Understanding Dopamine Mechanisms in Cocaine Addiction Using AMPT and Methylphenidate With [11C]RAC/[11C]PHNO PET

Study Overview
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Brief Summary
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Studies using positron emission tomography (PET) have been used with great success in demonstrating specific abnormalities in several facets of dopaminergic system function in human populations (Narendran and Martinez 2009). Among the first, most consistent, and broadly replicated of such findings in drug- (including cocaine) dependent individuals has been the reduction in subcortical (striatal) D2/3 receptors as imaged, most commonly, by the reversible, non-selective, D2/3 receptor antagonist radiotracer, [11C]raclopride. Certain dissociations on D2/3 availability by radioligand ([11C]raclopride vs. [11C]PHNO) and by brain region (striatum vs. SN; terminal vs. somatodendritic, respectively) are poorly understood in relationship to prior antagonist tracer results. In the current study the investigators will use pharmacological interventions (AMPT and methylphenidate) with both antagonist and agonist radiotracers to experimentally reconcile these discordant findings and clarify potential mechanistic inter-relationships.

Conditions
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Cocaine Dependence

Intervention / Treatment
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* Drug: Methylphenidate
* Drug: Alpha Methyl Para Tyrosine (AMPT)
* Other: [11C]PHNO
* Other: [11C]raclopride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 - 50 years, voluntary, written, informed consent, physically healthy by medical history, physical, neurological, ECG, and laboratory examinations, for females, non-lactating, no longer of child-bearing potential (or agree to practice effective contraception during the study), and a negative serum pregnancy (B-HCG) test. English speaking No other major Axis DSM-IV diagnosis present, besides required as below Inclusion criteria for cocaine dependent: DSM-IV criteria for Cocaine Abuse (305.60) or Cocaine Dependence (304.20) recent street cocaine use, intravenous and/or smoked (crack/ freebase) use, positive urine toxicology screen for cocaine, Inclusion criteria for healthy controls: No current, or history of, any DSM-IV diagnosis No first-degree relative with history of psychotic, mood, or anxiety disorder Exclusion Criteria: medical contraindications to AMPT administration (e.g., known sensitivity/reaction to AMPT); medical contraindications to MPH administration (e.g., history of cardiac problems, seizures, etc.) drug or alcohol dependence (except nicotine), a primary major DSM-IV psychiatric diagnosis (schizophrenia, bipolar disorder, etc.), unrelated to cocaine or pathological gambling positive answers on the cardiac screening questionnaire that may place the subject at higher risk, as determined by cardiologist review of both the questionnaire responses and screening ECG current use of psychotropic and/or potentially psychoactive prescription medication, physical or laboratory (B-HCG) evidence of pregnancy, clotting disorders or recent anticoagulant therapy, MRI-incompatible implants and other contraindications for MRI (i.e., aneurysm clip, metal fragments, internal electrical devices such as a cochlear implant, spinal cord stimulator or pacemaker), history of claustrophobia or feeling of inability to lie still on his back for the PET or MRI scans, history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over Radioactive Drug Research Committee (RDRC) limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year. donation or loss of 550 mL of blood or more (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to the first dose of study drug. use any prescription medications and/or over-the-counter medications, vitamins and/or herbal supplements within 2 weeks prior to study and for the duration of the study without approval from the study doctor. eat grapefruit or grapefruit products, and drink alcohol, and anything containing caffeine 3 days before study and during study For CD subjects, < 1 year of cocaine dependence, . Subjects with current, past, or anticipated exposure to radiation in the workplace.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baseline<br>Subjects will receive 2 baseline PET scans with the radioligands (11C)(+)PHNO and (11C)(+)raclopride | Other: [11C]PHNO<br> <br> Other: [11C]raclopride<br> <br> |
| Experimental: Dopamine Release<br>Subjects will receive 1 PET scan following a PO dose of 60mg of methylphenidate to facilitate dopamine release with the radioligand (11C)(+)PHNO | Drug: Methylphenidate<br> <br> Other: [11C]PHNO<br> <br> |
| Experimental: Endogenous Dopamine<br>Subjects will receive 2 PET scans following 48 hours of dopamine depletion via AMPT with the radioligands (11C)(+)PHNO and (11C)(+)raclopride | Drug: Alpha Methyl Para Tyrosine (AMPT)<br> <br> Other: [11C]PHNO<br> <br> Other: [11C]raclopride<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BPND | BPND is a measure of dopamine receptor availability | 2 weeks |