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Characterization of Increased Serum and Glucocorticoid-Inducible Kinase 1 Gene Expression in the Ventral Tegmental Area by Drugs of Abuse and Stress /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Characterization of Increased Serum and Glucocorticoid-Inducible Kinase 1 Gene Expression in the Ventral Tegmental Area by Drugs of Abuse and Stress // Samantha Caico.
Author:	Caico, Samantha,
Description:	1 electronic resource (208 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 87-05, Section: B.
Contained By:	Dissertations Abstracts International87-05B.
Subject:	Neurosciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32280320
ISBN:	9798297989184

Characterization of Increased Serum and Glucocorticoid-Inducible Kinase 1 Gene Expression in the Ventral Tegmental Area by Drugs of Abuse and Stress /
Caico, Samantha,

Characterization of Increased Serum and Glucocorticoid-Inducible Kinase 1 Gene Expression in the Ventral Tegmental Area by Drugs of Abuse and Stress /Samantha Caico. - 1 electronic resource (208 pages)

Source: Dissertations Abstracts International, Volume: 87-05, Section: B.

Substance use disorder (SUD) is a highly prevalent psychiatric disorder but despite this prevalence, treatment options for SUD remain inadequate. Furthermore, SUD is highly comorbid with other psychiatric illnesses, such as depression, contributing to the difficulty of developing effective therapeutics. A major reason for unsuccessful treatment is our limited understanding of the neurobiology underlying these disorders. Both drugs of abuse and stress can modulate the function of the dopamine (DA) neurons in the ventral tegmental area (VTA) that are instrumental for proper motivated behavior. Therefore, our lab seeks to identify cellular and molecular changes in the VTA that underlie drug and stress responses. We previously found that repeated injections of morphine or cocaine increase the expression of the gene serum- and glucocorticoid- inducible kinase 1 (Sgk1) in the VTA using RNA sequencing. Furthermore, chronic social defeat stress (CSDS) induces Sgk1 in the VTA as well, highlighting it as a common target for both drugs and stress in the VTA. Although we previously found that chronic drug exposure increases Sgk1 expression in the VTA 24 hours later, it was unclear whether similar regulation occurs with acute drug exposure and how persistent Sgk1 expression changes are. For this dissertation, I investigated other key timepoints in which drugs of abuse can induce molecular changes within the VTA such as acute exposure and abstinence. I discovered that acute exposure to morphine via a single injection is sufficient to increase VTA Sgk1 expression 1 hour later, but not 24 hours late. Furthermore, Sgk1 induction did not persist through abstinence. Drugs of abuse cause a sensitization of behavioral and molecular responses following repeated drug exposure such that subsequent exposures display enhanced effects; thus, I also investigated whether Sgk1 expression is sensitized by morphine exposure. However, I found that Sgk1 expression is not affected by prior morphine exposure. Together, these data indicate that acute and chronic morphine exposure regulate Sgk1 expression differently. Both acute and chronic exposure elicit an induction of Sgk1 1 hour later, likely due to Sgk1 being an immediate early gene, while only chronic exposure causes a more persistent Sgk1 induction (24 hours later) likely from activation of downstream signaling pathways involving Sgk1. Given that multiple classes of drugs of abuse increase VTA Sgk1, and our previous observation of an CSDS-induced increase in VTA Sgk1, we wanted to know if this regulation translated to other forms of stress. I found that subchronic variable stress, acute restraint stress, and repeated restraint stress all increase VTA Sgk1 expression. I then determined whether this stress-induced increase in VTA Sgk1 expression was driven by VTA DA neurons. Using transgenic mice and viral-mediated deletion strategies I discovered that neither Sgk1 knockout from VTA DA neurons, or all VTA neurons, was sufficient to blunt the stress effect, suggesting Sgk1 induction is occurring in non-neuronal cells. Given recent reports in the literature that VTA astrocytes respond to both stress and drugs of abuse and can modulate VTA DA function, I used RNAscope to assess Sgk1 expression in VTA astrocytes and found that both chronic morphine and acute restraint stress increase Sgk1 expression in VTA astrocytes. Together, my studies provide a more expansive understanding of how drugs of abuse and stress affect Sgk1 induction in the VTA, and the specific cells responsible. Future studies should determine the functional role, molecularly and behaviorally, of Sgk1 induction in VTA astrocytes by drugs of abuse and stress, as these will help determine if targeting Sgk1 is a feasible therapeutic option for treatment of comorbid SUD and depression.

English

ISBN: 9798297989184Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Substance use disorder

Characterization of Increased Serum and Glucocorticoid-Inducible Kinase 1 Gene Expression in the Ventral Tegmental Area by Drugs of Abuse and Stress /
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