Effects of galanin receptor agonists on locus coeruleus neurons

Ma, Xiaosong; Tong, Yongliang; Schmidt, Ralf; Brown, W. A.; Payza, Kemal; Hodzic, Lejla; Pou, Chantévy; Godbout, Claude; Hökfelt, Tomas; Xu, Zhi‐Qing David

doi:10.1016/s0006-8993(01)03033-5

Cited by 82 publications

(68 citation statements)

References 21 publications

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“…Galanin is not normally expressed in dentate granule cells and mossy fibers (2,6,48). However, GalR2 mRNA has been detected in these as well as in locus ceruleus neurons (6,49,50), in both cases possibly constituting a presynaptic receptor (51), which normally may be the target for galanin released from noradrenergic fibers (3,6,27). We propose that galanin, overexpressed in mossy fibers, is released during epileptic discharges and interacts with presynaptic GalR2 receptors on the mossy fibers themselves.…”

Section: Resultsmentioning

confidence: 86%

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Kokaia

Holmberg

Nanobashvili

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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103

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The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the plateletderived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.G alanin, a 29-aa neuropeptide (1), is widely distributed throughout the rat brain (2, 3) and coexists with classic transmitters in several systems (4), with particularly high levels in noradrenergic locus coeruleus neurons (5, 6). Galanin-binding sites have been mapped (7,8), and three receptor subtypes, GalR1 (9-11), 49), and GalR3 (15), have been cloned. There is evidence for involvement of galanin in multiple neuronal functions (16,17), as also revealed in recent studies on transgenic mice (18)(19)(20).Many studies support an important role of neuropeptides in seizure activity (21)(22)(23). This role is true also for galanin. Thus, intrahippocampal injection of galanin during status epilepticus (SE) in rats has powerful anticonvulsant effects (24). In accordance with these data, mice overexpressing the galanin gene under the dopamine-␤-hydroxylase promoter, presumably in noradrenergic fibers, show increased resistance to SE and kainate-and pentylenetetrazol-evoked seizures (25). Conversely, administration of galanin antagonists, such as M35 (26), and targeted disruption of the galanin gene increase seizure susceptibility in these models (24,25). Taken together, available data indicate that galanin released from noradrenergic fibers (3, 5, 27) can suppress epileptic seizures. Although the underlying mechanisms are not known, it has been shown that galanin can inhibit glutamate release by means of activation of presynaptic ATP-dependent K ϩ channels (28).We speculated that galanin release from neurons not normally containing this neuropeptide, e.g., in the epileptic focus, might be necessary to optimize the seizure-suppressant action of galanin. To explore the functional conseque...

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Section: Resultsmentioning

confidence: 86%

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Kokaia

Holmberg

Nanobashvili

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

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“…This finding is critical, since it suggests that the effects of galanin differ under basal (Counts et al, 2002) and stressful conditions. 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.…”

Section: Integrative Mechanism Of Galanininergic Regulation Of Depresmentioning

confidence: 99%

“…In the 5-HT neurons, however, the GalR2 receptor may be present and functional at the cell body level (Mazarati et al, 2005), in contrast to the LC (Ma et al, 2001). This receptor subtype could transmit an excitatory action of galanin, which is mediated via the phospholipase C pathway (see Branchek et al, 2000), as well as by inhibition of the G-protein coupled inwardly rectifying potassium (GIRK) channels (Kerekes et al, 2003).…”

Section: Integrative Mechanism Of Galanininergic Regulation Of Depresmentioning

confidence: 99%

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

Kuteeva

Wardi

Lundström

et al. 2008

Neuropsychopharmacol

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The present study on rat examined the role of galanin receptor subtypes in regulation of depression-like behavior as well as potential molecular mechanisms involved in the locus coeruleus (LC) and dorsal raphe (DR). The effect of intracerebroventricular (i.c.v.) infusion of galanin or galanin receptor GalR1-and GalR2-selective ligands was studied in the forced swim test, followed by quantitative in situ hybridization studies. Naive control, non-treated (swim control), saline-and fluoxetine-treated rats were used as controls in the behavioral and in situ hybridization studies. Subchronic treatment with fluoxetine reduced immobility and climbing time. Intracerebroventricular infusion of galanin, the GalR1 agonist M617 or the GalR2 antagonist M871 increased, while the GalR2(R3) agonist AR-M1896 decreased, immobility time compared to the aCSF-treated animals. Galanin also decreased the time of climbing. Galanin mRNA levels were upregulated by the combination of injection + swim stress in the saline-and the fluoxetine-treated groups in the LC, but not in the DR. Also tyrosine hydroxylase levels in the LC were increased following injection + swim stress in the saline-and fluoxetine-treated rats. Tryptophan hydroxylase 2 and serotonin transporter mRNAs were not significantly affected by any treatment. 5-HT 1A mRNA levels were downregulated following i.c.v. galanin, M617 or AR-M1896 infusion. These results indicate a differential role of galanin receptor subtypes in depression-like behavior in rodents: GalR1 subtype may mediate 'prodepressive' and GalR2 'antidepressant' effects of galanin. Galanin has a role in behavioral adaptation to stressful events involving changes of molecules important for noradrenaline and/or serotonin transmission.

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“…In the rat, GalR2 receptors are expressed in LC neurons (42), but local application of a selective GalR2 agonist has no membrane effects on LC neurons (49), suggesting that the GalR2 is presynaptic. GalR2 is known to activate phospholipase C (50), increasing Ca 2ϩ influx and possibly enhancing transmitter release.…”

Section: Discussionmentioning

confidence: 99%

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

Yoshitake

Wang

Kuteeva

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Effects of galanin receptor agonists on locus coeruleus neurons

Cited by 82 publications

References 21 publications

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

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

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

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