Brain Dopaminergic Signaling in Opioid Use Disorders

Objectives: Primary objective is to assess whether the balance between dopamine D1 (D1R) and
D2 receptors (D2R) signaling in striatum is disrupted in participants with an opioid use
disorder (OUD) who are on opioid agonist medication (MAT+: methadone or buprenorphine)
relative to OUD participants treated with the opioid antagonist medication (naltrexonel) and
OUD participants not being treated with medications (MAT). Secondary objectives are to assess
how striatal D1R to D2R availability (assessed with PET) influences: (1) striatal dopamine
(DA) release; (2) the function of brain reward and self-control networks (assessed with task
fMRI activation and with resting functional connectivity, RFC) and (3) behavior (locomotor
activity and neuropsychological tests) and (4) to assess if DA increases, as induced by oral
methylphenidate (MP), improve the function of brain reward and control networks in OUD; and
(5) to assess if there is recovery after protracted treatment (comparing treated and
non-treated) by repeating fMRI at 6 month follow-up.

Study population: We will complete studies in 120 (n=120) subjects: N=30 healthy control
adults and N=90 90 OUD participants (30 MAT+, 30 naltrexone-treated and 30 MAT-) aged 18-65
(male/female) will be included.

Design: Single-blind. Participants will undergo three scans with positron emission tomography
(PET): one with [11C]NNC-112 to assess baseline D1R, another with [11C]raclopride after
placebo to assess baseline D2R and a third one with [11C]raclopride after MP administration
(60mg oral) to assess striatal DA release (assessed as the difference in specific binding of
[11C]raclopride between baseline and MP). In addition, participants will undergo two imaging
sessions with MRI to assess functional reactivity to drug-cues and to a measure of
self-control (delayed discounting task), to assess RFC and to obtain structural brain
measures (including diffusion tensor imaging, DTI). One of the sessions will be done under
baseline conditions (no drug administered) and the other after MP (about one hour after the
[11C]raclopride MP scan is completed). Neuropsychological tests (NP) and accelerometers will
be used to assess cognitive performance and locomotor activity respectively

Outcome Measures: Main outcome: (1) Differences in D1R to D2R striatal ratio between
participants with an OUD and controls and between MAT+, natrexone, and MAT- groups. Secondary
outcomes: Correlations between striatal D1R to D2R and (1) striatal DA release; (2) fMRI
activation in reward and controls networks (assessed with cuereactivity and delay discounting
tasks, and with RFC) and (3) NP performance and locomotor activity. (4) Differences in fMRI
activation and RFC after MP when compared with baseline measures.

- INCLUSION CRITERIA:

Healthy Volunteer Participants

1. Males or females between 18 and 65 years of age.

2. Ability to provide written informed consent.

MAT- Opiate Use Disorder (OUD) Participants

1. Males or females between 18 and 65 years of age.

2. Ability to provide written informed consent.

3. DSM-5 diagnosis of a moderate or severe OUD (established through history and clinical
exam).

4. Active abuse of opiates (last use within one week of study as assessed by
self-reports).

5. Minimum 5 year history of opiate abuse - self-report.

6. Must consume opiates at least 5 days per week as per self-report.

7. Currently not receiving medications for OUD (methadone, buprenorphine or naltrexone).

MAT+ OUD Participants

1. Males or females between 18 and 65 years of age.

2. Ability to provide written informed consent.

3. DSM-5 diagnosis of a moderate or severe OUD (established through history and clinical
exam).

4. Active or non-active abuse of opiates.

5. Minimum 5 year history of opiate abuse as per self-report.

6. Must have consumed at least 5 days per week (prior opiate use) as per self-report.

7. Receiving opioid agonist therapy for OUD (e.g., methadone or buprenorphine) and must
have taken for at least week before imaging study.

Naltrexone OUD Participants

1. Males or females between 18 and 65 years of age.

2. Ability to provide written informed consent.

3. DSM-5 diagnosis of a moderate or severe OUD (established through history and clinical
exam).

4. Active or non-active abuse of opiates.

5. Minimum 5 year history of opiate abuse as per self-report.

6. Must have consumed at least 5 days per week (prior opiate use) as per self-report.

7. Receiving naltrexone treatment for their OUD and must have taken at least one week
before imaging study.

EXCLUSION CRITERIA:

All Subjects

-Unwilling or unable to refrain from use within 24 hours of scheduled study procedures:
psychoactive medications or medication that may affect study results (e.g., antibiotics
(must finish course at least 24 hours prior to a scheduled procedure), analgesics
(non-narcotic and narcotic for healthy volunteers only); 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 only); antacids; antiasthma agents that are not systemic corticosteroids;
antifungal agents for topical use; antihistamines (nonsedating); antihypertensives (except
beta blockers); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of
H2-Blockers/PPI (proton pump inhibitors), antihypertensives (other than beta-blockers),
antihyperlipidemics and/or diuretics are permitted if they have been taken for at least 1
month before procedure visits and dose has been stabilized. The episodic use of
benzodiazepines such as alprazolam ( Xanax), diazepam ( Valium) and lorazepam ( Ativan),
will not exclude participants from this study unless they have been taken within the last
24 hours prior to the study.

