Institutionen för neurovetenskap / Department of Neuroscience
Abstract
Major depressive disorder (MDD) is a serious mental illness, with a
complex etiology. It is a multifactorial disorder caused by a combination
of genetic, environmental and epigenetic factors. Exposure to stressful
life events seems to be a common, contributing cause of morbidity.
Discoveries during the last 60 years have provided increasing evidence
for a dysfunctional serotonergic and/or noradrenergic neurotransmission
in MDD. However, other transmitter systems also appear to be involved,
e.g. GABAergic, glutamatergic and cholinergic systems, as well as several
neuropeptide systems. Since its discovery in the 1980s at Karolinska
Institutet, the neuropeptide galanin has been implicated in a diversity
of physiological processes including not only feeding and nociception,
but also anxiety and stress.
The main aim of this thesis was to investigate the role of galanin and
galanin receptors in rodent models of mood disorders, and to evaluate the
possible interaction between exposure to stress and galanin receptor
subtype stimulation by measuring the expression of neuronal chemical
markers of relevance for depression in serotonin/5-hydroxytryptamine
(5-HT) and noradrenaline (NA) neurons. Several behavioral tests were
employed including the forced swim test. The validity of this test was
examined by the use of the 5-HT selective reuptake inhibitor fluoxetine,
a widely used antidepressant. Galanin, given intracerebroventricularly
(i.c.v.) to rats, increased immobility time in the forced swim test
indicative of depression-like behavior. Co-infusion of the unspecific
galanin receptor antagonist M35 blocked the effect of galanin.
Importantly, M35 alone decreased immobility time. The galanin receptor 1
(GalR1) agonist M617 and the galanin receptor 2 (GalR2) antagonist M871
both increased immobility time in the FST, whereas, the GalR2 agonist
M1896 caused a decrease.
In situ hybridization studies performed after infusion of galanin
(i.c.v.) and exposure to swim stress showed elevated levels of galanin
mRNA in the locus coeruleus versus control animals. However, a
significant increase of galanin mRNA levels was also observed in the
locus coeruleus in saline- and fluoxetine-treated animals indicating that
the stress of injection is adding to the stress of swimming. In contrast,
in the dorsal raphe nucleus, the swim/injection procedure did not change
the mRNA levels of galanin or tryptophan hydroxylase, indicating that
5-HT neurons are not as sensitive as the NA neurons in locus coeruleus to
stress. The levels of 5-HT1A receptor mRNA were reduced in the dorsal
raphe nucleus following galanin or the GalR2 agonist M1896 infusion.
These results support an involvement of brain galanin systems in
depression-like behavior in rodents, and galanin receptor subtypes appear
to play differential roles in modulation of depression-like behavior. The
action of galanin and galanin receptor ligands seems to modulate
depression-like behavior in rodents partly via changes in expression of
certain monoaminergic molecules relevant for depression.
To further analyze the functional role of GalR2 in rodent models of
depression, mice overexpressing this receptor (GalR2OE mice) under the
platelet-derived growth factor B promoter were generated. These mice
displayed decreased immobility time in the FST compared to the wild-type
controls indicative of antidepressant-like behavior. However,
anxiety-like behavior, emotional memory and locomotor activity measures
did not differ between the genotypes. Overexpression of the GalR2
transcripts and receptor protein was detected in limbic areas such as
subregions of the medial prefrontal cortex and subiculum. Thus, GalR2 in
these areas may contribute to the depression-like behavior observed in
these mice.
The present thesis gives evidence for a role of the neuropeptide galanin
and its receptors in rodent models of depression-like behavior and
suggests that GalR1 antagonists, and GalR2 agonists may represent new
candidates for the development of drugs for treatment of mood disorders