Three different imaging groups have demonstrated a blunting in stimulant induced dopamine release at the level of the striatum in cocaine dependent subjects. An important limitation of these studies is the fact that measurements of D2/3 receptors and amphetamine-induced dopamine release were restricted mostly to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2/3 receptors in extrastriatal regions. Given that functional imaging studies in cocaine dependence suggests a relationship between pathological activation of the prefrontal cortex (PFC) and cognitive deficits it is of extreme interest to understand the regulatory role of dopamine in this particular region. During the previous cycle of this award we validated the use of the high affinity dopamine D2/3 radiotracer [11C]FLB 457 to measure amphetamine-induced dopamine release in the PFC.
In aim 1 we propose to use this recently validated imaging paradigm in a clinical study in cocaine dependence to characterize amphetamine-induced dopamine release in the PFC, and relate it to cognitive deficits and relapse. We hypothesize that amphetamine-induced dopamine release will be decreased in the mesocortical dopaminergic system in cocaine abusers relative to healthy comparison subjects and be associated with cognitive impairments and less time to relapse. Recent basic investigations postulate that an imbalance between neurotransmitters that regulate stress and anti-stress underlie negative reinforcement and relapse in addiction. Nociceptin (N/OFQ) is one such peptide neurotransmitter that exerts anti-stress effects and prevents relapse in rodent models of addiction. No previous human studies have characterized N/OFQ in addiction.
In aim 2, we propose to use [11C]NOP-1A PET to measure the in vivo status of nociceptive opioid peptide (NOP) receptors in cocaine abusers, and evaluate its relationship with stress, anxiety, craving, and relapse.
This aim marks a cautious first step in a new direction for this renewal application, which we intend to follow up with further experiments in cocaine dependence as novel radiotracers become available to image other components of the brain stress (e.g., corticotrophin releasing hormone, orexin, vasopressin, etc.,) and anti-stress system (neuropeptide Y).

Public Health Relevance

In this renewal application we propose to measure prefrontal cortical dopamine transmission and NOP receptors in cocaine dependence and relate it to cognitive deficits and relapse. This information has the potential to elucidate mechanisms that lead to relapse in addiction. It also has the potential to inform medication development efforts to prevent relapse in cocaine dependence.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-R (02))
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Pariyadath, Vani
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University of Pittsburgh
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Gertler, Joshua; Tollefson, Savannah; Jordan, Rehima et al. (2018) Failure to detect amphetamine-induced dopamine release in the cortex with [11 C]FLB 457 positron emission tomography (PET): Methodological considerations. Synapse 72:e22037
Narendran, Rajesh; Ciccocioppo, Roberto; Lopresti, Brian et al. (2018) Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A. Biol Psychiatry 84:708-714
Narendran, Rajesh; Tumuluru, Divya; May, Maureen A et al. (2016) Cortical Dopamine Transmission as Measured with the [11C]FLB 457 - Amphetamine PET Imaging Paradigm Is Not Influenced by COMT Genotype. PLoS One 11:e0157867
Narendran, Rajesh; Jedema, Hank P; Lopresti, Brian J et al. (2015) Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates. Biol Psychiatry 77:488-92
Weidner, Lora D; Paris, Antonio; Frankle, W Gordon et al. (2015) Safety of Oral Amphetamine Administered during Positron Emission Tomography Scans in Medically Screened Humans. PLoS One 10:e0140647
Jedema, Hank P; Narendran, Rajesh; Bradberry, Charles W (2014) Amphetamine-induced release of dopamine in primate prefrontal cortex and striatum: striking differences in magnitude and timecourse. J Neurochem 130:490-7
Narendran, R; Jedema, H P; Lopresti, B J et al. (2014) Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [11C]FLB 457 PET study. Mol Psychiatry 19:302-10
Narendran, Rajesh; Lopresti, Brian J; Mason, Neale Scott et al. (2014) Cocaine abuse in humans is not associated with increased microglial activation: an 18-kDa translocator protein positron emission tomography imaging study with [11C]PBR28. J Neurosci 34:9945-50
Narendran, Rajesh; Himes, Michael; Mason, N Scott (2013) Reproducibility of post-amphetamine [11C]FLB 457 binding to cortical D2/3 receptors. PLoS One 8:e76905
Narendran, Rajesh; Mason, N Scott; Chen, Chi-Min et al. (2011) Evaluation of dopamine D?/? specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457: implications for measuring cortical dopamine release. Synapse 65:991-7

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