Nicotine and impulsivity in an animal model of ADHD

描述（由申请人提供）：烟草是一种广泛滥用的物质，具有昂贵的负面健康后果。吸烟在各种精神病人群中特别普遍，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，影响约5%的人口;其特征是冲动，多动和注意力不集中。ADHD患者的吸烟率估计是非ADHD人群的两倍。此外，ADHD与早期开始吸烟、吸烟频率高和戒烟成功率较低有关。有人认为，ADHD和吸烟习惯之间的联系反映了ADHD人群的自我药物治疗模式。在精神病和非精神病人群中进行的实验研究表明，尼古丁可以减轻与ADHD相关的行为症状。这个B/START提案的重点是确定尼古丁的有益作用是否可以在SHR（ADHD的动物模型）中复制。本提案旨在明确青少年和年轻成年SHR中ADHD相关冲动性是否（1）通过急性和（2）慢性皮下尼古丁暴露降低，（3）通过尼古丁戒断加重，以及（4）相对于对照品系，SHR中这些效应是否更强或更弱。实现这些目标涉及到一个关键的方法学挑战-在非人类动物中测量ADHD相关的冲动。通常减少精神病患者冲动性的刺激性治疗在各种品系的大鼠（包括SHR）中产生更高的冲动性指数。基于现有的证据和我们自己的初步数据，我们认为，这种不一致性是由于在传统的方法来评估啮齿动物的冲动性的激励引起的活动和反应抑制能力的措施混为一谈。该提案包括创新的经验和分析技术，以隔离冲动性参数的活动和动机相关的混乱，这可能是适用于本提案的范围之外。我们希望这些技术将揭示尼古丁是否对青少年和年轻成年SHR的ADHD相关症状有类似于在人类中观察到的影响。这一发现将为通过实验揭示ADHD与烟草滥用之间重叠的遗传、神经和行为机制提供可能性。提出了实现这一目标的长期计划。 公共卫生相关性：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。本项目将评估尼古丁降低ADHD动物模型（自发性高血压大鼠（SHR））中ADHD相关冲动性的假设。这种验证是精确识别ADHD与尼古丁依赖相关机制的关键第一步。

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.