Brain galanin sytems and their role in depression-like behaviour

Abstract: The aim of the present thesis was to investigate the role of the neuropeptide galanin and galanin receptor subtypes in behavioural functions with a particular focus on depression-like behaviour. In agreement with its wide distribution in the central nervous system, galanin has been implicated in various functions, including regulation of reproduction, endocrine functions, antinociception, attention, learning and memory as well as regulation of mood. Under normal circumstances the levels of galanin expression in several neuronal systems, including dorsal root ganglia, hippocampus and cerebral cortex, are low. However, they may be markedly upregulated following, for example, lesions and/or colchicine treatment. Moreover, in Alzheimer s disease, galanin levels are elevated in the cerebral cortex, hippocampus and basal forebrain. To further analyse the functional roles of galanin in the central and peripheral nervous systems, mice overexpressing galanin (GalOE) under the platelet-derived growth factor B (PDGF-B) promoter were generated and characterised both morphologically and behaviourally. In GalOE mice, a large proportion of sympathetic and sensory ganglia neurons as well as spinal motor neurons were galanin-positive. Expression of galanin in the brain of GalOE mice was more abundant than in wild type controls. A particularly high expression was observed in the olfactory bulb, cerebral cortex, hippocampus and some motor brainstem nuclei. GalOE mice showed an attenuated plasma extravasation in response to mustard oil, an increase in pain response in the formalin test, and changes in muscle physiology. This suggests that overexpressed galanin can be released and influence physiological processes via a receptor-mediated action. Young adult GalOE mice showed a slight increase in the spontaneous locomotor activity, but a decreased response to D-amphetamine treatment. Anxiety-like behaviour as well as spatial and emotional learning and memory were not affected in the GalOE mice. However, GalOE mice displayed an increased time of immobility in the forced swim test, suggesting that an increase in galanin levels may lead to a higher stress-susceptibility evidenced by the development of depression-like behaviour. In support, GalOE mice displayed a significantly higher increase of hippocampal noradrenaline and serotonin release in response to repeated forced swimming as measured by in vivo microdialysis, suggesting that hippocampal afferents of GalOE mice are hypersensitive to stressful stimuli. Intracerebroventricular infusion of galanin to rats resulted in an increased time of immobility in the forced swim test, indicative of depression-like behaviour. This effect was blocked by co-administration of the galanin antagonist M35, while M35 alone caused a decrease of immobility time. These results indicate a potential involvement of galanin in depression-like behaviour and suggest that galanin antagonists may have antidepressant properties. Intracerebroventricular infusion of the galanin receptor GalR1 agonist M617 significantly increased immobility time, similar to galanin itself. In contrast, the GalR2 agonist M1896 decreased, while the GalR2 antagonist M871 increased, time of immobility. These results indicate that galanin receptor subtypes have a differential role in modulation of depression-like behaviour. Galanin may mediate its pro-depressive action via GalR1 subtype, while GalR2 may mediate the putative antidepressant action of galanin. In situ hybridisation studies, performed following exposure to swim stress and galaninergic ligands infusion, showed that the combination of injection and swim stress upregulated tyrosine hydroxylase and galanin mRNA expression in the locus coeruleus, but not tryptophan hydroxylase 2 and galanin mRNA expression in the dorsal raphe. In contrast, following intracerebroventricular galanin infusion, galanin mRNA levels were upregulated both in the locus coeruleus and the dorsal raphe. The levels of the 5-HT1A receptor mRNA were reduced in the dorsal raphe following galanin infusion, and both in the dorsal and median raphe following infusion of the GalR2 agonist M1896. In contrast, serotonin transporter mRNA levels were not affected by any treatment. In summary, these results give evidence for an important role of the neuropeptide galanin in regulation of depressionlike behaviour in rodents. Physiological mechanisms underlying the action of galanin are probably mediated via alterations in neuronal activity of the locus coeruleus and the raphe nuclei, as indicated by changes in gene expression of neuronal markers relevant for noradrenaline, serotonin and galanin transmission. Galanin mechanisms may thus be relevant for mood disorders and galanin ligands may be useful in antidepressant therapy.