Dopamine Signaling Study for Opioid Use Disorder

Recruiting in Palo Alto (17 mi)

Overseen by Nora Volkow, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Must be taking: Opioid agonists, Naltrexone

Must not be taking: Antidepressants, Antipsychotics, Stimulants, Benzodiazepines

Disqualifiers: Psychiatric disorders, Major medical problems, others

Trial Summary

What is the purpose of this trial?

Background: The chemical messenger dopamine carries signals between brain cells. It may affect addiction. Heavy use of pain medicines called opioids may decrease the amount of dopamine available to the brain. Researchers want to study if decreased dopamine decreases self-control and increases impulsiveness. Objective: To learn more about how opiate use disorder affects dopamine in the brain. Eligibility: Adults 18-80 years old who are moderate or severe opiate users Healthy volunteers the same age Design: Participants will first be screened under another protocol. They will: * Have a physical exam * Answer questions about their medical, psychiatric, and alcohol and drug use history * Take an MRI screening questionnaire * Give blood and urine samples * Have their breath tested for alcohol Participants will have up to 3 study visits. They will have 2-3 positron emission tomography (PET) scans. A radioactive chemical will be injected for the scans. Participants will lie on a bed that slides in and out of the donut-shaped scanner. A cap or plastic mask may be placed on the head. Vital signs will be taken before and after the PET scans. Participants will get capsules of placebo or the study drug. They will rate how they feel before, during and after. Participants will have their breath and urine tested each day. Participants will have magnetic resonance imaging (MRI) scans. They will lie on a table that slides into a cylinder in a strong magnetic field. They may do tasks on a computer screen while inside the scanner. Participants will have tests of memory, attention, and thinking. Participants will wear an activity monitor for one week....

Will I have to stop taking my current medications?

The trial requires that participants not be on certain medications, such as methadone, buprenorphine, or naltrexone, for more than three weeks if they are in the MAT- OUD group. Participants in the MAT+ OUD and Naltrexone OUD groups must continue their current opioid treatment. Some medications, like stimulants, may need to be paused on specific test days.

What data supports the effectiveness of the drug for opioid use disorder?

Research shows that the drug [11C]raclopride, which is part of the treatment, has been used in studies to measure dopamine receptor activity in the brain. This is important because dopamine signaling is linked to addiction behaviors, suggesting that understanding and potentially modifying this signaling could help in treating disorders like opioid use disorder.

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Is [11C]raclopride safe for humans?

Studies involving [11C]raclopride, a compound used in brain imaging, have been conducted on healthy volunteers and have not reported any significant safety concerns. It is primarily used to study dopamine receptors in the brain and has been tested in various conditions without indicating harmful effects.

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How is the drug [11C]raclopride unique in treating opioid use disorder?

[11C]raclopride is unique because it is used in imaging studies to measure dopamine receptor activity in the brain, which can help understand the role of dopamine in opioid use disorder. Unlike typical treatments that directly target opioid receptors, this drug helps visualize and study brain activity related to dopamine, potentially leading to more personalized treatment approaches.

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Eligibility Criteria

Adults aged 18-65 with moderate to severe opioid use disorder (OUD) who haven't used opioids regularly for at least 3 months, or those on opioid agonist therapy. Healthy volunteers of the same age range can also participate. Exclusions include major medical issues, certain psychiatric disorders, pregnancy, and inability to lie flat or have an MRI.

Inclusion Criteria

Only individuals who have a certain medical condition can participate in this study.

You can read and understand information about the study and agree to participate by signing a form.

You have been diagnosed with Opiate Use Disorder.

Exclusion Criteria

I am a healthy volunteer without major medical issues or specific conditions listed.

You have a history of certain mental health disorders that require antipsychotic medications, or are currently receiving treatment for opioid addiction using specific medications. Additionally, you may be excluded if you have significant medical issues, have been exposed to radiation, are pregnant or breastfeeding, have certain eye conditions or difficulty lying flat, or are unable to communicate in English. Study investigators and staff are also not eligible to participate.

Additional exclusion criteria for MAT+ / MAT- / Naltrexone OUD participants: Participation in a court ordered residential treatment program

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

PET Scans

Participants undergo 2-3 PET scans to assess dopamine receptor availability and striatal dopamine release

3 visits

3 visits (in-person)

MRI and Neuropsychological Testing

Participants undergo MRI scans and neuropsychological tests to assess brain function and cognitive performance

2 visits

2 visits (in-person)

Follow-up

Participants are monitored for recovery and changes in brain function after treatment

6 months

Participant Groups

The study is examining how opioid addiction affects dopamine in the brain using PET scans with radioactive chemicals and MRIs. Participants will receive either a placebo or a drug alongside [11C]raclopride or [11C]NNC-112 to measure brain activity related to self-control and impulsiveness.

