Early Environment, Adolescent Alcohol Drinking and Neurobiological Responses to Drugs

100 Pages·2013·6.85 MB·English

Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Pharmacy 190
Early Environment, Adolescent
Alcohol Drinking and
Neurobiological Responses to
Drugs
SARA PALM
ACTA
UNIVERSITATIS
ISSN 1651-6192
UPSALIENSIS
ISBN 978-91-554-9011-9
UPPSALA
urn:nbn:se:uu:diva-229992
2014
Dissertation presented at Uppsala University to be publicly examined in B42, BMC,
Husargatan 3, Uppsala, Friday, 10 October 2014 at 09:15 for the degree of Doctor of
Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty
examiner: Professor Giancarlo Colombo (C.N.R. Institute of Neuroscience, Cagliari, Italy).
Abstract
Palm, S. 2014. Early Environment, Adolescent Alcohol Drinking and Neurobiological
Responses to Drugs. Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Pharmacy 190. 99 pp. Uppsala: Acta Universitatis Upsaliensis.
ISBN 978-91-554-9011-9.
Genes and environment interact to determine an individual’s vulnerability or resilience to
several psychiatric disorders, including alcohol use disorder (AUD). Alcohol use is often
initiated during adolescence and early onset drinking is associated with increased risk for
later AUD. Childhood and adolescence are periods of extensive brain maturation, which
makes young individuals more susceptible to environmental influence. However, little is
known about early environmental influence on reward pathways and behaviors involved in
the development of AUD. Changes in the endogenous opioid and dopamine systems, as well
as individual differences in risk behaviors are all believed to play important roles in the
increased vulnerability seen after adverse early life events and early onset drinking. The overall
aim of the thesis was therefore to investigate the influence of early environmental factors on
adolescent alcohol intake, endogenous opioids, dopamine dynamics and alcohol-induced effects
in rats to increase our knowledge of neurobiological factors underlying vulnerability to AUD.
Furthermore, individual behavioral differences and their correlation to basal and drug-induced
neurobiological responses in rats were also investigated. Animal models of different early
environments, e.g. maternal separation and social vs. single housing, and adolescent alcohol
consumption have been used to study effects on behavior, endogenous opioid peptides and
dopamine dynamics. The results identified the amygdala and dorsal striatum as interesting
brain regions in which endogenous opioids and dopamine, respectively, are impacted by early
environmental factors. The amygdala and the dorsal striatum are both hypothesized to be
involved in the shift from initial drug use to compulsive use and changes in these areas
may be underlying environmentally increased vulnerability to AUD. Furthermore, behavioral
phenotypes in relation to individual neurobiological responses were identified. High risk-taking
behavior was associated with a more pronounced response to amphetamine, but the inherent
dopamine response was instead associated with risk-assessment behavior. In conclusion, several
brain regions of interest for future research were identified. Furthermore, the results contribute
to increased understanding of factors involved in the development of vulnerability for AUD in
adolescents and young adults.
Keywords: adolescence, beta-endorphin, dopamine, dynorphin, endogenous opioids,
enkephalin, high-speed chronoamperometry, housing conditions, maternal separation,
multivariate concentric square field™ test, open field test, radioimmunoassay, voluntary
alcohol intake, Wistar rats
Sara Palm, Department of Pharmaceutical Biosciences, Box 591, Uppsala University,
SE-75124 Uppsala, Sweden.
© Sara Palm 2014
ISSN 1651-6192
ISBN 978-91-554-9011-9
urn:nbn:se:uu:diva-229992 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-229992)
Till Mammuten och Papputen

List of Papers
This thesis is based on the following papers, which are referred to in the text
by their Roman numerals.
I Palm S*, Daoura L*, Roman E, Nylander I (2013) Effects of
rearing conditions on behaviour and endogenous opioids in rats
with alcohol access during adolescence. PLoS One
8(10):e76591.
II Palm S, Nylander I (2014) Dopamine release dynamics change
during adolescence and after voluntary alcohol intake. PLoS
One 9(5):e96337.
III Palm S, Nylander I (2014) Alcohol-induced changes in opioid
peptide levels in adolescent rats is dependent upon housing
conditions. Submitted manuscript.
IV Palm S*, Momeni S*, Lundberg S, Nylander I, Roman E (2014)
Risk-assessment and risk-taking behavior predict potassium-
and amphetamine-induced dopamine response in the dorsal stri-
atum of rats. Frontiers in Behavioral Neuroscience 8:236.
*Authors contributed equally.
Reprints were made with permission from the respective publishers.

