NIH grant: Imaging brain energy use in cocaine use disorder: a [F-18]BCPP-EF PET study (1R61DA062821-01A1)

retained text

NIH grant 1R61DA062821-01A1: Imaging brain energy use in cocaine use disorder: a [F-18]BCPP-EF PET study
Institute: {'code': 'DA', 'abbreviation': 'NIDA', 'name': 'National Institute on Drug Abuse', 'admin_org_id': '12500072', 'admin_funding_url': ''}. PI: RAJESH  NARENDRAN. Award: $351314.
Start: 2026-08-15T00:00:00.
Basic investigations support cocaine-induced oxidative phosphorylation (OXPHOS) alterations in the
mitochondrial electron transport chain (ETC) in both neurons and microglia. This is important because
OXPHOS and the tricarboxylic cycle (Krebs cycle) provide much of the brain’s energy in the form of
adenosine triphosphate (ATP). Cocaine decreases the gene expression and activity of mitochondrial
Complex I (MC-I), the initial and rate-limiting enzyme in the ETC at which OXPHOS occurs. MC-I is also
one of the main sites at which reactive oxygen species (ROS) involved in signaling are generated in the
mitochondria. Decreases in MC-I increase the production of reactive oxygen species, potentially enhancing
oxidative stress, damaging mitochondrial DNA, and promoting apoptosis. Decreases in mitochondrial ETC
activity also modulate neurochemical transmission by decreasing the total number and plasticity of
synapses. No in vivo studies have examined the mitochondrial ETC, a major source of ATP and ROS in the
brain in substance use disorders. Based on basic investigations, we hypothesize that lower MC-I in cocaine
use disorder (CUD) subjects relative to healthy controls (HC) decreases ATP production and increases
ROS leakage in the ETC to promote relapse. Furthermore, we seek to characterize the relationship
between OXPHOS (MC-I) and glycolysis (glucose utilization) in the brain of CUD subjects. R61 phase 1
PET studies proposed in this application will contrast [18F]BCPP-EF binding to mitochondrial Complex-I
(MC-I) in 18 treatment-seeking CUD with that in matched HC (Aim 1). CUD subjects will be followed for
twelve weeks after PET to document relapse while they are incentivized with money to abstain. R33 phase
2 studies will extend [18F]BCPP-EF imaging to another 32 CUD and 32 HC if the proposed milestones
support lower MC-I binding in CUD. In this expanded cohort of 50 CUD, the relationship between MC-I
binding and relapse to cocaine will be examined (Aim 2). [18F]FDG PET scans will also be acquired in the
same 32 CUD subjects during the R33 phase 2 to measure OFC glucose metabolism (CGM). Relating MC-
I binding, which represents the rate of OXPHOS, and CGM, which represents the rate of glucose utilization,
both of which yield ATP, will expand our understanding of how the brain’s energy demands are met in CUD
(Aim 3). Studies proposed in this application will elucidate the role of abnormal brain energetics in
promoting addictive behaviors in CUD.

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