Nicotine and impulsivity in an animal model of ADHD

描述(由申请人提供)：烟草是一种被广泛滥用的物质，对健康造成昂贵的负面影响。吸烟在各种精神疾病人群中尤其普遍，包括患有注意力缺陷多动障碍(ADHD)的青少年和成年人。ADHD是一种神经行为障碍，影响大约5%的人口；它的特征是冲动、多动和注意力不集中。据估计，ADHD患者的吸烟率是非ADHD人群的两倍。此外，ADHD与早期开始吸烟、高吸烟频率和较低的戒烟成功率有关。有人认为，ADHD和吸烟习惯之间的联系反映了ADHD人群中的一种自我用药模式。在精神科和非精神科人群中的实验研究表明，尼古丁可以缓解与ADHD相关的行为症状。这项B/START建议的重点是确定尼古丁的有益影响是否可以在ADHD的动物模型SHR中复制。这项建议专门旨在确定青少年和年轻成人SHR中与ADHD相关的冲动是否(1)因急性和长期接触尼古丁而降低，(3)因尼古丁戒断而加剧，以及(4)与对照品系相比，SHR的这些影响是更强还是更弱。实现这些目标涉及一个关键的方法挑战--测量非人类动物中与ADHD相关的冲动。通常降低精神病患者冲动的刺激性治疗在包括自发性高血压在内的不同品系的大鼠中产生更高的冲动指数。基于现有的证据和我们自己的初步数据，我们认为这种不一致是由于在传统的啮齿动物冲动评估方法中，将激励诱导活动和反应抑制能力的测量混为一谈。这一建议包括创新的经验和分析技术，将冲动参数从与活动和动机相关的混乱中分离出来，这可能适用于本建议的范围之外。我们预计这些技术将揭示尼古丁是否对青少年和年轻成人自发性高血压患者的ADHD相关症状有类似于在人类中观察到的影响。这样的发现将为通过实验揭示ADHD与烟草滥用之间重叠的遗传、神经和行为机制开辟了可能性。建议了一项面向这一目标的长期计划。 与公共健康相关：患有注意力缺陷多动障碍(ADHD)的青少年和年轻人吸烟的可能性是非ADHD同龄人的两倍。该项目将在ADHD的动物模型--自发性高血压大鼠(SHR)中评估尼古丁降低ADHD相关冲动的假设。这种验证是准确识别ADHD与尼古丁依赖之间联系的机制的关键的第一步。

DESCRIPTION (provided by applicant): Tobacco is a widely abused substance with costly negative health consequences. Smoking is particularly prevalent among various psychiatric populations, including adolescents and adults with Attention-Deficit Hyperactivity Disorder (ADHD). ADHD is a neurobehavioral disorder that affects about 5% of the population; it is characterized by impulsivity, hyperactivity, and inattention. The prevalence of smoking in patients with ADHD is estimated to double that of non-ADHD population. Moreover, ADHD is associated with early initiation of cigarette smoking, high frequency of smoking, and a lower success rate in smoking cessation. It has been argued that the link between ADHD and smoking habits reflects a pattern of self-medication among ADHD population. Experimental research in psychiatric and non-psychiatric populations has shown that nicotine alleviates behavioral symptoms associated with ADHD. This B/START proposal is focused on determining whether the beneficial effects of nicotine are replicable in the SHR, an animal model of ADHD. This proposal is specifically aimed at establishing whether ADHD-related impulsivity in the adolescent and young adult SHR is (1) reduced by acute and (2) chronic exposure to subcutaneous nicotine, (3) exacerbated by nicotine withdrawal, and (4) whether these effects are stronger or weaker in SHR relative to control strains. Achieving these goals involves a critical methodological challenge - the measurement of ADHD-related impulsivity in non-human animals. Stimulant treatments that typically reduce impulsivity in psychiatric patients yield higher indices of impulsivity in various strains of rats, including SHR. Based on extant evidence and our own preliminary data, we argue that such inconsistency is due to the conflation of measures of incentive-elicited activity and response-withholding capacity in the traditional methods for assessing impulsivity in rodents. This proposal includes innovative empirical and analytic techniques to isolate impulsivity parameters from activity- and motivation-related confounds, which may be applicable beyond the scope of this proposal. We expect that these techniques will reveal whether nicotine has an effect on ADHD-related symptoms in adolescent and young adult SHR analogous to those observed in humans. Such finding would open up the possibility of experimentally uncovering the overlapping genetic, neural, and behavioral mechanisms that link ADHD with tobacco abuse. A long-term plan geared to this goal is suggested. PUBLIC HEALTH RELEVANCE: Adolescents and young adults with Attention-Deficit Hyperactivity Disorder (ADHD) are twice as likely to smoke cigarettes than their non-ADHD peers. This project will evaluate the hypothesis that nicotine reduces ADHD-related impulsivity in an animal model of ADHD, the Spontaneously Hypertensive Rat (SHR). Such validation is a critical first step for the precise identification of the mechanisms linking ADHD with nicotine dependence.