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Sorting Nexin 27 : a molecular brake on cocaine addiction

Author: Robert Aaron Rifkin; Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Biomedical Sciences Doctoral Program.
Publisher: New York, N.Y. : Icahn School of Medicine at Mount Sinai, ©2017.
Dissertation: Thesis (Ph. D.) Icahn School of Medicine at Mount Sinai 2017
Edition/Format:   Thesis/dissertation : Thesis/dissertation : English
Summary:
G protein-gated inwardly-rectifying potassium (GIRK) channels are critical regulators of neuronal firing in the brain, including in dopamine (DA) neurons. DA neurons in the ventral tegmental area (VTA) and, it is increasingly recognized, substantia nigra pars compacta (SNc), play a critical role in the development of addiction to psychostimulants. Understanding the regulators of GIRK channels in VTA and SNc DA  Read more...
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Genre/Form: Academic Dissertation
Academic theses
Material Type: Thesis/dissertation
Document Type: Book
All Authors / Contributors: Robert Aaron Rifkin; Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Biomedical Sciences Doctoral Program.
OCLC Number: 1012404045
Notes: This dissertation is also available on the World Wide Web. Access is restricted to computers located within Mount Sinai or to those users eligible for remote access services.
Reproduction Notes: PRINT REPRODUCTION of electronically published thesis.
Description: xv, 112 pages : llustrations (chiefly color), charts ; 28 cm
Responsibility: by Robert Aaron Rifkin.

Abstract:

G protein-gated inwardly-rectifying potassium (GIRK) channels are critical regulators of neuronal firing in the brain, including in dopamine (DA) neurons. DA neurons in the ventral tegmental area (VTA) and, it is increasingly recognized, substantia nigra pars compacta (SNc), play a critical role in the development of addiction to psychostimulants. Understanding the regulators of GIRK channels in VTA and SNc DA neurons may therefore provide insights into the development of addiction. Previous research has identified Sorting Nexin 27 (SNX27) as a regulator of GIRK channels in VTA DA neurons. Using a conditional knockout mouse lacking SNX27 only in DA neurons (SNX27 TH KO), and Cre-dependent viral constructs, I explored the role of SNX27 and GIRK channels in addictive behavior. I found that SNX27 regulates GIRK currents in VTA DA neurons that project to nucleus accumbens (NAc) and in SNc DA neurons that project to dorsal striatum (DS). This finding has implications for the mechanism by which SNX27 regulates GIRK channels, since SNc neurons lack the GIRK3 subunit, which some studies have shown is necessary for SNX27 to regulate GIRK channels. I also found that SNX27TH KO mice have an elevated locomotor sensitization response to cocaine, which can be rescued by exogenous GIRK2a. This demonstrates that SNX27 regulates addictive behavior via its regulation of GIRK channels. Previous experiments in vitro in HEK cells had suggested that overexpression of SNX27 causes downregulation of GIRK expression. To test whether this is also the case in vivo, I used a Cre-dependent viral construct to overexpress SNX27 in VTA DA neurons. I found that GIRK expression was indeed reduced, confirming that SNX27 regulates GIRK channels in a concentration-dependent manner in vivo.

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