Measuring Effects of Alcohol on Brain Chemistry

Rodent studies have indicated that modulation of glutamatergic transmission contributes to
alcohol intoxication, reinforcement, tolerance, and dependence. Brain microdialysis studies
have in general shown that acute alcohol suppresses glutamate release, while alcohol
withdrawal leads to progressively increased extracellular levels.

Here, we will use an acute, pharmacokinetically controlled alcohol challenge and magnetic
resonance spectroscopy (MRS) to study the relationship between brain alcohol and glutamate
concentrations, and correlate these with subjective feelings of alcohol effects, as measured
by the Drug Effects Questionnaire (DEQ) in human subjects. Correlations between MRS data and
other behavioral data from the Sensitivity to Punishment and Sensitivity to Reward
Questionnaire (SPSRQ), Alcohol Sensitivity Questionnaire (ASQ), and the Alcohol Effects
Questionnaire (AEFQ) will be investigated.

Healthy participants aged 21-45, without gross impairment of judgment or complicated
psychiatric or other morbidity, will receive a preliminary infusion to ensure no adverse
effects from intravenous (IV) alcohol administration to a target BAC of 0.08g/dl. In a
subsequent session, participants will be infused with alcohol to the same target level while
being scanned in the MR scanner and reporting subjective feelings using the DEQ. Two groups
of subjects will be recruited: heavy drinkers, classified as females who consume 15 plus
drinks per week and males who consume 20 plus drinks per weekthose who consume between 20 and
40 drinks per week, and light drinkers, classified as females who consume between 1 and 10
drinks per week and males who consume between 1 and 14 drinks per week. those who consume
between 1 and 14 drinks per week.

Central glutamate levels will be quantified at 3T using pharmacologically validated MRS
methodology recently published from our laboratory, and its relationship to central alcohol
levels will be determined. Relationships will also be analyzed between DEQ scores and brain
glutamate and alcohol levels. Finally, it will be examined whether drinking history (i.e.
being a light versus heavy drinker) is a moderator of any of these relationships.

- INCLUSION CRITERIA (Light Drinkers)

1. In good health as determined by medical history, physical exam, ECG and lab
tests;

2. Between 21 and 45 years of age;

3. Currently consuming between 1 and 10 drinks per week for females and 1 and 14
drinks per week for males.

EXCLUSION CRITERIA (Light Drinkers)

1. Have liver function tests (AST, ALT, GGT, ALP) 3-times the upper limit of normal
(ULN); or have Total Bilirubin above 1.5 ULN and Albumin below 3.5 g/dL.

2. Have fulfilled DSM-IV criteria for a current or past major psychiatric disorder
including alcohol or other substance dependnece (excluding nicotine);

3. Have a Body Mass Index (BMI) value over 35;

4. Unable to stop taking any prescribed, non-prescribed, or over-the-counter medication
or drugs 3 days prior to study days (excluding oral contraceptive agents). If a
subject is taking a prescribed medication (excluding oral contraceptive agents) that
is not take-as-needed they will be excluded from participation;

5. Are pregnant, as determined by a negative pregnancy test, or lactating;

6. Report to have a "facial flushing" response to the consumption of alcohol;

7. Have never consumed at least two standard drinks of alcohol within one hour;

8. Have ferromagnetic objects in their bodies, which might be adversely affected by MRI
including implanted pacemakers, medication pumps, aneurysm clips, metallic prostheses
(including metal pins and rods, heart valves or cochlear implants), shrapnel
fragments, permanent eye liner or small metal fragments in the eye that welders and
other metal works may have any doubt about presence of these objects will result in
exclusion from this study);

9. Regular tobacco users will be excluded from the study in order to avoid nicotine
withdrawal symptoms. Occasional (not daily) use of tobacco products is acceptable;

10. Unwilling to abstain from alcohol for at least 2 days prior to the studies.

INCLUSION CRITERIA (Heavy Drinkers)

1. In good health as determined by medical history, physical exam, ECG and lab tests;

2. Between 21 and 45 years of age;

3. Currently consuming 15+ drinks for females and 20+ drinks for males;

4. Not regularly abstinent for more than 3 days per week, but have abstained from alcohol
for 3 consecutive days without experiencing withdrawal symptoms;

5. Able to provide a plausible history that they can abstain from alcohol without
significant withdrawal symptoms when coming to the clinic. In addition, participants
will be asked to quantify their worst withdrawal symptoms using the Clinical Institute
Withdrawal Assessment (CIWA) Instrument. Participants who score 8 or above will not be
enrolled in the protocol;

6. Not seeking treatment for their alcohol consumption.

EXCLUSION CRITERIA (Heavy Drinkers)

1. Have liver function tests (AST, ALT, GGT, ALP) 3-times the upper limit of normal
(ULN); or have Total Bilirubin above 1.5 ULN and Albumin below 3.5 g/dL.

2. Have fulfilled DSM-IV criteria for a current or past major psychiatric disorder,
including any substance dependence (excluding alcohol or nicotine) at any time;

3. Have a Body Mass Index (BMI) value over 35;

4. Unable to stop taking any prescribed, non-prescribed, or over-the-counter medication
or drugs 3 days prior to study days (excluding oral contraceptive agents). If a
subject is taking a prescribed medication (excluding oral contraceptive agents) that
is not take-as-needed they will be excluded from participation;

5. Are pregnant, as determined by a negative pregnancy test, or lactating;

6. Report to have a "facial flushing" response to the consumption of alcohol;

7. Have never consumed at least two standard drinks of alcohol within one hour;

8. Have ferromagnetic objects in their bodies, which might be adversely affected by MRI
including implanted pacemakers, medication pumps, aneurysm clips, metallic prostheses
(including metal pins and rods, heart valves or cochlear implants), shrapnel
fragments, permanent eye liner or small metal fragments in the eye that welders and
other metal works may have any doubt about presence of these objects will result in
exclusion from this study);

9. Regular tobacco users will be excluded from the study in order to avoid nicotine
withdrawal symptoms. Occasional (not daily) use of tobacco products is acceptable;

10. Unwilling to abstain from alcohol for at least 2 days prior to the studies.