Advances in neurobiology suggest that a dysfunctional prefrontal cortex underlies not only cocaine addiction, but also attention deficit hyperactivity disorder. Moreover, ADHD and cocaine addiction are often co-morbid. There remains disagreement concerning the use of stimulant medication and whether it makes adolescents treated for ADHD more vulnerable or less vulnerable to later cocaine addiction. To continue our studies on cognitive aspects of addiction-related behavior, we propose to investigate, using a validated rat model of ADHD and intravenous self-administration procedures, the relationship between ADHD, evaluated during adolescence, to vulnerability to cocaine addiction, evaluated during adulthood. Using behavioral procedures, Aim 1 will investigate the relationship between ADHD and vulnerability to cocaine addiction. We will determine if rats with an ADHD phenotype exhibit 1) dysfunction of the prefrontal cortex during adolescence that is prevented by treatment with either the stimulant medication methylphenidate or the non-stimulant medication atomoxetine;2) augmented vulnerability to cocaine addiction during adulthood if never medicated;3) a greater vulnerability to cocaine addiction during adulthood if methylphenidate treatment is given during adolescence and then discontinued, but not if atomoxetine treatment is given during adolescence and then discontinued;4) reduced vulnerability to cocaine addiction during adulthood if methylphenidate and atomoxetine treatments are continued into adulthood.
Aim 2 will determine, via pharmacological analysis with selective antagonists, the importance of postsynaptic D1 and ?2A receptor function within the prelimbic and orbital prefrontal cortex for mediating the altered vulnerability to cocaine addiction during adulthood.
Aim 3 will evaluate, via neurochemical analysis within prefrontal cortex (prelimbic and orbital subregions) and striatum, the methylphenidate- and atomoxetine-induced changes in presynaptic DAT, NET and/or VMAT2 transporters. Procedures measuring uptake and clearance functions as well as subcellular localization will be used. This work will advance our knowledge of the consequences of stimulant and non-stimulant medication use in adolescents with ADHD on later vulnerability to cocaine addiction. Presynaptic (transporter function and localization) and postsynaptic (D1 and ?2A receptor function) mechanisms that may underlie vulnerability to cocaine addiction following treatment with these medications will be revealed. Information from these preclinical studies may assist in the rationale choice of how and when to medicate ADHD through the lifespan to improve prefrontal cortex-related neurocognitive functioning while reducing risk of substance use disorders.

Public Health Relevance

This work will advance our knowledge of the consequences of stimulant and non-stimulant medication use in adolescents with ADHD on later vulnerability to cocaine addiction. Presynaptic (transporter function and localization) and postsynaptic (D1 and ?2A receptor function) mechanisms that may underlie vulnerability to cocaine addiction following treatment with these medications will be revealed. Information from these preclinical studies may assist in the rationale choice of how and when to medicate ADHD through the lifespan to improve prefrontal cortex-related neurocognitive functioning while reducing risk of substance use disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011716-15
Application #
8489262
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
1998-04-20
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$434,015
Indirect Cost
$101,620
Name
Boston University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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Harvey, Roxann C; Jordan, Chloe J; Tassin, David H et al. (2013) Performance on a strategy set shifting task during adolescence in a genetic model of attention deficit/hyperactivity disorder: methylphenidate vs. atomoxetine treatments. Behav Brain Res 244:38-47
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