Moreines, Jared
(2017)
CIRCUIT AND PHARMACOLOGICAL APPROACHES FOR
COUNTERACTING STRESS EFFECTS ON THE DOPAMINE SYSTEM:
IMPLICATIONS FOR MAJOR DEPRESSION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Evidence from clinical and preclinical models suggests that an important component to MDD is dysfunction in the mesolimbic dopamine reward system. This thesis focused on better understanding the brain circuits potentially involved in driving this dopamine system dysfunction, as well as mechanisms of an antidepressant therapy that directly acts on the dopamine system. We used the chronic mild stress (CMS) rodent model of depression, which features a prominent hypodopaminergic phenotype, to answer two specific questions: 1) How do brain regions with identified involvement in MDD based on clinical literature regulate the dopamine system in normal and CMS-exposed rats; and 2) What effect does the atypical antipsychotic agent quetiapine have on normal and CMS-exposed rats with acute and repeated administration? In each case, we performed single-unit recordings of identified ventral tegmental area (VTA) dopamine neurons to assess the dopamine system’s functional status. For question 1, we found that activation of the Infralimbic Prefrontal Cortex (ILPFC; rodent homologue of human Brodmann Area 25) and Lateral Habenula (LHb) in normal rodents each inhibits a distinct subset of dopamine neurons based on their location in the VTA, that those inhibited by the ILPFC have greater overlap with those inhibited by CMS than do those inhibited by the LHb, and that ILPFC but not LHb inactivation following CMS restores dopamine system function to normal levels. For question 2, we found that quetiapine has distinct effects on the dopamine system based on duration of administration and history of exposure to CMS, with only repeated quetiapine administration restoring dopamine system function in CMS-exposed rats. Together, these results offer insight to clinically relevant questions regarding interactions among brain regions mediating hedonic and affective processes, as well as highlight potential dopaminergic mechanisms of novel antidepressant therapies.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
26 January 2017 |
| Date Type: |
Publication |
| Defense Date: |
22 November 2016 |
| Approval Date: |
26 January 2017 |
| Submission Date: |
9 December 2016 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
119 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Neuroscience |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Dopamine, Depression, Electrophysiology, Pharmacology, Quetiapine, Infralimbic, Habenula |
| Date Deposited: |
26 Jan 2017 18:54 |
| Last Modified: |
26 Jan 2019 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30538 |
Available Versions of this Item
-
CIRCUIT AND PHARMACOLOGICAL APPROACHES FOR
COUNTERACTING STRESS EFFECTS ON THE DOPAMINE SYSTEM:
IMPLICATIONS FOR MAJOR DEPRESSION. (deposited 26 Jan 2017 18:54)
[Currently Displayed]
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}