Effects of Dopamine D3 Receptor Antagonism on Morphine-induced Locomotor Activity Restricted; Files Only

Botz-Zapp, Christian (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/f1881k94d?locale=en
Published

Abstract

The misuse of prescription and recreational opioids has led to an alarming increase in the number of overdose deaths nationwide. Recently, the dopamine D3 receptor (D3R) has received attention as a potential site for the development of opioid abuse liability and dependence pharmacotherapies. Interest in the D3R initially peaked due to its primary expression in the ventral striatum, a target region of the mesolimbic dopamine (DA) system that mediates the reinforcing effects of many drugs of abuse. Early studies show that D2-like antagonists can attenuate abuse-related effects of opioids. However, D2-like antagonists non-preferentially bind to D2, D3, and D4 receptors (D2R, D3R, D4R), which makes it difficult to understand the precise role of the D3R in mediating the effects of opioids. Thus, the field has progressed towards the development of D3R-selective agents.

The present study uses the highly selective D3R antagonist PG01037 and the highly selective D2R antagonist L-741,626 to discern the role of the D3R in mediating behavioral effects of morphine. Specifically, we test the effects of PG01037 and L-741,626 pretreatment on morphine-induced locomotion in C57BL/6J mice. Systemic administration of morphine and other opioids stimulates locomotor activity in mice. Given the significant overlap between DA systems that influence motor function and the reinforcing effects of drugs, studying drug-induced locomotor activity is helpful for predicting aspects of abuse liability and addiction. In our study, we found that both PG01037 and L-741,626 significantly attenuate acute morphine-induced locomotion, which implies that DA signaling at the D3R and D2R is important for morphine-induced locomotion. Furthermore, specific time course actions of PG01037 and L-741,626 may reveal that the initial locomotor response to morphine is differentially affected by D3R and D2R antagonism. Next, we tested several morphine-induced locomotor sensitization protocols in hopes of understanding the impact of PG01037 pretreatment in mediating the chronic effects of morphine. After determining a protocol, we found that PG01037 delayed the development of morphine-induced locomotor sensitization. The results presented in this study are helpful for predicting a role of D3R-selective antagonists in the treatment of opioid abuse and addiction.

Table of Contents

Table of Contents

Introduction……….………………………………………………………………….……………1

Hypothesis……………………..…………………………………………………..…………...….4

Methods…………………...……………………………………………………………………….5

Results………..…………………………………………………………………………………..10

Discussion………………………………………………………………………………………..13

Figures………………………………………………..………………………………..…………19

References…...……………………….……………………………………………….………….29

About this Honors Thesis

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Degree
Submission
Language
  • English
Research field
Keyword
Committee Chair / Thesis Advisor
Committee Members
Last modified No preview

Primary PDF

Supplemental Files