Over the past decade, several groups have demonstrated a blunting in stimulant-induced dopamine (DA) release at the level of the striatum as a whole and ventral striatum (which includes the limbic-related nucleus accumbens) in alcohol dependent subjects (Martinez et al 2005;Volkow et al 2007). These findings have suggested an abnormal regulation of DA release following stimulant administration in the brain of patients with alcohol dependence. An important limitation of these studies is the fact that measurements of D2 receptors and amphetamine-induced DA release were restricted to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal regions. Given that metabolic PET imaging/fMRI data in alcohol dependence suggests a relationship between pathological activation of the prefrontal cortex and cognitive deficits, which in turn increase the risk for relapse to drugs, it is of extreme interest to understand the regulatory role of DA in this particular region as well. We obtained preliminary evidence using the high D2 receptor affinity PET radiotracer [11C]FLB 457 to measure amphetamine-induced DA release in the cortical regions of interest, including the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and medial temporal lobe (MTL, which includes the amygdala and hippocampus). In this application, we propose to use this technique to study amphetamine-induced DA release in the mesolimbic-related immediate reward system (ACC, OFC, MPFC, MTL) and mesocortical-related delayed reward system (DLPFC) in alcoholics and matched controls. Based on current clinical and preclinical evidence, the hypothesis is that amphetamine- induced dopamine release will be elevated in the mesolimbic DA system and blunted in the mesocortical DA system in patients with alcohol dependence as compared with matched controls. In addition, we propose to conduct fMRI experiments during a simple reward task and associate them with the PET findings to understand the functional significance of DA transmission in different cortical regions. The understanding of the cortical DA abnormalities and their functional significance in addictive disorders such as alcoholics will allow for the advancement of novel treatment strategies.

Public Health Relevance

In this application, we propose to use PET and fMRI to evaluate the functional significance of DA transmission abnormalities in the cortex of alcoholics.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Matochik, John A
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University of Pittsburgh
Schools of Medicine
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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
Narendran, Rajesh; Mason, Neale Scott; Paris, Jennifer et al. (2014) Decreased prefrontal cortical dopamine transmission in alcoholism. Am J Psychiatry 171:881-8
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
Forbes, Erika E; Rodriguez, Eric E; Musselman, Samuel et al. (2014) Prefrontal response and frontostriatal functional connectivity to monetary reward in abstinent alcohol-dependent young adults. PLoS One 9:e94640
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; May, Maureen A et al. (2011) Positron emission tomography imaging of dopamine D?/? receptors in the human cortex with [¹¹C]FLB 457: reproducibility studies. Synapse 65:35-40
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