TOBACCO ADDICTION IN INDIVIDUALS WITH SCHIZOPHRENIA

158 Pages·2016·2.29 MB·English

TOBACCO ADDICTION IN INDIVIDUALS
WITH SCHIZOPHRENIA:
A STUDY IN RATS

BY

UTA WATERHOUSE

A thesis
submitted to the Victoria University of Wellington
in fulfilment of the requirements of the degree of
Doctor of Philosophy

Victoria University of Wellington
2016
Copyright © Uta Waterhouse

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ABSTRACT

Schizophrenia as with most mental disorders develops due to an interaction of
multiple genetic and environmental factors. Prenatal exposure to a maternal immune
activation (MIA) is an environmental risk factor that can predispose offspring to develop
schizophrenia later in life. The neurodevelopmental theory suggests that an immune
challenge during gestation can lead to long-lasting impairments such as in learning, memory,
attention, or language (Brown & Patterson, 2012). Based on findings in human studies,
prenatal exposure to a MIA has been utilized in preclinical research. Thus, the first aim of
this study was to establish an animal model that generates subjects with schizophrenia-like
cognitive impairments. To this end, a bacterial endotoxin, lipopolysaccharide (LPS) was
used, which like most infectious agents, cannot cross the blood-placenta-barrier, yet reliably
mimics an infection and initiates a MIA. Pregnant rats were subcutaneously (sc) injected
with LPS (0.5 mg/kg) at one of three important neurodevelopmental time periods, gestation
days (GD) 10/11, 15/16 or 18/19 (Fortier, Luheshi, & Boksa, 2007; Graciarena, Depino, &
Pitossi, 2010). As individuals with schizophrenia commonly show deficits in multiple
domains, three assessment paradigms were used to examine sensory and cognitive abilities in
early and late adulthood. Tasks included prepulse inhibition to assess sensorimotor gating,
latent inhibition to measure selective attention, and delayed non-matching to sample to
evaluate working memory (WM).
Several theories have been suggested to explain high smoking incidence in
schizophrenic patients (75-90%) compared to the general population (23%). The self-
medication theory suggests high smoking rates amongst patients because nicotine, the
primary addictive constituent in tobacco smoke, ameliorates some of the symptoms of the
disorder such as cognitive deficits (D'Souza & Markou, 2012). Thus, the second aim of this
study was to determine whether repeated experimenter and self-administered nicotine
ameliorates or reduces schizophrenia-like cognitive deficits. Finally, the third aim was to
investigate the common substrate theory, which suggests that shared underlying biological
pathways may lead to increased susceptibility for an individual to develop both schizophrenia
and tobacco addiction (Chambers, Krystal, & Self, 2001).
In conclusion, the findings of this study were coherently consistent and revealed that
firstly, prenatal exposure to MIA early during foetal development led to long-lasting deficits
in cognitive domains such as selective attention and WM. Secondly, supporting the self-
medication theory, nicotine reversed MIA-induced cognitive impairments independent of the
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administration paradigm. Thirdly, increased responding rates for nicotine during self-
administration acquisition in animals prenatally exposed to MIA were observed, yet there
was no effect of prenatal treatment in dose response or progressive ratio testing. Thus, these
findings only offer weak support for the common substrate theory.
Importantly, the findings of this study revealed that animals can be repeatedly
assessed in these paradigms to examine the therapeutic efficacy of drugs and other
treatments. This is of particular importance considering the lack of effective pharmacological
treatments for cognitive deficits in schizophrenic patients.

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ACKNOWLEDGEMENTS

I would like to start by thanking my family, my parents Erika and Heinz-Otto Buer
and my brother Helge, for their endless love, encouragement and support. They taught me
the importance of hard work and perseverance in life. Without them I could not have become
the person I am today, full of happiness and enthusiasm to encounter new projects like this
one. Danke Mama und Papa fuer all die gluecklichen Kindheitserinnerungen, ihr seid die
besten Eltern der Welt. Most importantly, I would like to thank my husband Grant for his
love, constant support and patience throughout the years of my studies. Thank you for taking
me to New Zealand, this wonderful country that has embraced me with open arms. Without
you my dreams could not have become reality.

I would like to thank my friends, near and far, who have helped me through
challenging times with amazing “dinner deliveries” (Kathrine), for being a “daughter
replacement” in times of need for my parents in Germany and many long phone calls of
“counselling and distraction” (Lydia), encouraging words of admiration (Kerstin), for being
my rock during the first two years of my studies (Lynette) and many others.

I am truly grateful and privileged that I had the opportunity to work with the most
amazing and wonderful supervisors one could wish for, Professor Bart Ellenbroek and
Dr Katie Brennan. I am so very grateful that I had you by my side with all your expertise,
warmth and humour. You have been more supportive, enthusiastic and encouraging than I
could have ever imagined.

