Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

The proposed research program will investigate the changes in brain chemistry and circuitry that 're-wire' the brain during chronic cocaine use, promote relapse, and complicate treatment efforts. Currently-using and non-treatment-seeking individuals with a cocaine use disorder will undergo a cocaine self-administration paradigm 2-5 days prior to completing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).

Study Overview

• Status: Completed
• Conditions: Cocaine Dependence
• Intervention / Treatment: Behavioral: Psychiatric and Cognitive Testing; Drug: Cocaine Self-adminstration; Radiation: Positron Emission Tomography; Other: Magnetic Resonance Imaging

Detailed Description

Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments. Challenges to treating CUD include an imbalance in neurobiological systems that 're-wire' the brain such that appetitive and habitual processes influence decision-making and behavior. This research project aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamatergic plasticity and functional brain networks during initial (2-5 days) abstinence. To target this potentially critical period of recovery, currently-using and non-treatment-seeking individuals with CUD will undergo a cocaine self-administration paradigm 2-5 days prior to completing [18F]FPEB positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Healthy comparison (HC) subjects that have participated in [18F]FPEB PET as part of other Yale approved protocols will be recruited to participate in the fMRI portion of this study.

Aim 1: To determine the availability of mGluR5 using [18F]FPEB PET during initial abstinence in individuals with CUD. The investigators hypothesize individuals with CUD, relative to HC, will exhibit concurrently and regionally specific increases (e.g., in the striatum) and decreases (e.g., in the prefrontal cortex) in mGluR5 availability.

Aim 2: To determine patterns of resting-state, response-inhibition, an automaticity related connectivity within and between large-scale functional networks using fMRI during initial abstinence in individuals with CUD. The investigators hypothesize network-based analyses of fMRI will reveal lower frontoparietal and greater limbic network modulation in CUD as compared to HC.

Aim 3: To explore the relationships between mGluR5 availability and functional network activity during initial abstinence in individuals with CUD. The investigators will perform multi-modal analysis of PET and fMRI data to examine links between molecular and functional systems in CUD using emerging 'fusion' approaches. While exploratory in nature, the investigators expect to find links between alterations in mGluR5 systems and functional reorganization in CUD (e.g., greater dorsostriatal mGluR5 may be linked to blunted frontoparietal inhibition).

Aim 4: To explore the relationships between mGluR5 availability, functional network activity (and their linkages) with cocaine self-administration, disease severity and chronicity, and psychometric assessments of impulsivity and compulsivity. While exploratory in nature, the investigators expect more substantial neurofunctional alterations during initial abstinence will be associated with greater cocaine self-administration, disease severity, impulsivity and compulsivity in individuals with CUD.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jessica Costeines, MA; Phone Number: 203-974-7559; Email: jessica.costeines@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Connecticut Mental Health Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• All participants:

  • Age 21 - 60 years
  • Provide voluntary, written, informed consent
  • Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
  • For females: non-lactating, no longer of child-bearing potential or agreeing to practice effective contraception during the study (e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]; barrier methods: condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true abstinence when this is in line with the preferred and usual lifestyle of the subject), and a negative serum pregnancy test

• Participants with a cocaine use disorder:

  • DSM-5 criteria for moderate or severe cocaine-use disorder
  • Recent street cocaine use in excess of quantities used in the current study
  • Intravenous and/or smoked (crack/freebase) cocaine use
  • Positive urine toxicology screen for cocaine

• Healthy comparison participants:

  • Successful completion of an [18F]FPEB scan as part of another Yale approved protocol as a healthy control/comparison subject

Exclusion Criteria:

• All participants:

  • Any condition that, in the opinion of investigators, would prevent compliance with the study protocol
  • A history of significant medical or neurological illness (e.g., coronary artery disease, significant anemia, seizures)
  • Current use of psychotropic and/or potentially psychoactive medications
  • Physical or laboratory evidence of pregnancy
  • Meet any additional PET/MR imaging-related exclusion criteria, including:
  • Presence of MRI incompatible implants and other contraindications for MRI (e.g., pacemaker, artificial joints, non-removable body piercings, etc.)
  • Participation in other research studies involving ionizing radiation within one year of the PET scans that would cause the participant to exceed the yearly dose limits
  • History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto).
  • Claustrophobia
  • Severe motor problems that prevent the subject from lying still for PET/MR imaging
  • Complaints of chronic pain (e.g., as the result of rheumatoid arthritis)
  • Current, past or anticipated exposure to radiation in the work place

• Participants with a cocaine use disorder:

  • Other drug use disorder (except for tobacco-use disorder)
  • Less than 1 year of cocaine use disorder
  • A DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.) unrelated to cocaine

• Healthy comparison participants:

