One for all or one for one: does co-transmission unify the concept of a brain galanin “system” or clarify any consistent role in anxiety?

The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects.dorsal raphe | neuropeptide | siRNA | stress | transmitter coexistence T he indoleamine hypothesis of depression was formulated some five decades ago (1, 2), in parallel with the catecholamine hypothesis (3, 4), and has been supported by the success of selective serotonin reuptake inhibitors (SSRIs) for treatment of major depression (MD) (5). However, in a considerable number of cases, SSRIs are associated with side effects or lack of efficacy. For example, after treatment with SSRIs, only one-third of patients obtain full remission of symptoms (6). Therefore, there is an ongoing search for new medications targeting mood disorders, such as MD and anxiety. Here, neuropeptides and their receptors, the most diverse family of neurotransmitters in the brain (7), have been extensively explored (5,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), including galanin and its three receptors.Galanin is a 29-aa (30-aa in humans) neuropeptide (18) with a wide distribution in the rat brain (19,20), where it is coexpressed with noradrenaline/norepinephrine (NA) in locus coeruleus (LC) neurons and with 5-hydroxytryptamine (5-HT) in dorsal raphe nucleus (DR) neurons (21-25). There are three galanin receptors, GALR1-GALR3, which all belong to the family of seven transmembrane-spanning, G protein-coupled receptors (26-29). They are found in many areas of the rat brain, as first shown with autoradiographic ligand-binding methodology (30, 31), and later with in situ hybridization (ISH)/quantitative real-time PCR (qPCR) (32-36). The galanin system has been associated with numerous physiological and pathophysiological functions (29), including depression-and anxiety-like behaviors.There is early evidence from studies on the rat that central administration of galanin influences mood-related behavior in a region-specific way (37, 38), and also that galanin is prodepres...

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

Wang

Barde

et al. 2016

“…GAL itself has been reported to induce anxiolytic, anxiogenic, or no responses depending on several factors, such as the site of administration, behavioral paradigm used, and species tested (26). Anxiogenic-like actions of GAL were induced in the punished drinking test following microinjections of the peptide into the rat amygdala (27).…”

Section: Discussionmentioning

confidence: 99%

GAL ₃ receptor KO mice exhibit an anxiety-like phenotype

Brunner¹,

Farzi

Locker³

et al. 2014

The neuropeptide galanin (GAL) is widely distributed in the central and peripheral nervous systems. It is a modulator of various physiological and pathological processes, and it mediates its effects via three G protein-coupled receptors (GAL 1-3 receptors). A role for GAL as a modulator of mood and anxiety was suggested, because GAL and its receptors are highly expressed in limbic brain structures of rodents. In recent years, numerous studies of animal models have suggested an involvement of GAL and GAL 1 and GAL 2 receptors in anxiety-and depression-related behavior. However, to date, there is sparse literature implicating GAL 3 receptors in behavioral functions. Therefore, we studied the behavior of GAL 3 receptor-deficient (GAL 3 -KO) mice to elucidate whether GAL 3 receptors are involved in mediating behavior-associated actions of GAL. The GAL 3 -KO mouse line exhibited normal breeding and physical development. In addition to behavioral tests, phenotypic characterization included analysis of hematology, amino acid profiles, metabolism, and sudomotor function. In contrast to WT littermates, male GAL 3 -KO mice exhibited an anxietylike phenotype in the elevated plus maze, open field, and light/ dark box tests, and they were less socially affiliated than WT animals to a stranger mouse in a social interaction test. In conclusion, our data suggest involvement of GAL 3 receptors in GAL-mediated effects on mood, anxiety, and behavior, making it a possible target for alternative treatment strategies for mood disorders.T hirty years ago, Tatemoto et al. (1) isolated the neuropeptide galanin (GAL), a 29-aa (30-aa in humans) peptide, from porcine intestine. The peptide is highly conserved throughout evolution and found in many other species. GAL is widely distributed in the CNS and peripheral nervous system, and it has a variety of biological and physiological functions, ranging from energy homeostasis, reproduction, and feeding to cognition and learning (2). In the murine brain, GAL mRNA is extensively expressed in the hypothalamic and brainstem areas. The highest expression levels were observed in the preoptic, periventricular, and dorsomedial hypothalamic nuclei; bed nucleus of the stria terminalis (BNST); medial and lateral amygdala; locus coeruleus; and nucleus of the solitary tract (3). Furthermore, GAL coexists with the serotonin and norepinephrine systems in the rodent brain and acts as an inhibitory neuromodulator of norepinephrine, serotonin, dopamine, glutamate, and acetylcholine function (4). The expression pattern and neuromodulatory functions of GAL suggest a role for this neuropeptide in mood disorders like anxiety and depression. Accordingly, administration of GAL via the intracerebroventricular (i.c.v.) 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 und...

