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

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ClinicalTrials.gov Identifier: NCT02152670
Recruitment Status : Active, not recruiting
First Posted : June 2, 2014
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
Yale University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cocaine Dependence Drug: Methylphenidate Drug: Alpha Methyl Para Tyrosine (AMPT) Other: [11C]PHNO Other: [11C]raclopride Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Other
Study Start Date : May 2014
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Baseline
Subjects will receive 2 baseline PET scans with the radioligands (11C)(+)PHNO and (11C)(+)raclopride
Other: [11C]PHNO
Other: [11C]raclopride
Experimental: Dopamine Release
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
Other: [11C]PHNO
Experimental: Endogenous Dopamine
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)
Other: [11C]PHNO
Other: [11C]raclopride



Primary Outcome Measures :
  1. BPND [ Time Frame: 2 weeks ]
    BPND is a measure of dopamine receptor availability



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. age 18 - 50 years,
  2. voluntary, written, informed consent,
  3. physically healthy by medical history, physical, neurological, ECG, and laboratory examinations,
  4. 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.
  5. English speaking
  6. No other major Axis DSM-IV diagnosis present, besides required as below

Inclusion criteria for cocaine dependent:

  1. DSM-IV criteria for Cocaine Abuse (305.60) or Cocaine Dependence (304.20)
  2. recent street cocaine use,
  3. intravenous and/or smoked (crack/ freebase) use,
  4. positive urine toxicology screen for cocaine,

Inclusion criteria for healthy controls:

  1. No current, or history of, any DSM-IV diagnosis
  2. No first-degree relative with history of psychotic, mood, or anxiety disorder

Exclusion Criteria:

  1. medical contraindications to AMPT administration (e.g., known sensitivity/reaction to AMPT);
  2. medical contraindications to MPH administration (e.g., history of cardiac problems, seizures, etc.)
  3. drug or alcohol dependence (except nicotine),
  4. a primary major DSM-IV psychiatric diagnosis (schizophrenia, bipolar disorder, etc.), unrelated to cocaine or pathological gambling
  5. 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
  6. current use of psychotropic and/or potentially psychoactive prescription medication,
  7. physical or laboratory (B-HCG) evidence of pregnancy,
  8. clotting disorders or recent anticoagulant therapy,
  9. 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),
  10. history of claustrophobia or feeling of inability to lie still on his back for the PET or MRI scans,
  11. 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.
  12. 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.
  13. 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.
  14. eat grapefruit or grapefruit products, and drink alcohol, and anything containing caffeine 3 days before study and during study
  15. For CD subjects, < 1 year of cocaine dependence, .
  16. Subjects with current, past, or anticipated exposure to radiation in the workplace.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02152670


Locations
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United States, Connecticut
Connecticut Mental Health Center
New Haven, Connecticut, United States, 06519
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Robert Malison, MD Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02152670     History of Changes
Other Study ID Numbers: 1403013567
First Posted: June 2, 2014    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: December 2019
Additional relevant MeSH terms:
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Cocaine-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Dopamine
Raclopride
Methylphenidate
alpha-Methyltyrosine
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Protective Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Enzyme Inhibitors