Dopamine Rhythms in Health and Addiction

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
or DSM 5) 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). They will also undergo a total of 4 MRI scans, two after placebo and
two after MP to assess the circadian variations in the sensitivity of the brain reward
network. The two [11C]raclopride scans will be done on separate days at least one week apart,
one in the morning starting between (7-9 AM) and one in the early evening (5-7 PM) and they
will be followed by an MRI scan to assess the sensitivity of the brain reward network under
the influence of MP in the morning (9-11AM) and in the evening (7-9 PM). For the Placebo MRI
scans participants will be tested either on separate days or on the morning of the evening
session or on the evening prior to the morning session. We will use the MRI scans to assess
the sensitivity of the brain reward circuit to visual presentation of drug or food cues and
to evaluate resting functional connectivity.

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.

- INCLUSION CRITERIA - ALL PARTICIPANTS:

1. Between 21 and 55 years of age.

2. Ability to provide written informed consent.

INCLUSION CRITERIA - SPECIFIC FOR COCAINE USE DISORDER (CUD) PARTICIPANTS:

1. DSM-IV or DSM-5 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. Unwilling or unable to refrain from use within 24 hours of scheduled study procedures:
psychoactive medications or medications that may affect study results e.g.,
antibiotics (must finish course at least 24 hours prior to a scheduled procedure),
antidiarrheal preparations, anti-inflammatory drugs [systemic corticosteroids are
exclusionary], anti-nausea, cough/cold preparations) (self-report, medical history).
The following medications are allowable for entry on this study: analgesics
(non-narcotic and narcotic for OUD participants); antacids; antiasthma agents that are
not systemic corticosteroids; antifungal agents for topical use; antihistamines
(non-sedating); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of
antihyperlipidemics and/or diuretics are permitted if they have been taken for at
least 1 month before procedure visits and dose has been stabilized as determined by
medical history and physical exam. The episodic use of benzodiazepines such as
alprazolam ((TM)Xanax), diazepam ((TM)Valium) and lorazepam ((TM)Ativan), will not
exclude participants from this study unless they have been taken within the last 24
hours prior to the study.

2. Current or past DSM-IV or DSM-5 diagnosis of a psychiatric disorder (other than
cocaine for the cocaine abusers, and nicotine/caffeine for any of the participants)
that required hospitalization (any length), or chronic medication management (more
than 4 weeks) and that could impact brain function at the time of the study as
determined by history and clinical exam.

3. The following current chronically used medications are exclusionary from the study:
stimulant or stimulant-like medications (amphetamine, methylphenidate, modafinil) ;
analgesics containing narcotics (for controls only); anorexics (sibuteramine);
antianginal agents; antiarrhythmics; antiasthma agents that are systemic
corticosteroids; antibiotics; anticholinergics; anticoagulants; anticonvulsants;
antidepressants; antidiarrheal preparations; antifungal agents (systemic);
antihistamines (sedating); antihypertensives; anti-inflammatory drugs (systemic);
antineoplastics; antiobesity; antipsychotics; antivirals (except for treatment of HSV
with agents without CNS activity, e.g. acyclovir, ganciclovir, famciclovir,
valacyclovir); anxiolytics (benzodiazepine or barbiturates); hormones (exceptions:
thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy);
insulin; lithium; muscle relaxants; psychotropic drugs not otherwise specified (nos)
including herbal products (no drugs with psychomotor effects or with anxiolytics,
stimulant, antipsychotic, or sedative properties); sedatives/hypnotics. Note that
nicotine and/or caffeine use will not exclude participants and that the use of cocaine
will not exclude participants with CUD.

4. Major medical problems that can permanently 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 that could impact brain function or study procedures as evidenced from
clinical laboratory results. Since half of the participants in the study will have a
diagnosis of cocaine use disorder (CUD), we expect some clinically significant
findings that would reflect their recent cocaine use. As an example, a participant
might have a mildly elevated Creatinine Kinase as a result of recent cocaine use. The
test would reflect an acute rhabdomyolysis due to recent cocaine use, and it would be
clinically significant. Nevertheless, if it is a mild episode as expected with cocaine
use, it would not affect brain functioning or increase the risk of the procedures for
the participants in the study. Therefore, not all abnormal laboratory findings that
have clinical significance will be excluded. If a finding reflects altered brain
function (e.g., arrhythmias or renal failure) it will be exclusionary for the study.

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. 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.

9. History of coagulation disorder as evidenced from clinical laboratory results, medical
history.

10. History of glaucoma as determined by medical history. Since glaucoma is screened for
clinically at about the age of 40, any subjects 40 or older will undergo a glaucoma
screening test if they have not been tested by their primary care physician. A result
of 21 mmHg or higher will exclude.

11. 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.

12. Personal or family history for cerebral aneurism.

13. Past or present history of chest pain and trouble breathing with activity.

14. Diabetes as assessed by medical history.

15. High risk for silent heart diseases as evidenced by high levels of high-sensitivity
C-reactive protein or homocysteine in blood, or being overweight or obese. In addition
patients with high cholesterol or a family history of heart disease will be evaluated
by a cardiologist to determine their eligibility for participation. The cardiologist
might request additional tests if he deems it necessary to ensure fitness for
participation (ie treadmill stress test). Specifically the cardiologist involved will
review the findings of 1) an inability to reach these endpoints, 2) the development of
chest pain, 3) significant ST segment changes, 4) significant arrhythmias, and 5) an
inability to appropriately increase blood pressure or heart rate with exercise in
order to determine if the participant is suitable for inclusion in the study.

16. Cannot lie comfortably flat on your back for up to 2 hours in the PET and MRI scanners
- self-report.

17. Weight > 400 pounds which is the maximum weight the PET scanner can hold.

18. Study investigators and staff, as well as their superiors, subordinates and immediate
family members (adult children, spouses, parents, siblings).

- Note that subjects will not be excluded from enrollment onto this study if their
urine test is positive for drugs on initial screening. The following guidelines
will be followed for positive drug screens on study procedure days:

- If a Healthy Volunteer subject s urine drug screen test is positive on days
involving imaging (MRI and/or PET) and NP testing, the procedures will be
postponed and rescheduled. We will allow for up to 3 rescheduled study days
resulting from positive urine drug screens. If the drug test is positive on
the third rescheduled visit, the participant will be withdrawn from the
study.

- If a CUD subject s urine drug screen test is positive for drugs (except
cocaine), the procedures will be postponed and rescheduled to another day.
We will not place a limit on rescheduling study days in this participant
group.

- 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.