“…It has been proposed, based on animal experiments over the last few decades, that neuropeptide also receptors are putative targets for development of antidepressants, including receptors for substance P, neuropeptide tyrosine, corticotropin-releasing factor/ corticotropin-releasing hormone, melanocyte-concentrating hormone, vasopressin, and dynorphin (138)(139)(140)(141)(142)(143), as well as the galanin system. Thus, galanin interacts with 5-HT1A receptors, and galanin antagonists and agonists have anxiolytic and antidepressive effects in animal experiments (144)(145)(146)(147)(148)(149)(150)(151). Interestingly, association of genes encoding galanin and/or GalR3 has been reported for psychiatric phenotypes (152)(153)(154), including panic disorder (155), depression-related parameters (156)(157)(158), and nicotine dependence (159,160).…”

Section: Significancementioning

confidence: 99%

Distinct features of neurotransmitter systems in the human brain with focus on the galanin system in locus coeruleus and dorsal raphe

Maître

Barde

Palkovits

et al. 2013

Using riboprobe in situ hybridization, we studied the localization of the transcripts for the neuropeptide galanin and its receptors (GalR1-R3), tryptophan hydroxylase 2, tyrosine hydroxylase, and nitric oxide synthase as well as the three vesicular glutamate transporters (VGLUT 1-3) in the locus coeruleus (LC) and the dorsal raphe nucleus (DRN) regions of postmortem human brains. Quantitative real-time PCR (qPCR) was used also. Galanin and GalR3 mRNA were found in many noradrenergic LC neurons, and GalR3 overlapped with serotonin neurons in the DRN. The qPCR analysis at the LC level ranked the transcripts in the following order in the LC: galanin >> GalR3 >> GalR1 > GalR2; in the DRN the ranking was galanin >> GalR3 >> GalR1 = GalR2. In forebrain regions the ranking was GalR1 > galanin > GalR2. VGLUT1 and -2 were strongly expressed in the pontine nuclei but could not be detected in LC or serotonin neurons. VGLUT2 transcripts were found in very small, nonpigmented cells in the LC and in the lateral and dorsal aspects of the periaqueductal central gray. Nitric oxide synthase was not detected in serotonin neurons. These findings show distinct differences between the human brain and rodents, especially rat, in the distribution of the galanin system and some other transmitter systems. For example, GalR3 seems to be the important galanin receptor in both the human LC and DRN versus GalR1 and -2 in the rodent brain. Such knowledge may be important when considering therapeutic principles and drug development.he locus coeruleus (LC) and the dorsal raphe nucleus (DRN)/raphe median nucleus (MRN) have been the focus of clinical and preclinical monoamine research for almost half a century. Using the formaldehyde fluorescence (Falck-Hillarp) method (1), Dahlström and Fuxe (2) originally described these nuclei in the rat as containing noradrenaline (NA) (the A6 group) and 5-hydroxytryptamine (5-HT; serotonin) (the B7/8 groups), respectively. The LC harbors 2,800-3,600 neurons with an additional 260 neurons in the subcoeruleus area, the great majority of which are noradrenergic (3-6).The DRN forms a rostro-caudal, ventral midline column and is part of the periaqueductal central gray (PAG) (7) with a large number of 5-HT neurons that can be subdivided into several subgroups (2,(8)(9)(10)(11). Both the NA-LC (5, 6, 12) and the 5HT-DRN (8-11, 13) neurons have wide projections to most forebrain areas.In humans the LC is a compact, blue-pigmented nucleus consisting of a total of ∼50,000 neurons (both sides), almost all of which are noradrenergic (14-16). The DRN comprises about 165,000 5-HT neurons, which constitute around 70% of all DRN neurons (17). Thus, there are numerous nonserotonergic neurons in the human DRN, as is also the case in other species, including the mouse (18,19).It now is well established that most neurons synthesize and release several types of messenger molecules in the process known as "cotransmission" (20-26). For example, in the rat some serotonergic DRN neurons synthesize nitric oxide (NO), visualized as N...