Dysfunctional neuronal circuits are thought to be responsible for neuropsychiatric disorders, including obsessive-compulsive disorder, Parkinson?s disease and addiction. G protein-coupled receptors (GPCRs) differentially modulate the activity of neuronal circuits by interacting with different G proteins, (e.g. G-alpha-s, G-alpha-i, and G-alpha-q-families), and these receptors are well-established drug targets. Distinct subpopulations of neurons comprising these circuits often express similar receptor subtypes, making it impossible to create drugs that selectively target receptors in specific circuits. In order to determine how receptors might modulate neuronal circuits, it is necessary to selectively activate GPCR signaling in a specific neuronal population in vivo. For the past two decades, efforts have been made to create tools to selectively manipulate GPCR signaling in distinct neuron populations - from small molecule ligands to genetic deletion - but these approaches have off-target effects. These off-target effects effectively eliminate the possibility to determine how GPCR signaling in a specific neuronal population affects circuitry function. A promising advancement to enable this specific manipulation is the development of the Designer Receptors Exclusively Activated by Designer Drug (DREADD) family of receptors. The objective of this proposal is to validate this recently created tool in vivo using a transgenic mouse expressing the G-alpha-s DREADD in a specific population of neurons in the striatum.
Specific Aim 1 will validate the tool by determining whether the G-alpha-s DREADD activates canonical G-alpha-s signaling pathways by measuring cAMP accumulation, ERK1/2 phosphorylation, DARPP-32 phosphorylation, and c-Fos expression.
Specific Aim 2 will validate the physiological relevance of the G-alpha-s DREADD-induced signaling by assessing its effects on animal behavior. The completion of this proposal will provide neuroscientists a powerful new tool to exclusively modulate GPCR signaling in specific neuronal populations.

Public Health Relevance

To understand how drugs work in the brain, scientists need to be able to manipulate certain components of the brain in a very precise manner. This proposal will validate a new tool designed to provide an unprecedented level of specificity to scientists. Information gained using this tool will yield new insight into brain function and may lead to development of new drugs for treating neuropsychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH091921-03
Application #
8322176
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Rosemond, Erica K
Project Start
2010-07-01
Project End
2013-05-12
Budget Start
2012-07-01
Budget End
2013-05-12
Support Year
3
Fiscal Year
2012
Total Cost
$27,120
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599