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Title page for ETD etd-07272016-160908


Type of Document Dissertation
Author Reddy, India Anjuli
Author's Email Address india.a.reddy@vanderbilt.edu
URN etd-07272016-160908
Title From the Gut to the Brain: Hormonal Regulation of Brain Dopamine Homeostasis and Cocaine Reward
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Fiona Harrison Committee Chair
Aurelio Galli Committee Member
Brad Grueter Committee Member
Naji Abumrad Committee Member
Troy Hackett Committee Member
Keywords
  • bariatric surgery
  • GLP-1
  • cocaine
  • dopamine
  • addiction
  • reward
Date of Defense 2016-05-16
Availability unrestricted
Abstract
Addiction is a disorder characterized by drug use despite negative consequences. Drugs of abuse hijack circuits within brain centers which evolved to respond to natural rewards such as palatable, calorie-dense foods. This suggests that there may be overlap in the regulation of reward for food and drugs of abuse. Importantly, rewarded feeding is regulated by hormones produced within the gut. Thus, we hypothesized that reward for drugs of abuse, namely cocaine, may also be regulated by manipulations that alter rewarded feeding, including hormonal treatment and surgical approaches to weight loss. Cocaine is a psychostimulant that acts by blocking the dopamine (DA) transporter (DAT) within these brain reward centers, including the nucleus accumbens (NAc) and lateral septum (LS), to elevate extracellular DA levels. Here we first show that signaling through the receptor for glucagon-like peptide 1 (GLP-1), a hormone which reduces appetite and promotes weight loss, regulates DA homeostasis and reduces cocaine actions within the LS. It appears to do so, at least in part, through a retrograde signaling mechanism to modify DAT cell surface expression. We next describe changes in striatal DA homeostasis that occur following gastric bypass surgery in mice. Finally, we reveal that a novel gut-based weight loss surgery reduces cocaine-induced locomotor sensitization and cocaine conditioned place preference (CPP). Evidence suggests that hormonal bile acid signaling may be a critical mediator of this effect, as chronic treatment of mice with a synthetic bile acid reduces cocaine CPP while knockout of a major bile acid receptor increases cocaine CPP. Together, these results expand our understanding of the role gut hormones and surgical approaches to weight loss play in central reward processes and may suggest new avenues for therapeutic approaches to the treatment of addiction.
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