold a learned response, as has been observed in humans with ADHD. Thus, the first objective will be to determine which subtype(s) of nicotinic acetylcholine receptor mediates the beneficial effects of nicotine on inhibition. This will be done using pharmacological approaches in both normal rats and a strain of rats commonly used as a model of ADHD. The second objective is to determine the brain systems through which nicotine affects inhibition. These studies will use a combination of approaches consisting of selective cholinergic denervation of the prefrontal cortex or hippocampus, and treatment with nicotinic receptor subtype-specific compounds. Finally, the third objective is to test for sex differences in the effects of nicotine on inhibitory behavior. These final experiments are based on growing reports of sex differences in cognitive dysfunction in disorders such as ADHD and differences in smoking rates between males and females. Together, these results of the proposed studies will provide new insight into how nicotine affects inhibitory behavior and promote the development of enhanced smoking cessation and treatment regimens. PUBLIC HEALTH RELEVANCE: The proposed studies will provide new insight into how nicotine and nicotinic acetylcholine receptors modulate response inhibition. Deficits in inhibition are associated with various disorders that are characterized by high rates of nicotine abuse, including schizophrenia and Attention-Deficit/Hyperactivity Disorder (ADHD). A better understanding of the contribution of nicotinic cholinergic systems to inhibition will have direct bearing on efforts to reduce smoking in these and other populations. Indeed, cigarette smoking is the leading cause of preventable death and is linked to cancer and to other lung and cardiovascular diseases. Limiting nicotine use by adolescents (with ADHD for example) is particularly important given the potential negative effects of nicotine on the developing brain.

描述（由申请人提供）：尽管最近的反吸烟运动和立法在减少成年吸烟者数量方面取得了成功，但其他人群并未受到如此积极的影响。例如，青少年以及各种临床人群中尼古丁的使用率仍然很高，包括精神分裂症或注意力缺陷/多动障碍 (ADHD) 患者。尽管进行了大量研究，但仍不清楚为什么这些群体中尼古丁的使用率很高。人们提出了各种理论，包括尼古丁用于缓解功能失调的奖励系统以及尼古丁用于自我治疗认知障碍的概念。尼古丁对注意力和记忆等功能有有益的影响，为后一种理论提供了支持。然而，人们对尼古丁的作用以及烟碱乙酰胆碱受体在调节抑制行为中的作用知之甚少。抑制缺陷被认为是 ADHD 的核心损伤之一，也与精神分裂症相关。同样，正常的青春期通常以冲动和抑制缺陷为特征。为了填补文献中的这一空白，拟议的实验将使用反应抑制动物模型来确定尼古丁如何影响抑制作用，该模型类似于人类研究中常用的抑制任务。我们的初步数据表明，尼古丁特别增强了大鼠抑制习得反应的能力，正如在患有多动症的人类中观察到的那样。因此，第一个目标是确定烟碱乙酰胆碱受体的哪种亚型介导尼古丁对抑制的有益作用。这将通过药理学方法在正常大鼠和通常用作 ADHD 模型的大鼠品系中完成。第二个目标是确定尼古丁影响抑制作用的大脑系统。这些研究将采用多种方法相结合，包括前额皮质或海马的选择性胆碱能去神经支配，以及烟碱受体亚型特异性化合物的治疗。最后，第三个目标是测试尼古丁对抑制行为的影响的性别差异。这些最终实验基于越来越多的关于多动症等疾病认知功能障碍的性别差异以及男性和女性吸烟率差异的报告。总之，拟议研究的这些结果将为尼古丁如何影响抑制行为提供新的见解，并促进加强戒烟和治疗方案的发展。 公共健康相关性：拟议的研究将为尼古丁和烟碱乙酰胆碱受体如何调节反应抑制提供新的见解。抑制缺陷与各种以尼古丁滥用率高为特征的疾病有关，包括精神分裂症和注意力缺陷/多动症（ADHD）。更好地了解烟碱胆碱能系统对抑制的贡献将对这些人群和其他人群减少吸烟的努力产生直接影响。事实上，吸烟是可预防死亡的主要原因，并且与癌症以及其他肺部和心血管疾病有关。考虑到尼古丁对大脑发育的潜在负面影响，限制青少年（例如患有多动症）使用尼古丁尤为重要。