Psychostimulants, Attention Deficit and Basal Ganglia Disorders

注意力缺陷/多动障碍(ADHD)的主要特征是持续的三种主要模式 行为特征：多动、冲动和注意力不集中。这种紊乱涉及到大脑中 多巴胺能(DA能)通路。因此，多巴胺能精神刺激剂(即苯丙胺和安非他明) 哌醋甲酯(MPD))作为治疗。 在临床前和人类中都已证实，大剂量安非他明/甲基苯丙胺(冰毒)暴露 导致持续性的DAR缺乏症。这有几个原因令人感兴趣，包括发现DAR缺乏症 是帕金森氏症(PD)的特征。毫不奇怪，其他人和我们已经报告了患有 滥用安非他明/冰毒的证据更有可能发展为基底节退行性疾病，包括帕金森病。 鉴于DAR能系统的失调导致ADHD和PD，而且两者都受到 兴奋剂，我们小组调查了：1)ADHD与基底节和中枢神经系统紊乱的关系 小脑(BG&C)，包括帕金森病；和2)用兴奋剂治疗ADHD是否会影响 BG&C障碍。我们在一项回溯性队列研究中报告说，患有ADHD的个体大约有 与非ADHD患者相比，患BG&C疾病(包括帕金森病)的风险增加2倍。 重要的是，在ADHD患者中，服用了兴奋剂(即安非他明和MPD)的风险 年龄在21-49岁之间的疾病尤其明显，约为8倍。这是基于人口的 研究提出了与临床高度相关的问题：1)为什么表现出注意力缺陷的人更有可能 发生BG&C障碍；以及2)为什么刺激性治疗增加了发生BG&C的可能性 表现出注意力缺陷的个体的障碍？ 需要一种注意力缺陷受试者的DAR能缺陷的临床前模型来机械地解决 以上提出的问题。因此，我们建议在大鼠身上进行研究，展示其核心行为特征和认知能力 在ADHD中观察到的缺陷：特别是自发性高血压大鼠(SHR)。我们将测试该漏洞 使用两种神经毒素导致神经化学和/或行为缺陷的SHR到DAR能缺陷的模拟 帕金森病患者：6-羟基多巴胺(6-OHDA)和冰毒。对冰毒的关注尤为重要， 鉴于冰毒本身的普遍滥用，以及与其他药物的滥用相结合。我们假设 与类似的相比，青少年SHR更容易受到冰毒和6-OHDA引起的DA能损伤 处理对照组(目标1)。此外，我们假设慢性MPD治疗将增强神经毒性潜力。 在SHR中使用冰毒和6-OHDA(目标2)。第二个假设将在接受MPD的大鼠身上进行测试：A) 整个青春期；或b)整个青春期和进入青春期。这些假设将是 在雄性和雌性大鼠身上进行了测试，并提供了模型来研究DAR能的两种机制 退行性疾病及其治疗策略。

Attention-deficit/hyperactivity disorder (ADHD) is characterized largely by an ongoing pattern of three primary behavioral characteristics: hyperactivity, impulsivity and inattention. This disorder involves dysregulation of dopaminergic (DAergic) pathways. Thus, DAergic psychostimulants (i.e., amphetamine (AMPH) and methylphenidate (MPD)) are prescribed as treatment. It is established, both preclinically and in humans, that high-dose AMPH/methamphetamine (METH) exposure causes persistent DAergic deficits. This is of interest for several reasons, including findings that DAergic deficits are hallmarks of Parkinson’s disease (PD). Not surprisingly, others and we have reported that individuals with evidence of AMPH/METH abuse are more likely to develop basal ganglia degenerative disorders, including PD. Given that dysregulation of DAergic systems contribute to both ADHD and PD, and that both are impacted by stimulants, our group investigated: 1) the association between ADHD and disorders of the basal ganglia and cerebellum (BG&C), including PD; and 2) if treatment of ADHD with stimulants might impact the development of BG&C disorders. We reported in a retrospective cohort study that individuals with ADHD had an approximately 2-fold increased risk of developing BG&C disorders (including PD), compared with non-ADHD-affected persons. Importantly, in ADHD patients that were prescribed stimulants (i.e., AMPH-salts and MPD), the risk of these disorders between ages 21 – 49 y was especially pronounced, at approximately 8-fold. This population-based study raises highly clinically-relevant questions: 1) why are individuals displaying attention deficits more likely to develop BG&C disorders; and 2) why does stimulant therapy increase the likelihood of developing BG&C disorders in individuals displaying attention deficits? A preclinical model of DAergic deficits in subjects with attention deficits is needed to mechanistically address the questions posed above. Thus, we propose studies in rats that display the core behavioral features and cognitive deficits observed in ADHD: specifically, spontaneously hypertensive rats (SHRs). We will test the vulnerability of SHRs to DAergic deficits using two neurotoxins that induce neurochemical and/or behavioral deficits modeling those in PD; that is, 6-hydroxydopamine (6-OHDA) and METH. The focus on METH is particularly significant, given the prevalence of METH abuse per se, and in combination with other drugs of abuse. We hypothesize that adolescent SHRs will be more susceptible to DAergic damage caused by METH and 6-OHDA than similarly treated controls (Aim 1). In addition, we posit that chronic MPD treatment will enhance the neurotoxic potential of METH and 6-OHDA in SHRs (Aim 2). The second hypothesis will be tested in rats that receive MPD: a) throughout adolescence; or b) throughout adolescence and into young adulthood. These hypotheses will be tested in both male and female rats, and provide models to investigate both mechanisms underlying DAergic degeneration and strategies for treatment.