Contents
Introduction ................................................................................................... 11
Alcohol ..................................................................................................... 11
Alcohol use disorders ........................................................................... 11
Alcohol consumption ........................................................................... 12
Adolescent alcohol consumption ......................................................... 13
Alcohol intake models in experimental animals .................................. 13
Early life environment .............................................................................. 15
Maternal separation .............................................................................. 16
Adolescence in rats .............................................................................. 18
Social environment .............................................................................. 19
Dopamine .................................................................................................. 19
Dopamine-releasing actions of alcohol ................................................ 21
Dopamine in alcohol use disorders ...................................................... 22
Ontogeny of dopamine systems in rats ................................................ 23
Effects of adolescent alcohol on dopamine ......................................... 24
Dopamine analysis ............................................................................... 25
Endogenous opioids .................................................................................. 27
Endogenous opioids in alcohol use disorders ...................................... 29
Ontogeny of endogenous opioid systems in rats .................................. 31
Effects of maternal separation on endogenous opioids ........................ 31
Effects of social environment on endogenous opioids ........................ 32
Opioid analysis ..................................................................................... 32
Risk taking and individual differences in abuse liability ......................... 33
Animal models of individual differences ............................................. 33
Behavioral tests .................................................................................... 34
Aims .............................................................................................................. 36
Methods ......................................................................................................... 37
Animals ..................................................................................................... 37
Maternal separation .................................................................................. 39
Behavioral tests ......................................................................................... 39
Open field ............................................................................................. 39
Multivariate concentric square field™ ................................................ 40
Behavioral recordings .......................................................................... 40
Voluntary alcohol consumption ................................................................ 40
High-speed chronoamperometry .............................................................. 42
Tissue dissection and peptide analysis ..................................................... 43
Statistical analyses .................................................................................... 44
Conventional analyses ......................................................................... 44
Trend analysis ...................................................................................... 45
Multivariate analysis ............................................................................ 45
Results and discussion ................................................................................... 46
Maternal separation .................................................................................. 46
Behavior ............................................................................................... 46
Alcohol ................................................................................................. 48
Endogenous opioids ............................................................................. 49
Adolescent alcohol intake ......................................................................... 50
Behavior ............................................................................................... 50
Dopamine ............................................................................................. 51
Endogenous opioids ............................................................................. 52
Social environment ................................................................................... 56
Alcohol ................................................................................................. 57
Endogenous opioids ............................................................................. 57
Age-dependent effects .............................................................................. 59
Alcohol ................................................................................................. 59
Dopamine ............................................................................................. 59
Endogenous opioids ............................................................................. 63
Behavioral phenotypes ............................................................................. 64
Behavior ............................................................................................... 64
Dopamine ............................................................................................. 65
Conclusions ................................................................................................... 69
Populärvetenskaplig sammanfattning ........................................................... 71
Acknowledgements ....................................................................................... 73
References ..................................................................................................... 76
Abbreviations
ACTH Adrenocorticotropic hormone
AFR Animal facility reared
AL Anterior lobe of the pituitary gland
Ala Alanine
AMPT Alpha-methyl-p-tyrosine
AMY Amygdala
ANOVA Analysis of variance
Arg Arginine
Asn Asparagine
Asp Aspartate
AUD Alcohol use disorder
BE Bridge entrance
BEND Beta-endorphin
C Center
cAMP Cyclic-adenosine monophosphate
CC Central circle
CLIP Corticotropin-like intermediate lobe peptide
CNS Central nervous system
CRF Corticotropin-releasing factor
D Duration
D/F Duration per frequency
DSM Diagnostic and Statistical Manual of Mental Disorders
DYNB Dynorphin B
DCR Dark corner room
F Frequency
FAST Fast analytical sensing technology
fMRI Functional magnetic resonance imaging
FSCV Fast-scan cyclic voltammetry
GABA Gamma-aminobutyric acid
Gln Glutamine
Glu Glutamate
Gly Glycine
HPA Hypothalamic-pituitary-adrenal
HR High responsive
HRT High risk taking
IC Inner circle
ICD International Statistical Classification of Diseases and
Related Health Problems
Ile Isoleucine
L Latency
Leu Leucine
LR Low responsive
LRT Low risk taking
LSD Least significant difference
Lys Lysine
MCSF Multivariate concentric square field™
MEAP Met-enkephalin-Arg6Phe7
Met Methionine
MS Maternal separation
MS15 Maternal separation 15 min
MS360 Maternal separation 360 min
MSH Melanocyte-stimulating hormone
NAc Nucleus accumbens
NMDA N-methyl-D-aspartate
OC Outer circle
OF Open field
PCA Principal component analysis
PET Positron emission tomography
Phe Phenylalanine
PIT Pituitary gland
PLS Partial least squares projections to latent structures
PND Postnatal day
Pro Proline
Ref Reference
SAP Stretch attend posture
s.c. Subcutaneous
Ser Serine
SHRP Stress hypo-responsive period
STR Striatum
T80 Time for the peak to decline 80% of its amplitude
Thr Threonine
TOTACT Total activity
TOTCORR Total corridor
Trp Tryptophan
Tyr Tyrosine
Val Valine
VMAT2 Vesicular monoamine transporter-2
V Maximum rate
max
VTA Ventral tegmental area
WHO World Health Organization