Investigation of Cocaine Addiction Using mGluR5 PET and fMRI

Yale University32 enrolled

Overview

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).

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

Allocation

NON_RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Cocaine Dependence

Interventions

Psychiatric and Cognitive TestingBEHAVIORAL

Interviews, questionnaires, and computer testing.

Cocaine Self-adminstrationDRUG

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.

Positron Emission TomographyRADIATION

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Connecticut Mental Health Center

New Haven, Connecticut, United States

Outcomes

Primary Outcomes

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.

Time frame: 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).

Time frame: 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.

Time frame: Following 2-5 days of cocaine abstinence.

Data from ClinicalTrials.gov

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