The long-term goal is to determine how drugs of abuse disrupt mitochondrial energetics and harm embryonic development and health in later life. The timing of embryonic development is highly regulated and coordinated with energy (ATP) metabolism. Preliminary data reveal that inhibition of mitochondrial energetics via genetic means or by exposures to abused drugs cause specific defects in the development of the nervous and cardiovascular systems, which have high energy requirements and are thus dependent on mitochondrial function. Commonly abused ADHD drugs such as methylphenidate (MPH), amphetamine and methamphetamine (METH) impact energy metabolism, as revealed by decreased protein levels of the MRC. However, functional studies to measure respiration have not been performed. Furthermore, the mechanisms by which these drugs impact mitochondrial energetics in embryonic development are elusive. This gap in knowledge is due to the lack of methodology for measuring energetics in developing embryos. The PI's laboratory has developed an innovative high-throughput assay to measure respiration and bioenergetics in zebrafish embryos that takes advantage of the small size of zebrafish embryos, development of embryos outside of the mother, and sheer numbers (100s) of embryos produced by each breeding pair. This assay is indispensable for the proposed studies. The long-term effects of prenatal exposures to MPH or METH are poorly understood. It is important to study, because the lifetime prevalence of illicit METH use in the US population aged 18-49 exceeds 8%, and METH use is associated with risky sexual behavior, pregnancy and persistent behavioral impairments in adulthood. These data, along with our preliminary work leads us to test our central hypothesis: Prenatal exposures to MPH or METH compromise cellular energetics, disrupting the development of tissues that have the highest energetic requirements, resulting in long-term behavioral defects. The rationale for this research is that understanding how mitochondrial dysfunction caused by MPH/METH leads to embryonic defects will guide the development of new treatment strategies to prevent birth defects. This hypothesis will be tested by pursuing two Specific Aims: 1) Determine the mechanism by which MPH or METH exposure disrupts cellular energetics in zebrafish embryos;and 2) Determine the effects of MPH and METH on zebrafish development and behavior. The proposed research is significant, because these studies will elucidate the mechanisms by which prenatal exposures to MPH or METH cause neurobehavioral defects. These zebrafish models can then serve as high-throughput screens for candidate pharmacotherapies that reverse energetic and developmental defects. Preventing birth defects caused by stimulant abuse will vastly improve the quality of life for these children and human health in general.

Public Health Relevance

It is important to study the long-term effects of prenatal exposures to stimulants such as methamphetamine, as the lifetime prevalence of illicit methamphetamine use in the US population aged 18-49 exceeds 8%, and methamphetamine use is associated with risky sexual behavior, pregnancy, and neurobehavioral problems later in life. These studies will elucidate the mechanisms by which prenatal exposures to methylphenidate or methamphetamine cause neurobehavioral defects. Preventing birth defects caused by stimulant abuse will vastly improve the quality of life for these children and human health in general.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA037706-01
Application #
8722152
Study Section
Special Emphasis Panel (ZDA1-GXM-A (12))
Program Officer
Wu, Da-Yu
Project Start
2014-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$299,000
Indirect Cost
$99,000
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425