Group I: [11C]raclopride plus drug Active Control 2 Interventions

Methylphenidate 60 mg. po will be given 60 minutes prior to \[11C\]raclopride scan to measure striatal dopamine release. MRI scan to follow end of PET scan. Subject blind as to drug administration.

Group II: [11C]raclopride plus placebo Placebo Group 2 Interventions

Placebo (po) will be given 60 minutes prior to \[11C\]raclopride scan to measure baseline dopamine D2 receptors. MRI scan to follow end of PET scan. Subject blind as to drug administration.

Group III: [11C]NNC-112 Placebo Group 1 Intervention

\[11C\]NNC-112 PET scan obtained without any drug intervention to measure dopamine D1 receptors. Blind N/A

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Institute on Alcohol Abuse and Alcoholism (NIAAA) Lead Sponsor

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Multimodal predictive modeling of individual treatment outcome in cocaine dependence with combined neuroimaging and behavioral predictors. [2021] Developing personalized treatments for cocaine dependence remains a significant clinical challenge. Positron emission tomography (PET) has shown that the [(11)C]raclopride signal in the ventral striatum is associated with treatment success in a positively reinforced contingency management program. The present study investigates whether this signal can be used to predict treatment outcome at an individual level.

2. United States pubmed.ncbi.nlm.nih.gov

Long-term test-retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [(11)C]raclopride and high-resolution PET. [2018] We measured the long-term test-retest reliability of [(11)C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [(11)C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test-retest studies of [(11)C]raclopride binding in the striatum. A novel finding is the relatively low variability of [(11)C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [(11)C]raclopride PET to be verified in future studies.

3. England pubmed.ncbi.nlm.nih.gov

Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. [2021] The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.

4. United States pubmed.ncbi.nlm.nih.gov

Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study. [2021] Positron emission tomography (PET) studies performed with [(11) C]raclopride have consistently reported lower binding to D(2/3) receptors and lower amphetamine-induced dopamine (DA) release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D(2/3) antagonist radiotracers such as [(11) C]raclopride is the failure to provide information that is specific to D(2/3) receptors configured in a state of high affinity for the agonists (i.e., D(2/3) receptors coupled to G-proteins, D(2/3 HIGH) ). As the endogenous agonist DA binds with preference to D(2/3 HIGH) relative to D(2/3 LOW) receptors (i.e., D(2/3) receptors uncoupled to G-proteins) it is critical to understand the in vivo status of D(2/3 HIGH) receptors in cocaine dependence. Thus, we measured the available fraction of D(2/3) (HIGH) receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D(2/3) antagonist and agonist PET radiotracers [(11) C]raclopride and [(11) C]NPA.

5. Germany pubmed.ncbi.nlm.nih.gov

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers. [2018] This study reports on the whole-body biodistribution and radiation dosimetry of [11C]raclopride, a dopamine D2 receptor antagonist.

6. United States pubmed.ncbi.nlm.nih.gov

Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men. [2021] Label="BACKGROUND">Preclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [11C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid-experienced participants.

7. England pubmed.ncbi.nlm.nih.gov

PET radioligands for dopamine receptors and re-uptake sites: chemistry and biochemistry. [2019] This report, based on the past experience of European centres, offers practical guidance on the chemistry and biochemistry of PET radioligands used for the in vivo imaging of dopamine receptors and re-uptake sites. It mainly summarizes methods for the preparation of D1 and D2 receptor ligands labelled with positron-emitting radioisotopes. Some of these ligands (11C-labelled SCH23390, raclopride and nomifensine, 18F-labelled butyrophenones, [76Br]bromolisuride), which have been found useful in PET clinical investigations, have been emphasized. This report is intended as an introduction and guideline for new PET-groups who want to start research in the dopaminergic neurotransmission imaging field.

8. United States pubmed.ncbi.nlm.nih.gov

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. [2019] Extensive neuroanatomical, neurophysiological, and behavioral evidence demonstrates that GABAergic neurons inhibit endogenous dopamine release in the mammalian corpus striatum. Positron emission tomography (PET) studies in adult female baboons, using the dopamine D2-specific radiotracer 11C-raclopride, were undertaken to assess the utility of this imaging technique for measuring these dynamic interactions in vivo. 11C-raclopride binding was imaged prior to and following the administration of either gamma-vinyl-GABA (GVG), a specific suicide inhibitor of the GABA-catabolizing enzyme GABA transaminase, or lorazepam, a clinically prescribed benzodiazepine agonist. Striatal 11C-raclopride binding increased following both GVG and lorazepam administration. This increase exceeded the test/retest variability of 11C-raclopride binding observed in the same animals. These findings confirm that changes in endogenous dopamine concentrations resulting from drug-induced potentiation of GABAergic transmission can be measured with PET and 11C-raclopride. Finally, this new strategy for noninvasively evaluating the functional integrity of neurophysiologically linked transmitter systems with PET supports its use as an approach for assessing the multiple mechanisms of drug action and their consequences in the human brain.