Enhanced hippocampal noradrenaline and serotonin release in galanin-overexpressing mice after repeated forced swimming test

Abstract

Basal and forced swimming (FS) stress-induced release of noradrenaline (NA) and serotonin (5-HT) were determined by in vivo microdialysis in the ventral hippocampus of mice overexpressing galanin under the platelet-derived growth factor B promoter (GalOE͞P) or under the dopamine ␤-hydroxylase promoter (GalOE͞D) (only NA). WT mice served as controls. Intraventricular infusion of galanin significantly reduced basal extracellular NA in WT mice and in GalOE͞P mice (albeit less so). Microdialysis sampling during a 10-min FS showed that NA and 5-HT release were elevated to 213% and 156%, respectively, in the GalOE͞P group, whereas in the WT group the increases were only 127% and 119%, respectively. The second (repeated) 10-min FS (RFS) caused a marked enhancement of NA and 5-HT release in the GalOE͞P mice to 344% and 275%, respectively. However, the RFS caused only a 192% increase of extracellular NA levels in the GalOE͞D mice. Pretreatment with the putative peptidergic galanin receptor antagonist M35 almost completely blocked the elevation of NA and 5-HT levels in the GalOE͞P after RFS. These results suggest that the NA and 5-HT hippocampal afferents in GalOE͞P mice are hypersensitive to both conditioned and unconditioned stressful stimuli, such as FS, and that this effect is mediated by galanin receptors. The present findings support a role of galanin in the regulation of release of NA and 5-HT, two neurotransmitters involved in mood control.microdialysis ͉ 5-hydroxytryptamine ͉ transgenic mice ͉ hippocampus ͉ affective disorders G alanin, a 29-aa (30 in human) neuropeptide (1), is widely distributed throughout the central nervous system (2, 3), where it coexists with several classic neurotransmitters (4). A similarly widespread distribution of galanin-like immunoreactivity (LI) in neurons and fibers was observed in the brain of the mouse (5). Three galanin receptor subtypes (GalR1-GalR3) have been cloned (see refs. 6 and 7), all belonging to the 7-transmembrane, G protein-coupled receptor superfamily. Both the noradrenaline (NA) neurons of locus coeruleus (LC) and the 5-hydroxytryptamine (5-HT) neurons of the dorsal raphe nucleus (DRN) (8) can synthesize galanin (4, 9-11). In the rat brain, galanin-LI can be observed in the terminal ramifications of the NA nerve terminals in cortical͞hippocampal areas (11). However, it has been more difficult to demonstrate galanin-LI in 5-HT terminals, suggesting a higher galanin expression in the NA than in the 5-HT system.Recently, mice with a targeted disruption of the galanin gene (12), or overexpressing galanin under the dopamine ␤-hydroxylase (D␤H) promoter (GalOE͞D) (13, † †) or the plateletderived growth factor B promoter (GalOE͞P) (14, ‡ ‡), have been generated and characterized with regard to several functional parameters (see refs. 15 and 16).In vivo microdialysis studies on rats have suggested that galanin plays an important role in modulation of 5-HT (17) and NA (18) neurotransmission, supporting a possible role of galanin in mood control, anxiety, and stress response...

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…Under basal conditions, galanin has been shown to reduce LC neuronal activity (Pieribone et al, 1995) and NA release (see above), probably via stimulation of the GalR1(R3) receptors (Ma et al, 2001). Under stressful conditions, galanin would probably increase the stress-reactivity of the LC NA system (Yoshitake et al, 2004;Kuteeva et al, 2005) and/or exert a direct postsynaptic effect in the LC projection areas, further contributing to depression-like behavioral changes (Weiss et al, 1998(Weiss et al, , 2005.…”

“…A number of behavioral studies suggested a potential role of galanin in depression-like behavior in rodents (see Fuxe et al, 1998;Weiss et al, 1998Weiss et al, , 2005Yoshitake et al, 2004;Kuteeva et al, 2005Kuteeva et al, , 2007Lu et al, 2005aLu et al, , 2007Swanson et al, 2005;Barr et al, 2006;Karlsson and Holmes, 2006;Ö gren et al, 2006). Bilateral infusion of galanin into the ventral tegmental area (VTA) (Weiss et al, 1998), or intracerebroventricular (i.c.v.)…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…A large literature also demonstrates that extracellular fluid concentrations (ECF) of serotonin are increased in both the vicinity of the DRN and the corticolimbic targets of the serotonin system, including the mPFC, amygdala and hippocampus. The stressors shown to cause this increase in ECF, which is almost certainly due to increased serotonin release, range from exposure to a predator, tail pinch, elevated platform exposure, inescapable shock, social defeat, to restraint/immobilization (Adell et al, 1997;Amat et al, 2001;Bland et al, 2003;Funada and Hara, 2001;Grahn et al, 1999;Hajos-Korcsok et al, 2003;Jordan et al, 1994;Kang et al, 2005;Kawahara et al, 1993;Keck et al, 2005;Keeney et al, 2006;Kehr et al, 2001;Kirby et al, 1995Kirby et al, , 1997Kirby and Lucki, 1998;Maswood et al, 1998;Miyata et al, 2007;Mokler et al, 2007;Petty et al, 1994;Price et al, 2002;Renard et al, 2003;Rex et al, 2005;Rueter and Jacobs, 1996;Storey et al, 2006;Takahashi et al, 2000;Thorre et al, 1997;Yoshioka et al, 1995;Yoshitake et al, 2004). It is important to note however that not all studies have found increases in forebrain ECF serotonin in response to stress and there are actually some reports of stress-induced decreases (e.g., Kirby et al, 1997;Rueter and Jacobs, 1996).…”

GAL 3 receptor KO mice exhibit an anxiety-like phenotype

“…route or into the dopaminergic ventral tegmental area induced depression-like behavior in the rat forced swim test (FST) (5,6). Several studies in GAL-overexpressing transgenic mice reported an increased depression-like behavior in the FST (7,8) but found no differences in anxiety-related behavior under baseline conditions (7,9). Holmes et al (9) suggested, however, that GAL might have protective effects during periods of elevated stress, because GAL overexpression counteracted anxiogenic effects evoked by noradrenergic stimulation.…”