Oral Self-Dosing/Behavioral Assessment

描述(申请人提供)：在美国，大约3%-5%的3-17岁儿童被诊断为注意力缺陷/多动障碍(ADHD)，400万儿童被长期用药治疗ADHD。在大多数接受治疗的患者中，哌醋甲酯(MPD)和安非他明(Amph)可以控制ADHD。然而，服用MPD或AMPH的儿童在行为、神经化学、生长速度和潜在的药物滥用方面的长期发育变化令人担忧。这项拟议的研究将检验这样一种假设，即慢性MPD或AMPH会导致青春期前恒河猴的长期行为、生理和神经化学变化。口服自我给药技术将在治疗窗口内无应激性地给药MPD或Amph，用于治疗儿童ADHD。具体目标1将确定慢性MPD或AMPH是否会改变青春期前猴子的生理发育，包括昼夜节律、体重、食物摄入量和身体生长速度。在服用MPD或Amph 18个月后，还将进行苯丙胺行为敏化测试。《特定目标2》将测试慢性MPD或Amph改变发育中的中枢神经系统的假说，包括青春期前猴子小胶质细胞的慢性激活和多巴胺能功能的长期改变。多巴胺能功能的测量将包括多巴胺转运体、多巴胺D2受体和苯丙胺刺激的多巴胺释放的水平。具体目标3将确定慢性MPD或AMPH对执行功能发展的影响，包括抑制控制和注意力定势转移。《特定目标4》将测试一种假设，即之前接触过MPD或Amph的猴子有更高的自我注射可卡因的倾向。这项拟议的研究对治疗剂量的MPD和Amph在青春期前非人类灵长类动物中的慢性影响进行了全面的跨学科评估。这些研究将促进对慢性低剂量兴奋剂治疗的长期神经化学、行为和生理影响的了解，并直接应用于ADHD儿童的药物治疗。

DESCRIPTION (provided by applicant): Approximately 3-5% of children ages 3-17 in the U.S. are diagnosed with Attention Deficit / Hyperactivity Disorder (ADHD), and 4 million children are medicated chronically to treat ADHD. Methylphenidate (MPD) and amphetamine (Amph), control ADHD in the majority of those treated. However, there are concerns over long-lasting developmental changes in behavior, neurochemistry, growth rates and potential for substance abuse in children treated with MPD or Amph. The proposed research will test the hypothesis that chronic MPD or Amph results in long-term behavioral, physiologic and neurochemical alterations in preadolescent rhesus monkeys. Oral self-dosing techniques will provide non-stressful administration of MPD or Amph in doses within the therapeutic window for treatment of ADHD in children. Specific Aim 1 will determine if chronic MPD or Amph alters physiological development of preadolescent monkeys including circadian rhythms, body weights, food intake, and body growth rate. After 18 months of MPD or Amph administration, tests for behavioral sensitization to amphetamine will also be performed. Specific Aim 2 will test the hypothesis that chronic MPD or Amph alters the developing central nervous system including chronic activation of microglia and long-lasting alterations in dopaminergic function in preadolescent monkeys. Measures of dopaminergic function will include levels of dopamine transporters, dopamine D2 receptors and amphetamine-stimulated dopamine release. Specific Aim 3 will determine the effects of chronic MPD or Amph on development of executive function including inhibitory control and attentional set-shifting. Specific Aim 4 will test the hypothesis that monkeys previously exposed to MPD or Amph have a higher propensity to self-administer cocaine. The proposed studies provide a comprehensive interdisciplinary evaluation of the chronic effects of therapeutic doses of MPD and Amph in preadolescent nonhuman primates. These studies will advance understanding of the long-term neurochemical, behavioral and physiologic effects of chronic low-dose stimulant treatments and have direct translational application to the medication of children with ADHD.