CENTRAL AND PERIPHERAL ACTIONS OF AMPHETAMINE IN ADHD

这项拟议的研究有一个广泛的目标，就是阐明这些机制。 安非他明对注意力缺陷的治疗作用-- 多动症(ADHD)。安非他明的形式，目前 用于治疗ADHD(d-苯丙胺或右旋糖苷)有中枢和 外围操作。一种只有外周直接作用的安非他明 行为(4-羟基苯丙胺)已被证明会影响动物的学习。 我们计划调查实验室的实验措施或 4-羟基苯丙胺通过外周影响临床症状 随后调节中枢神经系统活动的机制。几个假设 将对具有理论和临床意义的产品进行测试。首先，一个 据预测，ADHD症状的子集对4-羟基苯丙胺有反应。 其次，这种外周作用的刺激物被假设为表现得更少 或较温和的副作用，刺激中枢作用。第三, 不同兴奋剂的剂量-反应曲线预计将显示 “认知毒性”现象(改善的恶化 努力学习)。 这项研究的具体目的是(A)比较安全和 4-羟基苯丙胺对苯丙胺的副作用 临床应用(d-苯丙胺)，和(B)比较 D-，和4-OHG苯丙胺对配对联想学习和努力记忆的影响 扫描、颠覆性社交行为、对行为的响应 注意缺陷多动障碍儿童的偶然性、运动活动和副作用 都被诊断出患有多动症。第一个目标将通过一个 医学监督下的三剂量单次给药开放试验 (.15、.3和.5毫克/公斤)4-羟基和d-苯丙胺。第二个目标是 使用受试者内交叉实验设计实现 每个儿童在接受四种剂量(0， .15、.3和.5 mg/kg)d、dl和4-羟基苯丙胺，为期一周 持续时间。来自3 x 4(药物x剂量)析因设计的数据将是 使用方差分析和趋势分析进行评估。

The proposed study has the broad goal of elucidating the mechanisms underlying the therapeutic action of amphetamine in Attention Deficit- Hyperactivity Disorder (ADHD). The form of amphetamine that is currently used to treat ADHD (d-amphetamine or Dexedrine) has both central and peripheral action. A form of amphetamine that has only peripheral direct action (4-OH amphetamine) has been shown to affect learning in animals. We plan to investigate whether experimental laboratory measures or clinical symptoms are affected by 4-OH amphetamine through a peripheral mechanism that subsequently modulates CNS activity. Several hypotheses that have theoretical and clinical significance will be tested. First, a subset of ADHD symptoms is predicted to respond to 4-OH amphetamine. Second, this peripherally acting stimulant is hypothesized to show fewer or milder side effects that stimulants with central action. Third, dose-response curves for the different stimulants are expected to show the phenomenon of "cognitive toxicity" (deterioration of improvement in effortful learning) . The specific aims of the study are (a) to compare the safety and side effects of 4-OH amphetamine to those of the form of amphetamine in clinical use (d-amphetamine), and (b) to compare dose-response curves for d-, and 4-OHG amphetamine on paired-associate learning, effortful memory scanning, disruptive social behavior, response to behavioral contingencies, motor activity, and side effects in children with ADHD who have been diagnosed as having ADHD. The first aim will be achieved by a medically supervised open trial of single administrations of three doses (.15, .3, and .5 mg/kg) of 4-OH and d-amphetamine. The second aim will be achieved using a within-subjects crossover experimental design in which each child will be assessed after receiving each of four doses (0, .15, .3, and .5 mg/kg) of d, dl, and 4-OH amphetamine for one-week durations. Data from this 3 x 4 (drug x dose) factorial design will be evaluated using analysis of variance and trend analysis.