Methamphetamine (Meth) and related amphetamine compounds, which are potent psychostimulants, are among the most commonly used illicit drugs. With > 35 million users worldwide, Meth abuse poses a significant health and economic threat globally. Acute and chronic doses of Meth have been shown to produce long-term damage in many brain regions. However, the mechanisms underlying Meth neurotoxicity are still not known. The current proposal focuses on one important and emerging player called extracellular vesicles (EVs) and their role in chronic Meth abuse. Extracellular vesicles (EVs) have been garnering increasing interest for their role in several neurological disorders and understanding their role in the brain during drug abuse is just beginning to emerge. EVs can release their cargo into target cells and trigger downstream signaling pathways . Our own recent study has revealed that EV associated microRNA (miRNA) cargo can be responsible for neuronal injury. However, EV miRNA cargo and their involvement in Meth associated neurotoxicity is not well understood thus warranting further studies in this direction. We are particularly interested in understanding the effect of such EV-carried miRNAs on neurons. The overarching goal of this proposal is to examine the role of EVs in the damaging effects of Meth on the central nervous system, specifically in a setting of chronic Meth exposure. During course of this study, we will investigate several key questions in the field including molecular and functional changes in neurons that are specifically driven by EVs during Meth abuse. These studies will be conducted in three specific aims; (1) In Specific aim 1 we will utilize a robust strategy to isolate EVs from archived monkey brain brains and from primary glial cells infected exposed to Meth, characterize them, and determine Meth induced alterations in EV associated miRNA cargo. (2) Specific aim 2 is specifically designed to study synaptodendritic injury and causative mechanism resulting from treatment with EVs isolated from brains and primary glial cells from Meth treated groups and finally in (3) Specific aim 3, we will use a chronic self-administration rat model to study the effects of brain EVs on neuronal damage and determine the importance of sex as a variable. The experiments proposed in this study will unravel crucial signaling events that mediate such neurotoxicity therefore providing a strong foundation to build further therapeutic studies for the eventual prevention of long-term neuronal damage in Meth abuse that considers the role of sex.

Public Health Relevance

Extracellular vesicles have been garnering increasing interest for their role in several neurological disorders including drugs of abuse. The cause of neuronal damage in methamphetamine abuse is unclear, however our studies indicate a role of extracellular vesicles. Our studies proposed here are designed to uncover their role in the progression of neuronal injury in a setting of chronic methamphetamine abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA042379-03
Application #
9507801
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Satterlee, John S
Project Start
2016-09-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198