Currently, there are no viable therapeutic treatments for psychostimulant addiction. Likely, because the mechanism of action of therapeutic candidates on select cell subtypes, in the heterogeneous central nervous system, is unknown. Shedding light on distinct molecular pathway events in distinct cell subtypes, that mediate stimulant addiction, is necessary for development of effective therapeutics. Recent studies demonstrate an imbalance of function and molecules in striatal medium spiny neuron (MSN) subtypes, those enriched in dopamine (DA) D1 vs. D2 receptors, in psychostimulant addiction. Yet, there are no systematic studies examining which synaptic inputs and signaling pathways regulate distinct transcriptional changes in MSN subtypes and how these molecular changes ultimately mediate psychostimulant addiction. We will investigate a transcription factor, early growth response 3 (Egr3), that is regulated by cocaine in a cell-type specific manner in the ventral striatum (nucleus accumbens-NAc) and in turn regulates transcription of key molecular players, in the cocaine addictive phenotype. Egr3 is regulated through dopamine (DA)-D1 and brain derived neurotrophic factor (BDNF)-TrkB signaling pathways. These signaling pathways, in the ventral tegmental area (VTA)-NAc circuit, are critical for mediating behavioral responses to cocaine. We will use optogenetic and pharmacological tools combined with novel cell-type selective transcriptome profiling to investigate how the Egr3 transcription factor pathway is mediated in MSN subtypes through VTA-NAc signaling pathways in cocaine abuse. We will then examine the functional role of the Egr3 transcription factor pathway in MSNs in mediating relapse for cocaine, a hallmark symptom of addiction, using genetic tools to selectively perturb levels of Egr3 or the Egr3 co-repressor, Nab2. Our findings could lead to novel and effective treatment strategies for psychostimulant addiction that target MSN subtypes, which would greatly impact the lives of individuals suffering from this chronic disease.

Public Health Relevance

We propose to study the transcriptional mechanisms occurring in nucleus accumbens cell subtypes in cocaine addiction. We will investigate the neuro-circuit and signaling pathways that mediate these transcriptional mechanisms in precise cell subtypes in cocaine abuse. We will further genetically target a transcription factor pathway, implicated in cocaine abuse, in nucleus accumbens neuronal subtypes to investigate the cell-type selective transcriptional mechanisms that mediate relapse in cocaine addiction. Our proposed studies can uncover novel molecular mechanisms occurring in precise cell subtypes in psychostimulant abuse. This can lead to novel therapeutic targeting for effective treatment of psychostimulant abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA038613-03
Application #
9068915
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
2014-09-15
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Lobo, Mary Kay (2017) Nuclear Arc Puts a Brake on Cocaine-Induced Chromatin Remodeling and Behaviors. Biol Psychiatry 81:550-551
Chandra, Ramesh; Lobo, Mary Kay (2017) Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction. Front Behav Neurosci 11:112
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