[C-11]NPA PET-amphetamine in Cocaine Use Disorders

Study Overview
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Brief Summary
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This study uses [11C]NPA positron emission tomography (PET) and a d-amphetamine challenge to image amphetamine induced dopamine release in the striatum in subjects with cocaine use disorders (CUD). Amphetamine-induced dopamine release data from this study will be correlated with [11C]NOP-1A VT measured at baseline in the midbrain. [11C]NOP-1A PET data will be used from aim 1 (see, Study Record: Imaging CRF X NOP interactions in Cocaine Use Disorders)

Detailed Description
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Cocaine use disorder (CUD) is a chronic disorder associated with numerous relapses and periods of abstinence. Studies in CUD suggest that   60 to 75% of abstinent addicts relapse over twelve months. Documenting specific neurochemical abnormalities that lead to relapse in individuals with CUD has the potential to accelerate the development of medications to prevent relapse. Basic investigations postulate an imbalance between brain stress and anti-stress/resilience systems as the underlying mechanism that drives negative reinforcement, craving, and relapse in addiction.. Nociceptin (N/OFQ), which binds to the nociceptive opioid peptide receptors (NOP) is a critical component of the brain's anti-stress system. N/OFQ exerts its anti-stress effect by counteracting the functional effects of the primary stress-promoting neuropeptide corticotrophin releasing factor (CRF) in the brain. Studies have also shown that acute increases in CRF and stress are countered by increased NOP receptor expression (  10% ) in brain regions that regulate stress such as bed nucleus of the stria terminalis. PET studies with the NOP radiotracer [11C]NOP-1A show increased binding to NOP in CUD compared to HC. PET studies also show NOP receptors to upregulate (  15%) in response to an acute intravenous hydrocortisone challenge (1 mg/Kg). NOP upregulation may represent an adaptive mechanism in the brain to counteract stress-induced increases in cortisol and CRF. Here, we postulate a failure in this adaptive mechanism as a reason that leads to relapse in CUD. CUD subjects and HC will be studied with [11C]NOP-1A before and after an intravenous hydrocortisone challenge (aim 1). Hydrocortisone is used as a challenge because it increases cortisol and CRF in brain regions that regulate stress. We hypothesize that hydrocortisone-induced increases in [11C]NOP-1A binding (DELTA VT) will be smaller in CUD relative to HC, and this will be associated with less time to relapse in a 12-week follow up. Mechanistic studies have also shown N/OFQ to act on ventral tegmental area/midbrain NOP receptors to inhibit the firing of dopamine neurons and limit reward to cocaine. Imaging amphetamine-induced dopamine release in a subset of CUD subjects who participate in aim 1 will allow us to link midbrain NOP receptor expression with ventral striatum (VST) dopamine release and examine its role in reinforcement (aim 2). The aims proposed in this study have the potential to clarify the role of N/OFQ and NOP in stress, reward, and relapse in CUD.

Official Title
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[C-11]NPA PET-amphetamine in Cocaine Use Disorders (Aim 2)

Conditions
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Cocaine Use Disorder

Intervention / Treatment
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* Radiation: Baseline [C-11]NPA PET Scan
* Drug: d-amphetamine
* Radiation: Post-amphetamine [C-11]NPA PET Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between 18 and 55 years old Fulfil DSM-5 criteria for cocaine use disorder No other current DSM-5 psychiatric or addictive disorders (such as major depressive disorder, bipolar disorders, psychotic disorders, etc.,) No current abuse (six months) of opiates, sedative-hypnotics, amphetamines, and MDMA as well as moderate to severe alcohol or cannabis use (twice a week). Nicotine use will be quantified and controlled between groups using the Fagerstrom Test for Nicotine Dependence (Heatherton et al., 1991); Not currently on prescription medical or psychotropic medications No current or past severe medical, endocrine or neurological illnesses including glaucoma, seizure disorders, hypertension, hypercholesterolemia as assessed by a complete medical history and physical Not currently pregnant or breastfeeding No history of significant radioactivity exposure in past year from another research study or occupation that exceeds RDRC guidelines No metallic objects in the body that are contraindicated for MRI No baseline BP ≥ 140/90 and/or HR ≥ 100. No first-degree relative with an MI or stroke prior to middle age No first-degree relative with psychosis or mania. Completed a baseline [11C]NOP-1A PET scan in Aim 1 (Study Record: Imaging CRF X NOP interactions in Cocaine Use Disorders)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Single group, correlational analyses
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PET<br>[C-11]NPA PET Scan | Radiation: Baseline [C-11]NPA PET Scan<br>* Radiotracer<br>Drug: d-amphetamine<br>* Oral, 0.5 mg/Kg<br>Radiation: Post-amphetamine [C-11]NPA PET Scan<br>* Radiotracer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DELTA binding potential relative to non displaceable uptake (BPND) | DELTA BPND is the change in BPND from the baseline PET scan to post-amphetamine PET scan that will be acquired 2.5 to 3 hours after d-amphetamine administration (0.5 mg/Kg, oral) | Baseline, and 2.5 to 3 hours post-amphetamine | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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[C-11]NOP-1A, [C-11]NPA , nociceptive opioid peptide receptors, dopamine release