Teenagers, Drug Addiction, and Reward and Impulse Control

Background: Even under similar drug use patterns, the risk for drug addiction varies from
individual to individual. However, the neurobiological mechanisms underlying this
variability are poorly understood and characterized. Studies suggest that certain traits
observed in substance dependent individuals may actually precede drug use, and could augur
future substance dependence. Understanding how the presence of these traits increases
vulnerability to substance addiction could aid in the development of early intervention,
preventative measures, as well as better treatment strategies.

Objective: The primary goal of this protocol is to improve our understanding of increased
susceptibility to developing substance addiction. We focus here on reward and punishment
learning, and impulse control, with an emphasis on the underlying role of dopamine and
serotonin function in these two cognitive functions. Further, given that cortical plasticity
is enhanced during childhood and adolescence, we begin to address whether early exposure to
substances enhances neurobiological changes that make an individual vulnerable to subsequent
substance addiction.

Subject Population: We focus on adolescents (13-17 years old) with known increased
vulnerability to substance addiction - individuals with early exposure to substances, i.e. ,
those who have used drugs on multiple occasions before the age of 15, and those diagnosed
with conduct disorder - and who are not as yet substance dependent, along with matched
controls.

Experimental Design: This study involves cognitive, pharmacological and functional magnetic
resonance imaging (fMRI) testing in a mixed, within/between-subject design. Based upon power
analyses, we estimate needing 30 participants in each of 4 groups - early exposure (EE),
conduct disorder (CD-NE), conduct disorder with early exposure (CD-EE), and controls with no
early exposure (NE) - to complete the experiment. This is a within subjects, placebo
controlled, crossover design with participants tested before and after 1) cabergoline (D2
receptor agonist) treatment, 2) acute tryptophan depletion, and 3) placebo.

Outcome Measures: The primary outcome measures will be BOLD fMRI activation and behavioral
performance on various cognitive tasks that deal with impulse control and reward learning
before and after each of the three treatments listed above. Secondary outcome measures
include gene x environment interactions and stress and novelty-seeking measures.

- INCLUSION CRITERIA:

All participants:

1. Between 13 and 17 years old (inclusive);

2. Must be able to provide informed assent and have a parent/guardian who can provide
informed consent;

3. Blood pressure (BP) and heart rate (HR) while sitting at or below the following
values after five min rest: Systolic BP (SBP) 140 mm Hg, diastolic BP (DBP) 90 mm Hg,
heart rate (HR) 100 bpm;

4. 12-lead standard ECG and three-minute rhythm strip without clinically relevant
abnormalities;

5. Estimated IQ >= 85 determined by the Wechsler Abbreviated Scale of Intelligence (The
Psychological Corporation, 1999);

6. Right-handed (based on Edinburgh Handedness Inventory).

7. Eligible to enter the MRI scanner, as determined though self and parent (guardian)
report on the MRI screening form (from the screening protocol 06-DA-N415).

Group EE:

- History of substance use on 5 or more occasions (not including over-the-counter
medications and energy drinks) as assessed through the Substance Use Questionnaire.

Group CD-NE:

- History of diagnosis with conduct disorder, assessed from parental or self-report (and
verified by study-clinician).

Group CD-EE:

- History of diagnosis with conduct disorder, assessed from parental or self-report
(and verified by study-clinician);

- History of substance use on 5 or more occasions (not including over-the-counter
medications and energy drinks) as assessed through the Substance Use Questionnaire.

EXCLUSION CRITERIA

All participants:

1. Report of a history of significant medical/neurological illness that might interfere
with imaging data such as HIV positive status, cerebral vascular accident (CVA),
central nervous system (CNS) tumor, traumatic brain injury, multiple sclerosis (MS)
or other demyelinating diseases, epilepsy, or movement disorders;

2. History of psychosis or any current DSM-IV axis I disorder (other than simple phobia
and conduct disorder);

3. Current use of psychotropic medication that may alter attentional functioning (e.g.,
Clonidine, antipsychotics, Venlafaxine, stimulants);

4. Current use of substances (not including over-the-counter medications and energy
drinks) as assessed by self-report, carbon monoxide (CO) monitoring, alcohol
breathalyzer and urine testing;

5. Pregnancy, which will be assessed by history during screening and by urine testing on
scan days;

6. Claustrophobia by self and/or parent (guardian) report, or through response to the
mock-scanner environment, severe enough to preclude toleration of the scanning
environment.

Group NE:

- History of substance use on 5 or more occasions (not including over-the-counter
medications and energy drinks) as assessed through the Substance Use Questionnaire;

- History of diagnosis with conduct disorder, assessed from parental or self-report
(and verified by study-clinician).

Group EE:

- History of diagnosis with conduct disorder, assessed from parental report (and verified
by study-clinician).

Group CD-NE:

- History of substance use on 5 or more occasions (not including over-the-counter
medications and energy drinks) as assessed through the Substance Use Questionnaire.