| Purpose: |
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Background:
- Brain imaging studies, genetic research, and investigations of stress have provided
more information about the role of dopamine in processing reward and punishment, and in
vulnerability to substance dependence. Researchers are interested in learning more
about how the brain responds to rewards, including drugs of abuse, and how these
responses may involve genetic factors or previous stressful events.
- Researchers intend to use the drug amphetamine to increase levels of dopamine in the
brain and study the effects through two kinds of scanning: functional magnetic
resonance imaging (fMRI) and positron emission tomography (PET).
Objectives:
- To examine the relationship among dopamine function, brain activity, reward processing,
genetic profile and exposure to stress in normal healthy adults.
- To examine the variation in these factors between normal healthy adults and individuals
with current cocaine-dependence.
Eligibility:
- Individuals 18 to 45 years of age who are either current cocaine users or healthy
volunteers with no history of substance abuse or dependence.
Design:
- The study will consist of an initial evaluation session and six study visits, four of
which will involve fMRI scans (3 hours each) and two of which will involve PET scans (8
to 9 hours each).
- Cocaine-using participants will enter the inpatient clinical research ward at the
National Institute on Drug Abuse Addiction Research Center the night before each
scanning session and will be discharged the following day. Healthy volunteer subjects
will not be required to stay overnight and will arrive as outpatients for the PET
session. Participants will not be released until researchers have determined that
participants are not experiencing significant effects of the drug.
- Initial session (1): Participants will complete questionnaires about past reactions to
stressful situations, and will be trained to do thinking tasks that will be performed
in fMRI visits. The tasks will be practiced in a mockup of an MRI machine.
- MRI sessions (2-5): Participants will receive either oral amphetamine or a placebo, and
will perform thinking, short-term memory, and reward tasks during MRI scanning as
directed by researchers.
- PET sessions (6-8): Participants will receive either oral amphetamine or a placebo, and
will provide blood samples during the PET scanning sessions. Participants will have
short breaks during the PET scanning sessions.
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| Study summary: |
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Objective: This protocol will integrate functional brain imaging of reward processing,
together with assessment of the response to oral dextroamphetamine (d-AMPH), monoaminergic
genotyping, and evaluation of past exposure to stress, in order to examine: (1) the
relationship between these factors (i.e. dopamine function, brain activity, reward
processing, genetic profile and exposure to stress) in normal healthy adults; and (2)
variation in these factors between normal healthy adults and individuals with current
cocaine-dependence, and how this variation contributes to observed behavioral and functional
differences between these populations.
Study Population: The study populations will consist of adult (18-45 years old) healthy
volunteers with no history of substance abuse or dependence and a matched group of
individuals with current primary cocaine-dependence.
Experimental Design and Method: After being medically cleared and giving informed consent,
each participant will undergo fMRI (four sessions, on separate days) and PET scanning (two
sessions, on separate days). All brain imaging sessions will take place after single-blind
administration of either d-AMPH (0.43 mg/kg orally) or placebo. Functional MRI will
commence after dosing and will include several measures (both cognitive and affective)
designed to activate neural circuitry involved in the processing of reward and punishment.
PET scanning will also take place after d-AMPH or placebo and will involve administration of
the radioligand [18F] Fallypride to assess CNS dopamine function.
Outcome Measures: This study is concerned with differences in the noted factors between
experimental cohorts (controls vs. cocaine-dependent adults) and conditions (baseline vs.
post d-AMPH). The primary outcome measures, used to ascertain these differences, will be:
(1) the percentage change in fMRI BOLD signal during performance of measures of reward
processing and cognitive function; (2) alterations or differences in the binding potential
of [18F]Fallypride; (3) variations in genes related to DArgic function between individuals
and groups, and the contribution of this variation to other outcome measures; and (4)
history of exposure to stressful events and its role in behavioral and functional outcomes. |
| Criteria: |
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- INCLUSION CRITERIA:
1. Aged between 18 - 45 years;
2. In good health, based on history and physical examination; and
3. Right-handed (as assessed using the Edinburgh Handedness Inventory; Oldfield,
1971)
All participants in the cocaine group must meet DSM-IV criteria for cocaine dependence at
the time of participation. Cocaine-dependent participants must also be positive for
cocaine use in their urine toxicology screen.
