Cross-Species Studies on the Mechanisms Underlying Abnormal Behavior in Bipolar Disorder

238 Pages·2014·7.08 MB·English

Cross-Species Studies on the Mechanisms
Underlying Abnormal Behavior in Bipolar
Disorder: A Dopaminergic Focus
Thesis, Utrecht University & University of California, San Diego, with a summary in Dutch

Cover design: Jordy van Enkhuizen

Printed by: Ridderprint

ISBN/EAN: 978-90-5335-811-5

© 2014 Jordy van Enkhuizen, Utrecht, the Netherlands
Cross-Species Studies on the Mechanisms Underlying
Abnormal Behavior in Bipolar Disorder: A
Dopaminergic Focus

Translationele studies naar de onderliggende mechanismen van afwijkend gedrag in
bipolaire stoornissen: Een dopaminerge focus
(met een samenvatting in het Nederlands)

PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector
magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor
promoties in het openbaar te verdedigen op dinsdag 1 april 2014 des middags te 12.45
uur

door

Jordy van Enkhuizen

geboren op 10 mei 1986 te Ridderkerk
Promotoren:
Prof.dr. B. Olivier
Prof.dr. M.A. Geyer

Co-promotor:
dr. J.W. Young

Publication of this thesis was financially supported by:
Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, the Netherlands
“Normality is a paved road: It’s comfortable to walk, but no flowers grow on it”
- Vincent van Gogh
CONTENTS

Chapter 1 General introduction 9

Chapter 2 Exploratory behavior of DAT models quantified with the reverse-
translated multivariate behavioral pattern monitor

2.1 Chronic valproate attenuates some, but not all, facets of mania-like
behaviour in mice
International Journal of Neuropsychopharmacology, 16(5) (2013);
1021-1031 21

2.2 Dopamine depletion attenuates some behavioral abnormalities in a
hyperdopaminergic mouse model of bipolar disorder
Journal of Affective Disorders, 155 (2014); 247-254 39

2.3 Cannabis use for reward or symptom relief in psychiatric disorders
International Journal of Neuropsychopharmacology, [Submitted] 55

Chapter 3 Assessment of risk-based decision-making in mice and patients
with bipolar disorder in species-specific Iowa gambling tasks

3.1 Increased risk-taking behavior in dopamine transporter knockdown
mice: further support for a mouse model of mania
Journal of Psychopharmacology, 25(7) (2011); 934-943 63

3.2 Differential effects of dopamine transporter inhibitors in the rodent
Iowa gambling task: relevance to mania
Psychopharmacology, 225(3) (2013); 661-674 81

3.3 Reduced dopamine transporter functioning induces high-reward
risk-preference consistent with bipolar disorder
Neuropsychopharmacology, [Submitted] 105

Chapter 4 The effects of sleep deprivation on attentional performance in
both mice and humans

4.1 Sleep deprivation impairs performance in the 5-choice continuous
performance test; Similarities between humans and mice
Behavioural Brain Research, 261 (2014); 40-48 133
Chapter 5 Pharmacological modeling of both manic and depressive phases
of bipolar disorder in mice

5.1 Reproducing bipolar depression- and mania-like behaviors in mice
by increasing acetylcholine or dopamine: Chronic lithium treats
most, but not all
Neuropharmacology, (2014) [Resubmitted] 157

Chapter 6 A model animal for bipolar disorder based on dysfunctional
circadian rhythms assessed in cross-species behavioral paradigms

6.1 Further evidence for ClockΔ19 mice as a model for bipolar disorder
mania using cross-species tests of exploration and sensorimotor
gating
Behavioural Brain Research, 249 (2013); 44-54 183

Chapter 7 Discussion and conclusions 207

List of abbreviations 220

Summary 221

Nederlandse samenvatting 224

Acknowledgements 228

Dankwoord 231

About the author 234

Over de auteur 235

List of publications 236

CHAPTER 1

General introduction
Chapter 1
The current use of psychopharmacological interventions in patients with major psychiatric
disorders is often characterized by a trial and error approach. Although ‘trial and error’ is
a fundamental method of solving problems, the repeated and varied attempts until
success form a poor strategy for chemical substances that can induce serious side-effects
in humans.

Bipolar disorder (BD) is one of these major psychiatric disorders, affecting approximately
2% of the global population (1). It often develops in the late teens or early adult years and
presents in different forms. As the name suggests, together with its older term ‘manic-
depressive illness’, the disease is characterized by episodes of manic and depressive
behavior, where patients in-between these extreme mood states are labeled as euthymic.
Additionally, mixed features of both depressive and manic symptoms can occur
simultaneously and a state of hypomania exists where one may feel good and function
well, but is at serious risk of developing a manic or depressive episode. The DSM-V
essentially categorizes BD into BD-I and BD-II, the latter distinguished by an absence of
full-blown mania or mixed episodes (2). The opposite extremes of manic and depressive
episodes result in markedly different changes in both mood and behavior during these
phases (3). Symptoms of mania include long periods of feeling ‘high’ or overly happy
(euphoria), hypersexuality, hyperactivity, reduced sleep, extreme irritability, racing
thoughts, aggression, and hedonic behavior. Although irritation and psychotic symptoms
such as delusions are often observed during mania, hyperactivity is a conspicuous feature
during acute manic states (4). Accordingly, the latest edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM V) added an emphasis on changes in activity
and energy being required for diagnosis of a manic episode on top of an ‘increase in goal-
directed activity’ or ‘psychomotor agitation’ (2). Symptoms of bipolar depression are
largely opposite and include long periods of feeling sad or hopeless (dysphoria), reduced
libido, feeling tired or ‘slowed down’, increased sleep, anhedonia, and increased risk for
suicide. It is worth noting that at least one manic or hypomanic episode is required for
diagnosis of BD, including bipolar depression (2). Besides changes in mood and behavior,
BD is also associated with various significant neurocognitive impairments in domains such
as executive dysfunction, vigilance deficits, impulsivity, and poor decision-making
characterized by increased risk-taking (5, 6). Although BD is classically viewed as a mood
disorder, these neurocognitive deficits are irrefutably important since they correlate
closely with the patients’ daily living abilities (7, 8).

Because untreated or poorly maintained BD is devastating to the patients’ quality of life
including that of their families, developing novel therapies is required. The paucity of
current treatments is reflected by the fact that no approved treatments have been
developed with BD as a target (9). Commonly used treatments approved for BD include
the mood stabilizer lithium, anticonvulsants such as valproate and lamotrigine, and
10