Oral Self-Dosing/Behavioral Assessment

口服自我给药/行为评估

• 批准号: 7003218
• 负责人: MICHAEL R WEED
• 金额: $ 80.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7003218
• 关键词: Macaca mulatta; amphetamines; attention deficit disorder; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; behavioral medicine; body weight; central nervous system; circadian rhythms; cocaine; developmental neurobiology; dopamine receptor; dopamine transporter; executive function; growth /development; human therapy evaluation; mental disorder chemotherapy; methylphenidate; microglia; middle childhood (6-11); neurochemistry; nutrient intake activity; oral administration; therapy adverse effect

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.

描述（由申请人提供）：在美国，大约3-5％的3-17岁儿童被诊断出患有注意力缺陷 /多动症（ADHD），而400万儿童长期接受治疗多动症。大多数接受治疗的甲化苯二甲酸酯（MPD）和苯丙胺（AMPH），控制多动症。但是，人们担心行为，神经化学，生长速度和用MPD或AMPH治疗的儿童滥用药物的潜力的长期发展变化。拟议的研究将检验以下假设：慢性MPD或AMPH会导致前前恒河猴的长期行为，生理和神经化学改变。口服自我剂量技术将在治疗窗口内以剂量为儿童治疗多动症的MPD或AMPH提供非压力。具体目标1将确定慢性MPD或AMPH是否会改变包括昼夜节律，体重，食物摄入量和体内生长速度在内的前猴子的生理发展。经过18个月的MPD或AMPH给药后，还将进行对苯丙胺的行为敏化测试。具体的目标2将检验以下假设：慢性MPD或AMPH会改变发展中心神经系统的发展，包括小胶质细胞的慢性激活和preadolectent猴子多巴胺能功能的持续变化。多巴胺能功能的度量将包括多巴胺转运蛋白，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，包括抑制性控制和注意设置转移。特定的目标4将检验以下假设：先前暴露于MPD或AMPH的猴子具有更高的自我管理可卡因倾向。拟议的研究对MPD和AMPH治疗剂量的慢性影响提供了全面的跨学科评估。这些研究将提高人们对慢性低剂量兴奋剂治疗的长期神经化学，行为和生理作用的了解，并直接转化为多动症儿童的药物。