Heroin is a highly addictive drug and its abuse continues to be a major public health problem. Heroin abuse is associated with high mortality due to overdose, high risk of contracting diseases such as HIV/AIDS and viral hepatitis, and crime that often exceed that of most other abused drugs. Extensive research efforts have been dedicated to understanding the regulation of 5-opioid receptor (MOR), molecular target of heroin metabolites such as morphine, but limited studies have been conducted directly in the human brain regarding MOR and its intracellular signaling in relation to heroin abuse. Heroin abuse has a high genetic load and mutation of the MOR gene (OPMR1) has been linked with heroin abuse risk. During the first funding period for our studies, we documented that H 90% of subjects with the A118G mutation in our postmortem brain bank collection, from a homogenous Caucasian population, were heroin abusers. Neurobiological studies revealed that the polymorphism was relevant to opioid neuropeptide expression in the nucleus accumbens linked to reward and goal-directed behavior. Moreover, subjects with the 118G allele had higher functional coupling of the MOR in the nucleus accumbens. The proenkephalin (PENK) opioid neuropeptide is also strongly associated with reward and individuals with genetic polymorphism of this gene also had sensitized opioid receptor G-protein coupling in the nucleus accumbens. It is the aim of the next phase of our project to investigate more thoroughly the regulation of MOR;the intracellular G-protein signaling cascades that mediates the physiological actions of this receptor in heroin abusers and in relation to the OPMR1 polymorphism. Factors that modulate MOR function such as receptor density, phoshorylation state, dimerization with 4-opioid receptors, and coupling to 2-arrestin will be studied. Cluster and network analysis will be conducted on RNA data already collected from microarray analysis and customized real-time PCR datasets to identify the intracellular regulatory pathways linked to opioid receptor G-protein signaling. Key proteins within these networks will also be studied to validate the functional disturbances in relation to heroin use and the OPMR1 mutation. Expanding knowledge regarding MOR and its intracellular signaling machinery directly in the human brain will provide a major insight as to the neurobiological correlates linked with heroin abuse vulnerability and targets for medication development.

Public Health Relevance

Heroin is a highly addictive drug and its abuse continues to be a major public health problem. Expanding knowledge regarding the regulation and function of mu opioid receptor, the target for heroin, directly in the human brain and in relation to genetic mutations will provide a major insight as to the neurobiological correlates linked with heroin abuse vulnerability. As such targeted for medications can be development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015446-09
Application #
8215916
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Boyce, Cheryl A
Project Start
2002-09-30
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$475,132
Indirect Cost
$184,267
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Egervari, Gabor; Jutras-Aswad, Didier; Landry, Joseph et al. (2016) A Functional 3'UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits. Neuropsychopharmacology 41:2512-20
Kozlenkov, Alexey; Wang, Minghui; Roussos, Panos et al. (2016) Substantial DNA methylation differences between two major neuronal subtypes in human brain. Nucleic Acids Res 44:2593-612
Egervari, Gabor; Landry, Joseph; Callens, James et al. (2016) Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target. Biol Psychiatry :
Urban, Daniel J; Zhu, Hu; Marcinkiewcz, Catherine A et al. (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404-15
Koo, Ja Wook; Mazei-Robison, Michelle S; LaPlant, Quincey et al. (2015) Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nat Neurosci 18:415-22
Michaelides, Michael; Hurd, Yasmin L (2015) DREAMM: a biobehavioral imaging methodology for dynamic in vivo whole-brain mapping of cell type-specific functional networks. Neuropsychopharmacology 40:239-40
Moeller, Scott J; Beebe-Wang, Nicasia; Schneider, Kristin E et al. (2015) Effects of an opioid (proenkephalin) polymorphism on neural response to errors in health and cocaine use disorder. Behav Brain Res 293:18-26
Kovacs, Gabor G; Horvath, Monika Cs; Majtenyi, Katalin et al. (2015) Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions. Neurobiol Aging 36:3100-7
Kozlenkov, Alexey; Roussos, Panos; Timashpolsky, Alisa et al. (2014) Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites. Nucleic Acids Res 42:109-27
Linnertz, Colton; Lutz, Michael W; Ervin, John F et al. (2014) The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet 23:4814-21

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