Galanin receptor subtypes in rodent models of mood disorders

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.