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 #
5R01DA015446-07
Application #
7799923
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
2010-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2010
Total Cost
$475,842
Indirect Cost
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
Hurd, Yasmin L; O'Brien, Charles P (2018) Molecular Genetics and New Medication Strategies for Opioid Addiction. Am J Psychiatry 175:935-942
Egervari, Gabor; Ciccocioppo, Roberto; Jentsch, J David et al. (2018) Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms. Neurosci Biobehav Rev 85:117-125
Miller, M L; Ren, Y; Szutorisz, H et al. (2018) Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23:1328-1335
Egervari, Gabor; Kozlenkov, Alexey; Dracheva, Stella et al. (2018) Molecular windows into the human brain for psychiatric disorders. Mol Psychiatry :
Fullard, John F; Hauberg, Mads E; Bendl, Jaroslav et al. (2018) An atlas of chromatin accessibility in the adult human brain. Genome Res 28:1243-1252
Mazzone, C M; Pati, D; Michaelides, M et al. (2018) Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23:143-153
Egervari, Gabor; Landry, Joseph; Callens, James et al. (2017) Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target. Biol Psychiatry 81:585-594
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
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
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

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