Oral Self-Dosing/Behavioral Assessment

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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.