This study seeks more information about the biology of substance dependency by exploring the
brain areas involved in feeling positive and negative emotions. Specifically, it will
determine whether a brain chemical called dopamine affects activity in certain brain regions
during performance of a game that involves winning and losing money. Brain activity will be
examined using magnetic resonance imaging (MRI), a test that uses a magnetic field and radio
waves to produce images of brain structure and function.
Young to middle-aged healthy adults may participate in this study. Candidates will be
screened with a medical history, physical examination, electrocardiogram (EKG), psychiatric
interview, and blood and urine tests. Participants will be assigned to one of the two study
procedures, as follows:
This study requires two overnight stays at the NIH Clinical Center. For each stay, subjects
are admitted to the hospital the afternoon before the MRI scan. From the time of admission
until after the scan, their diets are restricted to food relatively low in amino acids,
prepared by NIH dietitians. The next day, participants undergo MRI scanning. For this
procedure, the subject lies on a table that is moved into the scanner, a metal cylindrical
machine. Earplugs are worn to muffle loud noises that occur with electrical switching of the
radio frequency circuits. Imaging of brain structure takes about 10 to 15 minutes.
Additional scans are then taken to measure brain activity while the subject plays simple
computer games for money. These scans take about another 20 to 45 minutes. Five hours before
the MRI, the subject drinks one of two beverages containing amino acids. A different
beverage is given for each of the two visits: one drink lacks the essential amino acids
tyrosine and phenylalanine, from which the body makes dopamine; the other contains balanced
amounts of these two amino acids. Finally, subjects fill out mood-rating questionnaires
before and after drinking each of the beverages.
This study requires two outpatient visits to the NIH Clinical Center. For one visit,
participants are given an injection of 0.2 mg/kg body weight of the drug dextroamphetamine;
for the other, they are given an injection of saline (salt water). After each injection,
they undergo MRI scanning while playing computer games for money, as described above. They
will fill out mood-rating questionnaires before and after each brain scan.
The purpose of this protocol is to advance the understanding of the behavioral neurobiology
underlying substance dependency by exploring regional brain activity in response to
appetitive and aversive stimuli in human subjects. In this protocol, brain activation is the
dependent measure, as measured by blood oxygenation level dependent (BOLD) signal acquired
during functional magnetic resonance (fMRI) imaging. Previous work in this laboratory has
found that cues of anticipated monetary reward versus threat of negative reinforcement
causes increased BOLD signal in the nucleus accumbens (NAcc) and other parts of the ventral
striatum. This protocol is intended to extend these findings by exploring whether the
recently reported BOLD activation (a hemodynamic response) in certain brain regions in
response to motivational cues can be perturbed by dopaminergic pharmacological
In a series of two, repeated-measures, within-subject experiments, we propose to temporarily
alter subjects' brain monoamine neurotransmitter systems with pharmacological interventions
prior to presenting the subjects with appetitive and aversive visual stimuli as well as cues
signaling potential punishment and reward. In the first experiment, brain catecholamine
systems will be deactivated by dietary restrictions of amino acid precursors Tyrosine (Tyr)
and Phenylalanine (Phe), respectively. In the second experiment, the brain dopamine (DA)
release will be transiently increased with administration of dextroamphetamine (Amph). Based
on a wealth of existent findings, we predict that acutely enhancing synaptic DA by Amph will
augment reward-elicited activation in the ventral striatum. Conversely, acute dietary
restriction of the DA precursor Tyr, (along with Tyr precursor Phe) will blunt this
activation. Since substance use disorders (SUD) such as alcoholism may result from
disordered neural systems regulating approach and avoidance behavior (with respect to the
substance), this experiment can yield useful knowledge relevant to SUD.
- INCLUSION AND EXCLUSION CRITERIA:
Subjects are physically healthy as determined by medical evaluation at the NIAAA
outpatient clinic. In particular, subjects must demonstrate no cardiovascular or blood
pressure abnormalities, such as a resting blood pressure of 140/90 or greater. All values
of laboratory test must be within the NIH defined normal range and all radiological and
cardiac evaluations must be considered normal by the NIH radiologist or cardiologist
reading the scan or record. As is usual clinical practice, in the case of minor
abnormalities a lab test may be repeated to ensure the validity of the initial report.
Are between 18-65 years of age.
Have 20/20 vision or wear corrective contact lenses. Plastic glasses with pop-in lenses of
different strengths are available in the NMR center for use with nearsighted subjects who
do not wear contacts.
Have no ferromagnetic objects in their bodies which might be adversely affected by MRI
(e.g. surgical clips; metal fragments in or near brain; eye or blood vessels; cardiac or
neurological pacemaker; cochlear or eye implant - any doubt about absence of these objects
will result in exclusion from this study).
Test HIV negative.
Have no indication of any organic brain syndrome.
Do not meet criteria for any present or past Axis I psychiatric disorder, including
nicotine dependence. Smokers will be excluded.
Have no active homicidal or suicidal ideation, or active symptoms of post-traumatic stress
Are not currently receiving psychotropic medication or medication likely to affect brain
Have no indication of recent drug use as evidenced by urine drug screen and self-report.
Are not pregnant or lactating.