Investigation of Cocaine Addiction Using mGluR5 PET and fMRI
Condition: Cocaine Dependence
MeSH terms: Cocaine-Related Disorders; Behavior, Addictive
Study type: Interventional
Phase: Phase 1

Summary: 
      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).
    

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.
    

Intervention name(s): Psychiatric and Cognitive Testing; Cocaine Self-adminstration; Positron Emission Tomography; Magnetic Resonance Imaging
Intervention type(s): Behavioral; Drug; Radiation; Other
Intervention description(s): Interviews, questionnaires, and computer testing.; 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.; 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.; 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 intervention name(s): cocaine hydrochloride; PET; MRI, functional MRI
Intervention MeSH terms: Cocaine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Cocaine Dependence; Cocaine Addiction