Attention-deficit/hyperactivity disorder (ADHD) affects attention and motor capacities in approximately 6% of school-aged children, making it the most prevalent childhood disorder. ADHD can be treated effectively with stimulants including methylphenidate (MPH; RitalinTM), which are indirect dopamine (DA) agonists, and their use is rising. However, the use of such stimulants has been limited by concerns over their abuse or the possible role they play as a """"""""gateway"""""""" to the abuse of other substances. Recent clinical data show that ADHD children treated with stimulants experience an 85% reduction in substance abuse compared with those who do not receive pharmacotherapy. The interpretation of these clinical observations, however, is difficult since effectively treated ADHD patients have improved psychosocial and academic skills that reduce other risk factors, such as social impairment. In addition, they do not address potential mechanisms leading to alternative interpretations including the possibility that early treatment with MPH can imprint on the underlying neurobiological substrate of stimulant abuse. In other words, juvenile exposure to MPH potentially can produce enduring effects on the neurobiology of the developing brain that outlast the period of drug treatment itself. Some of these questions can potentially be answered using animal models and it has been shown that chronic exposure to stimulant drugs, such as MPH, causes long-lasting increases in rewarding effects, thereby increasing vulnerability to substance abuse. However, these studies have been performed in adult animals limiting their interpretation for drug treatment in juvenile (developing) brains. We have, therefore, developed an animal model using MPH exposure in juvenile rats. In this model, MPH exposure made moderate doses of cocaine aversive and high doses less rewarding later in life demonstrating reduced vulnerability to stimulant abuse. Thus, our results indicate that imprinting and/or age differences in pharmacokinetics of MPH could mediate its enduring effects. In the proposed set of studies we endeavor to determine: 1) the age-related contribution of bioavailability of MPH to cocaine reward later in life; 2) the effect of chronic MPH treatment on dopamine release in the pre-pubertal rat; 3) whether pre-pubertal exposure to MPH changes dopamine receptor expression; and 4) the role of dopamine in the underlying mechanism of MPH-induced changes in the pre-pubertal rat.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015403-05
Application #
7253287
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Frankenheim, Jerry
Project Start
2003-09-30
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$187,266
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Lukkes, Jodi L; Meda, Shirisha; Norman, Kevin J et al. (2018) Anhedonic behavior and ?-amino butyric acid during a sensitive period in female rats exposed to early adversity. J Psychiatr Res 100:8-15
Lukkes, Jodi L; Meda, Shirisha; Thompson, Britta S et al. (2017) Early life stress and later peer distress on depressive behavior in adolescent female rats: Effects of a novel intervention on GABA and D2 receptors. Behav Brain Res 330:37-45
Jordan, Chloe J; Andersen, Susan L (2017) Sensitive periods of substance abuse: Early risk for the transition to dependence. Dev Cogn Neurosci 25:29-44
Lukkes, Jodi L; Freund, Nadja; Thompson, Britta S et al. (2016) Preventative treatment in an animal model of ADHD: Behavioral and biochemical effects of methylphenidate and its interactions with ovarian hormones in female rats. Eur Neuropsychopharmacol 26:1496-1506
Freund, Nadja; Thompson, Britta S; Sonntag, Kai et al. (2016) When the party is over: depressive-like states in rats following termination of cortical D1 receptor overexpression. Psychopharmacology (Berl) 233:1191-201
Andersen, Susan L (2016) Commentary on the special issue on the adolescent brain: Adolescence, trajectories, and the importance of prevention. Neurosci Biobehav Rev 70:329-333
Lukkes, Jodi L; Thompson, Britta S; Freund, Nadja et al. (2016) The developmental inter-relationships between activity, novelty preferences, and delay discounting in male and female rats. Dev Psychobiol 58:231-42
Schrantee, Anouk; Tamminga, Hyke G H; Bouziane, Cheima et al. (2016) Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial. JAMA Psychiatry 73:955-62
Andersen, Susan L (2015) Exposure to early adversity: Points of cross-species translation that can lead to improved understanding of depression. Dev Psychopathol 27:477-91
Brenhouse, Heather C; Thompson, Britta S; Sonntag, Kai C et al. (2015) Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor. Neuropharmacology 95:22-8

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