- Current DSM-5 diagnosis of a psychiatric disorder (other than OUD or mild/moderate
alcohol/substance use disorders in OUD participants and nicotine/caffeine use in all
participants) that requires/required daily medications in the past three months and
that could impact brain function at the time of the study as determined by history and
clinical exam. Healthy Volunteers with current co-morbid psychiatric disorders, which
may confound the data, will not be enrolled.

- Current DSM-5 diagnosis of a psychiatric disorder (other than OUD or mild/moderate
alcohol/substance use disorders in OUD participants) that required hospitalization in
the past year and that could impact brain function at the time of the study as
determined by history and clinical exam.

- 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 (orlistat); antianginal
agents; antiarrhythmics; antiasthma agents that are systemic corticosteroids;
antibiotics; anticholinergics; anticoagulants; anticonvulsants; antidepressants;
antidiarrheal preparations; antifungal agents (systemic); antihistamines (sedating);
beta-blocker 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. OUD subjects are excluded
if use of listed medications were taken chronically in the past 3 months. Note that
nicotine and/or caffeine use will not exclude participants and that the use of opiate
drugs will not exclude participants with OUD. Also note that subjects on stable
hypertensive medications (except for beta blockers) may be included on the study
provided they are on stable dose for at least one month [BP less than or eual to 90].

- Current or past month continuous treatment (> 3 weeks) with methadone, buprenorphine
or naltrexone for controls or MAT- OUD participants; or naltrexone for MAT+ OUD
participants; or agonist treatment (methadone or buprenorphine) for OUD participants
treated with Naltrexone.

- Major medical problems that can permanently impact brain function (e.g., CNS including
seizures and psychosis; cardiovascular including uncontrolled hypertension [BP >
140/90] and clinically significant arrhythmias except bradycardia; metabolic,
autoimmune, endocrine; +HIV) as determined by history. OUD subjects with Hepatitis
(HCV) who have normal liver synthetic functions (normal alb, PT, PLT, bili, no
clinical evidence of active liver disease) and no more than minimally elevated ALT
(<1.5 UNL) may be included.

- 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. Only abnormal laboratory findings associated with altered
brain function (e.g., arrhythmias or renal failure) will be exclusionary.

- 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.

- Head trauma with loss of consciousness for more than 30 minutes as determined by
medical history and physical exam.

- Pregnant or breast-feeding: Females of childbearing potential, or with tubal ligation,
or are post-menopausal and are age 60 or less will undergo a urine pregnancy test and
it must be negative to continue participation. Urine pregnancy tests will be repeated
on subsequent days of study. Females must not be currently breastfeeding.

- 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.

- Personal or family history for cerebral aneurysm.

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

- Glaucoma as assessed by medical history.

- Diabetes as assessed by medical history.

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

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

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

Additional exclusion criteria for MAT+ / MAT- / Naltrexone OUD participants:

- Participation in a court ordered treatment program.

- Scores on MADRS 20 or higher.

Additional exclusion criteria for MAT- OUD participants only:

-Currently seeking treatment for OUD, for the MAT- group.

--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 urine drug screen is positive for THC-COOH, a saliva drug screen will be
performed and subject may proceed with

MRI/PET/NP testing procedures if saliva results for THC are negative. If the urine/saliva
drug test is positive on the third rescheduled visit, the participant will be withdrawn
from the study.

--- If an OUD subject s urine drug screen test is positive for drugs (except opiates), the
procedures will be postponed and rescheduled to another day. If the urine drug screen is
positive for THC-COOH, a saliva drug screen will be performed and subject may proceed with
MRI/PET/NP testing procedures if saliva results for THC are negative. We will not place a
limit on rescheduling study days in this group.

Also, note that at any time during participation in this study any subject expresses that
he/she wants to get treatment for their OUD, we will immediately refer him/her to a
treatment program. The subject will be withdrawn from the study at that time. No
medications will be stopped or held for participation in this protocol.