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TABLE OF CONTENTS

General introduction: 12

Chapter 1: Schizophrenia, definitions, symptoms aetiology 14

Chapter 2: Tobacco/nicotine addiction 29

Chapter 3: Tobacco addiction in schizophrenia,
explanatory theories 40

Chapter 4: Cognitive assessment 52

Chapter 5: Nicotine ameliorates cognitive deficits induced by
maternal LPS exposure: A study in rats 58

Chapter 6: Contingent versus non-contingent drug
administration 85

Chapter 7: Nicotine self-administration reverses cognitive
deficits in a rat model for schizophrenia 89

Chapter 8: General discussion 114

Appendix A.: Self-administration chamber 135

References: 136

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LIST OF FIGURES

5.1 Prepulse inhibition (PPI) per prenatal treatment group at three
gestational periods before/after experimenter administered nicotine 67

5.2 Latent inhibition (LI) per prenatal treatment group at three gestational
periods and LI pre-exposure before/after experimenter administered
nicotine 69

5.3 Choice accuracy in delayed non-matching to sample (DNMTS)
per prenatal treatment group at three gestational periods
before/after experimenter administered nicotine 71

5.A1 Pre-pulse inhibition startle chamber 80

5.A2 Delayed non-matching to sample T-maze trial 1 and 2 82

7.1 Latent inhibition (LI) per prenatal treatment group and LI pre-exposure
before and after nicotine self-administration 97

7.2 Choice accuracy in delayed non-matching to sample (DNMTS)
per prenatal treatment group before and after nicotine/saline
self-administration 98

7.3 Active lever responding per prenatal treatment group during
nicotine/saline self-administration on fixed ratio schedule (FR5) 100

7.4 Inactive lever responding per prenatal treatment group during
nicotine/saline self-administration on fixed ratio schedule (FR5) 100

7.5 Dose response responding on FR5 schedule during nicotine/
saline self-administration 101

7.6 Breakpoints on a progressive ratio schedule (PR) during
nicotine/saline self-administration 102

7.7 Latent inhibition (LI) per prenatal treatment group and LI
pre-exposure before/after saline self-administration 103

7.A1 Delayed non-matching to sample (DNMTS)
group average number of correct second arm visits over
four inter-trial-intervals 113

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LIST OF TABLES

5.S1 Timeline of experimental design experimenter administered nicotine 79

5.S2 Group sizes experimenter administered nicotine 79

5.S3 Basal amplitude PPI experimenter administered nicotine 79

7.S1 Timeline of experimental design part 2 109

7.S2 Timeline of experimental design cognitive tests after self-administration 109

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ABBREVIATIONS

Acetylcholine ACh
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA
Animal Ethics Committee AEC
Analysis of variance ANOVA
Apomorphine-susceptible APO-SUS
Average startle response ASR
Cannabinoid-1 CB1
Central nervous system CNS
Conditioned place preference CPP
Copy number variation CNV
Catechol-O-methyl transferase COMT
Dopamine DA
Diagnostic and Statistical Manual of Mental Disorders DSM
Disrupted in schizophrenia 1 DISC 1
Deoxyribonucleic acid DNA
Delayed non-matching to sample DNMTS
Dose response DR
Fixed ratio FR
Functional magnetic resonance imaging fMRI
Gestation day GD
Genome-wide association study GWAS
Interleukin IL
Intraperitoneally ip
Inter-trial-interval ITI
Intravenous iv
Intelligent quotient IQ
Latent inhibition LI
Lithium Chloride LiCl
Lipopolysaccharide LPS
Magnetic resonance imaging MRI
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Maternal immune activation MIA
Mecamylamine MEC
Nucleus accumbens NAcc
Natriumhydroxid NaOH
Nicotinic acetylcholine receptor nAChRs
Nicotine NIC
Nicotine replacement therapy NRT
N-methyl-D-aspartate NMDA
Non pre-exposed NPE
Neonatal ventral hippocampal lesion NVHL
New Zealand Dollar NZD
Phencyclidine PCP
Pre-exposed PE
Prefrontal cortex PFC
Positron emission tomography PET
Postnatal day PND
Polyinosinic polycytidylic acid PolyI:C
Prepulse inhibition PPI
Progressive ratio PR
Radial arm maze RAM
Roll your own RYO
Saline SAL
Self-administration SA
Subcutaneous sc
Substantia nigra SN
Transforming growth factor TGF
Tobacco particulate matter TPM
Tyrosine hydroxylase TH
Substance use disorder SUD
Ventral tegmental area VTA
Wisconsin Card Sorting Test WCST
Working memory WM
World Health Organization WHO

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