Imaging CRF X NOP Interactions in CUD

Imaging Corticotrophin-releasing Factor (CRF) X Nociceptive Opioid Peptide (NOP) Interactions in Cocaine Use Disorders (Aim 1)

This study uses [11C]NOP-1A positron emission tomography (PET) and a hydrocortisone challenge to image the interaction between nociceptive opioid peptide (NOP) receptors and cortisol/corticotrophin releasing factor (CRF) in subjects with cocaine use disorders (CUD) and matched healthy controls (HC). It will also examine whether alterations in CRF x NOP interactions predict relapse in subjects with CUD.

Study Overview

• Status: Recruiting
• Conditions: Cocaine Use Disorder
• Intervention / Treatment: Radiation: Baseline [C-11]NOP-1A PET Scan; Drug: Hydrocortisone; Radiation: Post-hydrocortisone [C-11]NOP-1A PET Scan

Detailed Description

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 counteracts the functional effects of the primary stress-promoting neuropeptide corticotrophin releasing factor (CRF) in the brain to exert its anti-stress effects. 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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Rajesh Narendran, MD; Phone Number: 4126475176; Email: narendranr@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh
      • Contact: Rajesh Narendran; Phone Number: 4126475176; Email: narendranr@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Cocaine use disorders (CUD)

1. Males or females between 18 and 55 years old
2. Fulfil DSM-5 criteria for cocaine use disorder
3. No other current DSM-5 psychiatric or addictive disorders (such as major depressive disorder, bipolar disorders, psychotic disorders, etc.,)
4. No current abuse (six months) of opiates, sedative-hypnotics, amphetamines, MDMA, etc., 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);
5. Not currently on prescription medical or psychotropic medications
6. 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
7. Not currently pregnant or breastfeeding
8. No history of significant radioactivity exposure in past year from another research study or occupation that exceeds RDRC guidelines
9. No metallic objects in the body that are contraindicated for MRI

Healthy Controls (HC)

1. Males or females between 18 and 55 years old
2. No present or past DSM-5 disorders (other than nicotine dependence)
3. Criteria 5 to 9 as listed previously.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PET; [C-11]NOP-1A	Radiation: Baseline [C-11]NOP-1A PET Scan; Radiotracer; Drug: Hydrocortisone; Intravenous, 1mg/Kg; Radiation: Post-hydrocortisone [C-11]NOP-1A PET Scan; Radiotracer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DELTA VT	VT is the volumes of distribution expressed relative to total plasma ligand concentration; Delta VT is the change in VT from baseline to 3-hours post-hydrocortisone.	Baseline, and 3 hours post-hydrocortisone

Collaborators and Investigators

• Sponsor: Rajesh Narendran
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Rajesh Narendran, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2020
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: August 11, 2021
• First Submitted That Met QC Criteria: August 13, 2021
• First Posted (Actual): August 17, 2021

Study Record Updates

• Last Update Posted (Estimated): June 5, 2025
• Last Update Submitted That Met QC Criteria: June 2, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Cocaine use disorder; [C-11]NOP-1A PET; Nociceptive opioid peptide receptors
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: STUDY20060171 (Aim 1); R01DA026472 (U.S. NIH Grant/Contract); STUDY19110156 (Other Identifier: University of Pittsburgh)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No