Modulation of dopamine release is one way that drugs of abuse likely hijack reward circuitry and lead to addiction. For instance, nicotine directly modulates dopamine release through nicotinic receptors on presynaptic terminals of dopaminergic neurons. However, current methodologies to monitor dopamine release and its modulation are missing an important level of spatiotemporal sensitivity that is taken for granted at fast transmitter synapses like glutamate and GABA synapses. Ligand-gated channels on target cells at fast synapses allows faithful detection of single quanta with temporal resolution below 1 ms. This level of resolution is not possible with current electrochemical and optical techniques that are applied to dopamine synapses, which activate G protein coupled receptors rather than ionotropic receptors. Here we propose to heterologously introduce an invertebrate ligand-gated dopamine channel into postsynaptic targets of rodent dopamine neurons. This will allow us to study dopamine release and nicotinic modulation of dopamine release with spatiotemporal resolution typically reserved for fast synapses. We anticipate that this new methodology will fill an important gap in our understanding of the actions of abused substances and may lead to new therapeutic strategies.

Public Health Relevance

Drug abuse and addiction take an enormous societal toll. In any attack on the problem, we should include strategies to enhance understanding of the earliest changes wrought by drugs of abuse on brain signaling systems. Unfortunately, we are currently unable to peer into the fastest, earliest changes in signaling induced by abused drugs because of limitations in methodologies. We propose to introduce a new tool that will allow us to examine changes induced by nicotine, an exemplar drug of abuse, with unprecedented resolution. We will thereby gain new insights into how nicotine and other abused drugs hijack normal brain circuitry and signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA032915-01
Application #
8240801
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pilotte, Nancy S
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$228,000
Indirect Cost
$78,000
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zorumski, Charles F; Mennerick, Steven; Izumi, Yukitoshi (2014) Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol 48:1-17
Kress, Geraldine J; Shu, Hong-Jin; Yu, Andrew et al. (2014) Fast phasic release properties of dopamine studied with a channel biosensor. J Neurosci 34:11792-802