This study will examine the role of the brain chemical dopamine in people's response to
alcohol consumption. Dopamine is thought to influence whether people have a strong or weak
response to alcohol and how pleasurable that response is. The findings of this study may
shed light on why some people are at higher risk of developing problem drinking behaviors.
Healthy normal volunteers between 21 and 25 years of age who have never had a serious
problem with alcohol abuse or drug abuse may be eligible for this study. Candidates will be
screened with a medical history and physical examination, and will be interviewed about
their smoking and drinking behaviors. Participants will undergo test procedures on two
separate days, as follows:
Test Day 1
Upon arrival at the Clinical Center, participants will take a breathalyzer test for alcohol
and provide a urine sample for a drug screen. Women will also have a urine pregnancy test.
They will then lie on a hospital bed and two intravenous catheters (IV lines) will be
placed, one into each arm. One line will be used to collect blood samples during the test
session; the other will be used to infuse alcohol into the bloodstream. The alcohol will
rapidly increase the blood alcohol level to between 0.06 and 0.08 grams per deciliter. (0.08
g/dL is the level at which a person is charge with driving under the influence of alcohol in
all States.) Before, during, and after the infusion, subjects will be asked about their
feelings in response to the alcohol, such as confusion, elation, level of discomfort or
dizziness, ability to concentrate, and so forth. At 35 and 60 minutes after the infusion
begins, subjects will take a body sway test. This involves standing on a machine to
determine how the alcohol has affected the sense of balance. Subjects will then relax in
the clinic for a few hours. During this time, a blood sample will be collected and a
questionnaire will be given hourly until the blood alcohol level has gone down to 0.02 g/dL.
When the alcohol level has declined to 0.02 g/dL (usually 3 to 4 hours after the infusion),
the subject will be sent home in a taxi.
Test Day 2
Participants will again take a breathalyzer test for alcohol and provide a urine sample for
drug screen and, for women, a pregnancy test. Subjects will lie on a hospital bed and three
IV lines will be inserted, one to draw blood samples, one to infuse alcohol, and one to give
raclopride, a radioactive substance used for positron emission tomography (PET) scanning.
For PET, the subject lies on a table in the scanner with a mask placed over his or her head
to help hold the head still during the scan. After a brief scan to adjust the machine, a
small amount of radioactive water (O-15 water) is injected through the IV line and a series
of pictures is taken over a period of about 1 minute. These images show how the radioactive
water distributes in the brain, indicating blood flow. After the water scan, raclopride is
given through the IV line and more pictures of the brain are taken over the next 2 hours.
Blood samples are collected during and after the raclopride scan. During this procedure,
subjects are asked the same questions about their feelings in response to the alcohol as
they did during the earlier session. After he scans, they will be monitored in the clinic
with hourly blood tests and questionnaires until the blood alcohol concentration decreases
to 0.02 g/dL and will then be sent home in a taxi.
Some persons are more likely to develop alcoholism than others. Understanding the
difference between persons at high vs. low risk of developing alcoholism could be important
for both prevention and treatment strategies.
Tolerance for the sedative effects of alcohol has been shown in young adults to predict
development of alcoholism later in life. The basis for this increased risk is unclear. It
may be that persons who tolerate alcohol well as young adults experience more of the
rewarding effects of alcohol (e.g., euphoria), or that they experience less of the negative
effects of alcohol (e.g., sedation), or some combination of the two. Fortunately,
brain-imaging tools can shed light on the brain's reward response mechanisms to alcohol.
Differences in the reward circuits of persons who experience a euphoric response to alcohol
may help explain why some people go on to develop alcoholism while others do not. Both
human and animal research point toward a difference in the density of dopamine receptors in
the striatum of alcohol-preferring and non alcohol-preferring subjects. The following
experiment is designed to examine the relationship between response to alcohol, dopamine
receptor density in the striatum, and dopamine release in response to alcohol.
We propose classification of subjects as 'low response' or 'high response' on the basis of
their level of response to a controlled alcohol challenge in the laboratory, using the
established methods of Schuckit et al to gather systematic data on subjects' response to
alcohol. Next, baseline levels of dopamine D2 receptor density in mesolimbic reward
circuits of subjects in each group would be assessed in the PET scanner by using the
radioactive dopamine antagonist C-11 raclopride. C-11 raclopride binds to D2 receptors,
which will provide a signal proportional to the number of D2 receptors present. This will
allow us to measure and compare the baseline D2 receptor density in high and low response
groups. Directly after obtaining this baseline D2 receptor measurement, we propose
administration of a controlled alcohol challenge. Acute alcohol administration causes
release of dopamine in the striatum, and can dislodge a portion of the C-11 raclopride that
was bound to D2 receptors. This will allow us to compare high and low response groups for
differences in the displacement of C-11 raclopride induced by dopamine release, thereby
providing a measure of dopamine release in response to alcohol.
The data obtained will allow us to compare the response to alcohol of young adults who are
high vs. low responders. It will also permit comparison of these groups in terms of
baseline striatal dopamine receptor density and striatal dopamine release in response to
Results of this experiment may identify a physiological basis for the increased risk in some
young adults for development of alcoholism. It may also provide a model for further studies
of the relationship between response to alcohol, risk for developing alcoholism, and brain
Subjects who are included:
1. will be between the ages of 21 and 25.
2. will have a score on the telephone administered SRE at least one standard deviation
above the mean, in the case of subjects to be evaluated further as potential
Low-Response group participants.
3. will have a score on the telephone administered SRE at least one standard deviation
below the mean, in the case of persons to be evaluated further as potential High
4. will be willing to undergo a complete medical and psychiatric evaluation, as
described in NIAAA protocol 98-AA-0009.
5. will be willing to undergo indicated laboratory and EKG examination, as described in
NIAAA protocol 98-AA-0009.
6. will be willing to have the results of their intake evaluation become part of their
record at NIH, as described in NIAAA protocol 98-AA-0009.
7. will be willing to submit a urine sample for the purpose of drug screening and, in
the case of females, for pregnancy testing.
8. will be willing to submit blood samples for the genetic testing described herein.
9. must be essentially physically and emotionally healthy, as determined by the
screening procedures in Criteria 4& 5.
10. must be willing to be contacted at five year intervals for purpose of interview about
their drinking behavior in the interim, and provide identification and contact
information which would facilitate such follow-up.
A subject will be excluded from the study if they:
1. have an intermediate score on the telephone administered SRE (within one standard
deviation of the mean).
2. have an abnormal physical exam or laboratory values outside the normal ranges.
3. are pregnant.
4. have a positive drug screen.
5. have fulfilled DSM-IV criteria for ethanol or other substance dependency at any time
within the past 5 years.
6. have a history of stimulant use or abuse.
7. have a history of smoking within the last year, or a lifetime history of smoking more
than 100 cigarettes.
8. have fulfilled DSM-IV criteria for any major (non substance-related) Axis I
9. have taken any prescribed, non-prescribed, or over-the-counter medications or drugs
within 14 days prior to the study days (excluding oral contraceptive agents, aspirin,
10. have a history of claustrophobia.
11. have a history of facial flushing syndrome in response to alcohol exposure.