Opiate use, dependence, and addiction have dramatically increased to epidemic proportions in recent years, leading to substantial financial and societal health burdens, as well as an increasing number of overdoses. Thus, there is a crucial need for novel therapies to treat opiate dependence and cravings occurring with abstinence, which lead to relapse. Many studies indicate dysfunctional brain circuits in opiate use and abstinence, while other studies have identified distinct molecular adaptations underlying opiate-induced behaviors. Such studies emphasize a need to approach opiate use from a combined circuit and molecular perspective to link candidate opiate use and abstinence molecules to dysfunctional neuronal subtypes. This could uncover molecules in disease vulnerable neuron subtypes that can be pharmacologically targeted for opiate use therapeutics. The neuronal subtypes in the nucleus accumbens (NAc) deserve considerable attention in opiate abuse. The NAc is a critical brain hub for altered molecular processes that mediate behavioral responses to opiates and other drugs of abuse. Further, we previously demonstrated distinct roles of the two NAc projection medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor 1 vs. 2 (D1-MSNs vs. D2-MSNs), in opiate induced behaviors. However, there is little information into the molecular adaptations, and corresponding neuronal adaptations occurring in specific NAc neuron subtypes in opiate use and abstinence. To provide insight into this we will perform translatome profiling, using RiboTag, in the two MSN subtypes after opiate use. Since cellular and behavioral plasticity associated with opiate exposure occurs along a continuum we will perform this translatome profiling in D1-MSNs vs. D2-MSNs following abstinence from heroin self-administration at early and prolonged time periods. The studies proposed in this grant application will, for the first time, identify the distinct translatome adaptations occurring temporally following discontinuance of heroin in a cell-type-specific manner. Such studies are essential for uncovering molecules underlying cellular and circuit dysfunction in opiate use and abstinence, thus providing multiple avenues of investigation into the subtype-specific neurobiological underpinnings of opiate abuse.

Public Health Relevance

We propose to study neuron subtype translatomics after short and long-term abstinence from opiate use. We will perform translatome profiling in the two main nucleus accumbens neuron subtypes in opiate abuse. Our studies will provide new information into the molecular mechanisms occurring in key reward brain region neuron subtypes in opiate abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA048554-01A1
Application #
9835778
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Lossie, Amy C
Project Start
2019-09-15
Project End
2021-08-31
Budget Start
2019-09-15
Budget End
2020-08-31
Support Year
1
Fiscal Year
2019
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