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Dopamine Rhythms in Health and Addiction

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Cocaine Abuse

Intervention: Brain Dopamine Reactivity (Drug); Brain Dopamine Receptor (Drug)

Phase: Phase 0

Status: Suspended

Sponsored by: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Official(s) and/or principal investigator(s):
Gene-Jack Wang, M.D., Principal Investigator, Affiliation: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Summary

Background:

- Dopamine is a chemical signal linked to the rewarding effects of drugs. Certain genes make

these effects sensitive to the time of day they are taken. Cocaine can affect these genes in the brain. Researchers want to measure brain dopamine at different times of day. Objectives:

- To look for changes to a person s biological clock in the function of the dopamine

reward system. To test if cocaine disrupts this. Eligibility:

- Adults age 21 55 with a cocaine use disorder.

- Healthy volunteers age 21 55.

Design:

- Participants will be screened with medical history, physical exam, interview, and blood

and urine tests. Their breath will be tested for alcohol and recent smoking.

- Participants will have 3 overnight clinic visits.

- Visit 1: They will have blood and urine collected and a heart test.

- A plastic tube (catheter) will be placed into a vein in each arm by needle.

- Participants will have a PET scan in a donut-shaped machine. They will lie on a bed

that slides in and out of it, wearing a cap. A radiotracer (measures dopamine) and a drug (blocks dopamine removal) will be injected via catheter. Vital signs will be measured and blood will be drawn throughout.

- Visit 2: repeats Visit 1, except at night.

- Visit 3, participants will have urine collected.

- They will have MRI scans in a metal cylinder surrounded by a magnetic field. They will

lie on a table that slides in and out of it, with a coil over their head.

- Participants may answer questions, take computer or paper tests, and perform simple

actions.

- For 1 week, participants will wear a wrist device that measures daily activity.

Clinical Details

Official title: Dopamine Rhythms in Health and Addiction

Study design: Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Primary outcome: To assess if there are diurnal rhythms in DA signaling and in reward brain circuits and to determine if these are disrupted in cocaine addiction.

Secondary outcome:

To determine if differences in measures of DA signaling between morning and evening correlate with circadian typology.

To determine if measures of DA signaling correlate with measures of spontaneous motor activity and with sleeping patterns.

To assess if DA signaling correlates with reactivity of brain regions to exposure of drug and with functional connectivity of the reward network and to assess if the reactivity of reward network shows circadian variability.

Detailed description: OBJECTIVES: The primary objective is to assess if there is disruption of circadian DA rhythms in cocaine addiction. The secondary objective is to assess if dopamine modulates the sensitivity of the brain reward network in a circadian dependent manner. STUDY POPULATION: Non-treatment seeking cocaine abusers (moderate or severe cocaine use disorder as per DSM-IV) and healthy controls. Males and females will be included. DESIGN: Participants will undergo two PET scans with [11C]raclopride using a bolus infusion paradigm to assess baseline D2R availability followed by an infusion to assess changes in DA as measured by [11C]raclopride s displacement following an intravenous injection of methylphenidate (MP). The two [11C]raclopride scans will be done on separate days, one in the morning starting between (7-9 AM) and one in the early evening (5-7 PM) with at least one week between drug administrations. On a separate day we will perform MRI scans to assess sensitivity of brain reward circuits to visual presentation of drug or food cues and to evaluate resting functional connectivity and these measures will be obtained at three time periods, 6-8 AM, 2-4 PM and 9-11 PM. OUTCOME PARAMETERS Main outcome measure is to assess if there are differences in DA release between the morning and the evening (displacement of [11C]raclopride binding after MP) and to determine if these diurnal patterns differ in cocaine addiction. Secondary outcome measures are: To assess if DA signaling correlates with reactivity of brain regions to exposure of food and drug cues and with functional connectivity of the reward network and to assess if the reactivity of the reward network shows circadian variability. We will also assess if differences in DA signaling between morning and evening correlate with circadian typology and with measures of spontaneous motor activity and with sleeping patterns.

