Clinical Neurobiology of Serotonin and Addiction

Specific Aim 1: We will test the hypothesis that cocaine-dependent subjects will exhibit
greater impulsivity than controls as determined by a battery of impulsivity measures and that
impulsivity will be associated with specific profiles of 5-HT2AR and/or 5-HT2CR expression in
platelets. We predict that treatment of cocaine-dependent subjects with escitalopram and/or
mirtazapine will reduce impulsivity and cocaine-positive urines, in concert with a normalized
balance of platelet 5-HT2AR and/or 5-HT2CR expression.

Specific Aim 2: We will test the hypothesis that cocaine-dependent subjects will exhibit
greater cue reactivity than controls as determined by a modified Stroop task, and that cue
reactivity will be associated with specific profiles of 5-HT2AR and/or 5-HT2CR expression in
platelets. We predict that treatment of cocaine-dependent subjects with escitalopram and/or
mirtazapine will reduce cue reactivity and cocaine-positive urines, in concert with a
normalized balance of platelet 5-HT2AR and/or 5-HT2CR expression.

Specific Aim 3: We will test the hypothesis that specific polymorphisms in the 5-HT2AR and/or
5-HT2CR will predict baseline impulsivity and/or cue reactivity as well as treatment response
to serotonergic medications in cocaine-dependent subjects.

Inclusion Criteria:

- Non-Drug Abusing Control Subjects: Male and female subjects age 18 to 55 who do not
meet current or past DSM-IV criteria for any Axis I disorder including substance abuse
or dependence.

- Cocaine Dependent Subjects: Male and female subjects age 18 to 55 who meet current
DSM-IV criteria for cocaine dependence.

- Female subjects: a negative pregnancy test.

Exclusion Criteria:

- Non-Drug Abusing Control Subjects:

1. Current or past DSM-IV Axis I disorder

2. Any serious non-psychiatric medical illness requiring ongoing medical treatment
or which could affect the central nervous system.

3. Positive HIV test.

4. For female subjects: a positive pregnancy test or breast feeding.

5. Concomitant use of prescription medications that could affect the central nervous
system.

6. Active suicidal ideation.

7. Hamilton Depression or Anxiety Scale score greater than 15

- Cocaine Dependent Subjects:

1. Current DSM-IV Axis I disorder other than substance abuse/dependence

2. Current diagnosis of other substance dependence besides cocaine.

3. Any serious non-psychiatric medical illness requiring ongoing medical treatment
or which could affect the central nervous system.

4. Positive HIV test.

5. For female subjects: a positive pregnancy test or breast feeding.

6. Concomitant use of prescription medications that could affect the central nervous
system.

7. Active suicidal ideation.

8. Subjects within 14 days of discontinuing a monoamine oxidase inhibitor.

9. Subjects with cardiac arrythmias.

10. Subjects with known hypersensitivity to escitalopram or citalopram, or
mirtazapine

11. Hamilton Depression or Anxiety Scale score greater than 15.

12. Current alcohol abuse or dependence.