  • Any DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.), except tobacco-use disorder
  • Positive drug screen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Psychiatric and Cognitive Testing; All participants will complete psychiatric assessment and cognitive testing.	Behavioral: Psychiatric and Cognitive Testing; Interviews, questionnaires, and computer testing.
Active Comparator: Cocaine Self-adminstration; This arm plans to assess the subjective (e.g., euphoric) and behavioral effects (e.g., self-administration) of cocaine in experienced, non-treatment seeking users of the drug in a human laboratory study of self-regulated cocaine administration.	Drug: Cocaine Self-adminstration; The intervention will include a training and safety session that consists of physician/nurse-administered cocaine followed by a self-regulated cocaine administration period under carefully controlled and closely monitored conditions.; Other Names: cocaine hydrochloride
Active Comparator: Positron Emission Tomography; All participants will complete a PET scan to assess mGluR5 receptors using [18-F]FPEB	Radiation: Positron Emission Tomography; PET scans will be performed on a High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available. Antecubital venous catheters will be used for IV administration of the radiotracer and for venous blood sampling. A radial artery catheter may also be inserted by an experienced physician before the PET scan. At the beginning of each scan, the participants's head will be immobilized and a 6-minute transmission scan, using an orbiting 137Cs point-source, is obtained and used for attenuation correction. PET scans will be acquired using bolus or bolus plus constant infusion administration of [18F]FPEB.; Other Names: PET
Active Comparator: Magnetic Resonance Imaging; All participants will complete one MRI scan to assess brain structure and function.	Other: Magnetic Resonance Imaging; Structural and functional MRI data will be acquired using a Siemens Trio TIM 3.0T system at the Yale Magnetic Resonance Research Center. High-resolution structural MRI data will be acquired to facilitate analysis of PET data and may be used in additional analysis of tissue volume and brain structure. Resting-state and task-based functional MRI data will be acquired using state-of-the-art multiband echo-planar imaging (EPI) gradient-echo sequences. Diffusion-weighted MRI data will also be acquired using multiband imaging sequences to investigate anatomical connectivity.; Other Names: MRI, functional MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional Availability of Metabotropic Glutamate Type-5 Receptors (mGluR5)	Receptor availability assessed as the volume of distribution (VT) of [18F]FPEB radiotracer, measured using positron emission tomography (PET). Higher [18F]FPEB VT values indicate a greater availability of mGluR5 receptors.	Following 2-5 days of cocaine abstinence
Functional Brain Network Engagement Associated With Response Inhibition	Independent component analysis (ICA) of functional MRI data separates brain activity associated with distinct functional networks. Comparing the activity in these networks to the fMRI task events using a regression analysis produces a beta-weight where a larger beta indicates the network was more activated or 'engaged' in processing the task demands. In this study, participants completed a Go/NoGo task to assess brain processing associated with infrequent-stimulus response inhibition (i.e., correct NoGo's) compared to frequent-stimulus responses (i.e., correct Go's).	Following 2-5 days of cocaine abstinence.
Resting-state Functional Brain Network Activity, Fractional Amplitude of Low-frequency Fluctuations (fALFF)	Independent component analysis (ICA) of functional MRI data separates brain activity associated with distinct functional networks. The fractional amplitude of low-frequency fluctuations (fALFF) during resting-state reflects a measure of the general health status of a network, comprised of both the strength of network activity and within-network connectivity absent of any specific cognitive demands.	Following 2-5 days of cocaine abstinence.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain activity patterns	Brain activity patterns as measured during task-based and resting-state fMRI	Within 2-5 days of self-administration in cocaine participants; within 5 days of PET as possible for healthy comparison participants

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Patrick Worhunsky, PhD, Assistant Professor

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2018
• Primary Completion (Actual): August 18, 2022
• Study Completion (Actual): August 18, 2022

Study Registration Dates

• First Submitted: February 26, 2018
• First Submitted That Met QC Criteria: March 13, 2018
• First Posted (Actual): March 20, 2018

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Cocaine Addiction; Cocaine Dependence
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Compulsive Behavior; Impulsive Behavior; Behavior, Addictive; Cocaine-Related Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Anesthetics, Local; Dopamine Uptake Inhibitors; Vasoconstrictor Agents; Cocaine
• Other Study ID Numbers: 2000021196; 1K01DA042998-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Consistent with NIH Grants Policy on Sharing of Unique Research Resources, including the "Sharing of Biomedical Research Resources: Principles and Guidelines for Recipients of NIH Grants and Contracts" (December, 1999), all research resources generated will be freely distributed, as available, to appropriate, qualified academic investigators for non-commercial research purposes. All data will be de-identified before sharing, using procedures in compliance with HIPPA and Yale Human Investigation Committee standards. No available data sets or supporting information will contain subject names, addresses or other specific personal identification.
• IPD Sharing Time Frame: In accordance with institutional standards and guidelines, after termination of this study and completion of all analysis and publications, all data and screening information will be anonymized and kept in a secure fashion for the purpose of further analyses indefinitely unless prevailing University or Federal guidelines at the time require a change.
• IPD Sharing Access Criteria: In accordance with institutional standards and guidelines, researchers must submit a requisition form that describes their specific hypotheses and details specific data or supporting information being requested. Requests will be reviewed by senior study personnel.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No