Eligibility

Minimum age: 21 Years. Maximum age: 55 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

All Participants 1. Between 21 and 55 years of age. 2. Ability to provide written informed consent as determined by successful completion of consent quiz prior to signing consent. Inclusion Specific For Cocaine Use Disorder (CUD) Participants 1. DSM-IV diagnosis of a moderate or severe cocaine use disorder (established through history and clinical exam).

2. Non-treatment seeking cocaine users (actively consuming cocaine - last use within one

week of study as assessed by self-reports).

3. Minimum 10 years history of cocaine abuse predominantly via smoking or injection -

self-report.

4. Must consume at least 4 grams of cocaine per week - self-report.

EXCLUSION CRITERIA: All Participants 1. Use, in the past two weeks, of psychoactive medications (four weeks for fluoxetine) or medications that may affect brain function (including but not limited to meperidine, tricyclic antidpressants, selective serotonin reuptake inhibitors (SSRIs), or serotonin norepinephrine reuptake inhibitors (SNRIs) as determined by medical history and physical exam. 2. Current DSM-IV diagnosis of a psychiatric disorder (other than cocaine for the cocaine abusers and nicotine for any of the participants) as determined by history and clinical exam. Past history of a mental disorder as defined by DSM IV will be excluded only if it was severe enough as to require treatment. 3. Current or previous chronic treatment (greater than 3 months) with stimulant medications (amphetamine or methylphenidate). 4. Major medical problems that can impact brain function (e. g., CNS including seizures and psychosis; cardiovascular including hypertension [BP > 140/90] and clinically significant arrhythmias except bradycardia; metabolic, autoimmune, endocrine; +HIV) as determined by history. 5. Any clinically significant laboratory finding as determined during the screening procedures as evidenced from clinical laboratory results. 6. Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that, with the exposure from this study, would exceed NIH annual research limits as determined by medical history and physical exam. 7. Head trauma with loss of consciousness for more than 30 minutes as determined by medical history and physical exam; 8. Positive test for drugs on the day of the PET, the MRI or the NP tests as evidenced from clinical laboratory results. 9. Pregnant or breast feeding: Females must have negative urine pregnancy test and are not currently breastfeeding. Post-menopausal or surgically sterile (tubal ligation or hysterectomy); or not sexually active with a male partner and able to get pregnant; or documented agreement to use an effective form of birth control. Acceptable forms of contraception include: hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring hormones); IUD; diaphragm with spermicide; condom with spermicide. 10. History of coagulation disorder as evidenced from clinical laboratory results, medical history. 11. History of glaucoma as determined by medical history. 12. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner,

implanted delivery pump, or shrapnel fragments) or fear of enclosed spaces -

self-report checklist. 13. Cannot lie comfortably flat on your back for up to 2 hours in the PET and MRI scanners self-report. 14. BMI > 30 or weight > 150 kilograms.

- Note: At any time a subject expresses that he/she wants to get treatment for

their cocaine use, we will immediately refer him/her to a treatment program. The subject will be withdrawn from the study at that time.

Locations and Contacts

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States
Additional Information

NIH Clinical Center Detailed Web Page

Related publications:

Wang GJ, Volkow ND, Fowler JS, Logan J, Pappas NR, Wong CT, Hitzemann RJ, Netusil N. Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate. J Nucl Med. 1999 Aug;40(8):1285-91.

Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS. Brain dopamine and obesity. Lancet. 2001 Feb 3;357(9253):354-7.

Dunn JP, Cowan RL, Volkow ND, Feurer ID, Li R, Williams DB, Kessler RM, Abumrad NN. Decreased dopamine type 2 receptor availability after bariatric surgery: preliminary findings. Brain Res. 2010 Sep 2;1350:123-30. doi: 10.1016/j.brainres.2010.03.064. Epub 2010 Mar 31.

Starting date: September 2014
Last updated: July 30, 2015

Page last updated: August 23, 2015

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