EXCLUSION CRITERIA:
Potential participants for either experimental group will be excluded from participation
in this study according to the following criteria:
1. Current drug use: Subjects may smoke regular cigarettes, use moderate amounts of
alcohol and caffeine, or smoke an occasional marijuana cigarette. Moderate alcohol
use is defined as for men, less than ten drinks and for women less than 7 drinks of
liquor (1.5 oz) or the equivalent beer (12 oz) or wine (5 oz) per week. Moderate
caffeine use is defined as less than 500 mg of caffeine per day, where one 5-oz
serving of coffee and 2 12-oz servings of caffeinated soft drinks or tea each
contain 100 mg. Occasional marijuana use is defined as less than or equal to 2
cigarettes/month. Participants may not use alcohol or marijuana for at least 24
hours prior to scanning, but will be allowed to smoke regular cigarettes according to
their normal usage pattern. Participants who do not meet these guidelines for current
drug use will not be allowed to participate in this study.
2. Current or Past Medication Use: Volunteers may not currently use chronic (defined as
daily for more than 10/14 days in the last month) prescription or over the counter
medications that might interfere with the imaging signal (PET or MRI) or which may
interact adversely with any of the substances being given in this protocol. This
will include, but not be limited to, anti-hypertensive, anti-allergy, and pain
medications. In addition, the use of psychotropic medications, particularly
antidepressants or antipsychotic medication, will be exclusionary. Past use of
antidepressant medication will be evaluated on a case by case basis; however, use of
MAOI's within 14 days of AMPH administration will be exclusionary due to the
possibility of precipitating hypertensive crisis. Over the counter or prescription
medications may be used on an occasional basis (for example, for the treatment of
self-limited conditions, such as occasional headache, musculoskeletal discomfort,
allergic symptoms or pain), but medications which can interact with AMPH such as
Vitamin C, L-glutamine, sodium bicarbonate, and sodium phosphate will be
exclusionary. In addition, current use of over-the-counter estrogen-like compounds
will be exclusionary for female participants. Subjects who have previously had
significant exposure to medications that act on the DA system (antipsychotics,
psychostimulants) will also be excluded from the study.
3. CNS disease: History of known structural brain abnormalities (e.g. neoplasm,
subarachnoid cysts), cerebrovascular disease, infectious disease (e.g. abscess),
history of head trauma (defined as documented loss of consciousness > 5 min or
injury requiring hospitalization), history of seizures as an adult, sleep apnea, or
tic disorder will all be exclusionary.
4. Cardiovascular, pulmonary, or systemic disease: Repeated (measured on three separate
occasions) diastolic blood pressure > 90 mm Hg, or systolic blood pressure > 135 mm
Hg, known arrhythmia, symptomatic or known coronary artery disease; history of
endocarditis, cerebral embolism, obstructive pulmonary disease, asthma, active
tuberculosis, known endocrine disease (derangements in adrenal, thyroid, bone or
reproductive function), known chronic renal or hepatic dysfunction, known HIV
seropositive, known current autoimmune disease involving the CNS, glaucoma, allergy
to amphetamine, dextroamphetamine or known hypersensitivity to sympathomimetic
amines.
5. Female participants who are currently pregnant or nursing will not be allowed to
participate in this study. Female subjects will be given a serum pregnancy test a
maximum of 24 hours prior to each PET session and a urine pregnancy test on the day
of each fMRI session.
6. Radiation exposure: Any subject who has participated in any research studies in which
he/she received a radiation exposure or has been exposed to radiation for medical or
other purpose , which in combination with the present study would result in a total
effective radiation exposure (from research studies) exceeding 5.0 rem in a year
will be excluded.
7. Children under the age of 18 will be excluded to avoid unnecessary exposure to
radiation to this population.
8. Presence in body of metallic implants or materials that could be moved by the magnet
of the MRI scanner will exclude participants from this study. This will include, but
not be limited to, pacemakers, surgical implants, aneurysm clips, dental braces, or
bullet(s). A history of working with metal with consequent possible metal fragments
in the body may also result in study exclusion.
9. Miscellaneous exclusionary criteria: Body mass greater than 300 lbs. Hematocrit <
39.0% for males or < 35.0% for females. Participants will also be excluded if veins
are inaccessible.
10. Claustrophobia will also serve as an exclusion criterion.
Control Participants
In addition to those criteria outlined above, potential control participants will be
excluded if they meet the following criteria:
1. Current or past psychiatric illness: DSM-IV criteria will be used (DSM-IV, APA,
1994) to determine this criterion. No subject with a current axis I diagnosis will
be allowed to participate.
2. History of Drug Abuse: Control volunteers reporting either current or a significant
history of illicit drug abuse (defined as single illicit substance use of more than
30 times in a lifetime for any given substance, except marijuana) will be excluded
from the study.
3. Positive urine toxicology screen for either amphetamines or cocaine prior to study
participation.
Cocaine-Dependent Subjects
Candidates for the cocaine-dependent group will be excluded from the study if:
1. They are actively seeking or engaged in substance abuse treatment.
2. They are dependent on other substances except nicotine or cocaine at the time of
participation. |