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.

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

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.

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.

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.

In addition to participants enrolled in this study (N=17 CUD, N=8 HC-MRI), baseline characteristics are provided for the sample of comparison adults completing PET procedures (N=20 HC-PET) as part of other studies.

Less than 30 days, typically 1-2weeks

The group of Historical Healthy Comparison adults completing PET procedures during participation in other studies (HHC-PET) were monitored for Adverse Events by their original studies.

This study was greatly impacted by a COVID-related suspension in research activities and subsequent restrictions on facility operations. This resulted in lower participation and study adjustments including the discontinuation of cocaine self-administration procedures, the use of historical HC-PET data, and the collection of an HC-MRI sample (no HC completed both PET and fMRI). These alterations limit the statistical power of primary outcomes and the ability to perform planned secondary analyses.