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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Xu, Su; Zhu, Wenjun; Wan, Yamin et al. (2018) Decreased Taurine and Creatine in the Thalamus May Relate to Behavioral Impairments in Ethanol-Fed Mice: A Pilot Study of Proton Magnetic Resonance Spectroscopy. Mol Imaging 17:1536012117749051
Divakaruni, Sai Sachin; Van Dyke, Adam M; Chandra, Ramesh et al. (2018) Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction. Neuron 100:860-875.e7
Engeln, Michel; Fox, Megan E; Lobo, Mary Kay (2018) Dopamine Is Differentially Encoded by D2 Receptors in Striatal Subregions. Neuron 98:459-461
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
Förstera, B; Muñoz, B; Lobo, M K et al. (2017) Presence of ethanol-sensitive glycine receptors in medium spiny neurons in the mouse nucleus accumbens. J Physiol 595:5285-5300
Francis, T C; Chandra, R; Gaynor, A et al. (2017) Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry 22:1512-1519
Chandra, Ramesh; Engeln, Michel; Schiefer, Christopher et al. (2017) Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence. Neuron 96:1327-1341.e6
Terrillion, C E; Dao, D T; Cachope, R et al. (2017) Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. Genes Brain Behav 16:495-505
Castro, Alberto; Li, Ying; Raver, Charles et al. (2017) Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons. Pain 158:1366-1372
Chandra, Ramesh; Engeln, Michel; Francis, T Chase et al. (2017) A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1? in Nucleus Accumbens Neuron Subtypes in Cocaine Action. Biol Psychiatry 81:564-572

Showing the most recent 10 out of 17 publications