Methamphetamine abuse is a major public health problem with no effective treatment strategies or FDA-approved pharmacotherapies. Methamphetamine addiction is thought to be a chronic disease rooted in numerous neurobiological adaptations induced by this psychostimulant. Arguably, the greatest promise for the treatment of methamphetamine abuse lies in determining the underlying molecular mechanisms of these neuronal adaptations to generate the opportunity of developing targeted therapies. The long-term goal of this work is to identify these underlying molecular mechanisms. The dopamine transporter (DAT) is the primary target for psychostimulants such as methamphetamine and cocaine. By inhibiting dopamine transporter uptake, these drugs are able to increase extracellular dopamine concentration, which modulates dopamine-associated behaviors. However, what is not often recognized is that methamphetamine is a substrate for the dopamine transporter and a high affinity ligand at the sigma-1 receptor (sigma1R), an intracellular chaperon protein. Our preliminary data suggest that: 1) the sigma1R is expressed in the soma and dendrites of midbrain dopaminergic neurons; 2) the sigma1R is co-localized and interacts with the DAT; 3) the administration of either a sigma1R agonist or methamphetamine increases the co-localization and interaction of DAT/sigma1R; and 4) co-administration of a sigma1R agonist influences methamphetamine-regulation of dopamine uptake, dopamine efflux, and the excitability of dopaminergic neurons. In this application we will test the overarching hypothesis that methamphetamine regulation of dopamine transporter function relies in part on methamphetamine-induced increases in sigma1R/DAT interactions and their functional consequences. We will focus on determining the mechanism of DAT/sigma1R interaction (how Aim1), the cellular localization of DAT/sigma1R interaction (where, Aim 2), and the functional consequence of this interaction (what, Aim 3). If, as we postulate, the interaction with the sigma1R represents a main intracellular mechanism for mediating methamphetamine-regulation of DAT, then we will have identified a possible target for treating methamphetamine addiction and other psychiatric diseases involving dysregulation of dopamine neurotransmission.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026947-11
Application #
9683880
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Tsai, Shang-Yi Anne
Project Start
2009-07-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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