Catecholamines and Arousal Público

Abstract

Abstract

The catecholamines norepinephrine and dopamine are involved in the
initiation and maintenance of arousal states. Sleep is found in all animals studied to date, from humans to flies, and is regulated through a complex network of neuromodulatory systems. However, sleep and
arousal disorders are common, and are treated with a variety of pharmacotherapies, many of
which require catecholaminergic mechanisms. A common symptom of depression is a disturbance in arousal levels, and this can often be exacerbated by antidepressant medications. To explore NE in antidepressant-induced changes in arousal, we
administered antidepressants that inhibit the NE transporter and increase extracellular NE levels, and measured locomotor behavior. When administered acutely or chronically, NET blocking antidepressants decreased locomotor behavior, unless combined with DA transporter blockade (e.g. the dual NET/DAT inhibitor antidepressant bupropion). To
further investigate the importance of catecholamines in arousal pharmacology, we examined
modafinil, a commonly-prescribed treatment for excessive sleepiness. While the
molecular mechanism for modafinil is unknown, previous research has suggested that both NE
and DA are involved in its actions. We used mice lacking NE, in combination
with antagonists for both dopaminergic and adrenergic receptors, to show that complex NE/DA
interactions likely underlie modafinil efficacy. Finally, we characterized behavior in a mouse
model for Lesch-Nyhan Disease, a devastating condition with symptoms of self-injurious
behavior and losses of DA in the brains of human patients. We found that this mouse model had
"hyperarousal-like" alterations similar to those found in humans, as measured by
increased aggression and a unique form of amphetamine-induced stereotypy. These studies used
diverse models to explore the importance of catecholamines in basal and pharmacologically-
induced arousal states.

Table of Contents

Table of Contents

CHAPTER 1: CATECHOLAMINERGIC PHARMACOLOGY AND
AROUSAL

1

1.1
Abstract








2

1.2
Sleep and arousal states






3

1.3
Disorders of the arousal system





3

1.4
Regulation of arousal states






4

1.5
Norepinephrine and arousal






6

1.6
Dopamine and arousal






7

1.7
Stimulants








8



Amphetamines






8



Cocaine







11



Modafinil







12



Caffeine







14

1.8
Antidepressants







16

1.9
Summary








18

CHAPTER 2: THE EFFECTS OF NOREPINEPHRINE TRANSPORTER
INACTIVATION ON LOCOMOTOR ACTIVITY IN MICE


24

2.1
Abstract








25

2.2
Introduction








26

2.3
Methods








27

2.4
Results








29



Acute administration






29

About this Dissertation

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• 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	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Pharmacology
Palavra-chave	Antidepressants Modafinil Arousal Catecholamines Mouse models Norepinephrine Sleep Lesch-Nyhan Disease Dopamine
Committee Chair / Thesis Advisor	Weinshenker, David, Emory University
Committee Members	Hall, Randy A, Emory University Iuvone, P Michael, Emory University Rye, David, Emory University Cubells, Joseph, Emory University

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