Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior

Holmes, Andrew; Li, Qian; Koenig, Elizabeth; Gold, Eric N.; Stephenson, Dejaimenay; Yang, Rebecca; Dreiling, Jennifer L.; Sullivan, Tim R.; Crawley, Jacqueline N.

doi:10.1007/s00213-004-1997-1

Cited by 41 publications

(26 citation statements)

References 44 publications

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“…However, studies on mice with genetically deleted Galr1 (Galr1-KO) showed no effect in the tail suspension test, pharmacological manipulations did not alter the depression profile (65), and such mice showed increased anxiety-like behavior in the elevated plus-maze (66). It should be noted that the 5-HT neurons in the mouse DR, in contrast to the rat DR, do not express galanin (67)(68)(69)(70) and that the KO mice, of course, lack this receptor throughout life and in all parts of the brain (body).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Barde

et al. 2016

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

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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...

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Section: Discussionmentioning

confidence: 99%

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

Wang

Barde

et al. 2016

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

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“…In total, 83 unique genes were upregulated and 17 genes were downregulated by chronic fluoxetine treatment (Table 2, Supplementary Table S1). Most highly upregulated were Preproenkephalin 1, a possible quantitative trait gene for bipolar disorder (Ogden et al, 2004), and Galanin, antagonists of which prevent the behavioral effect of fluoxetine in the TST and the FST (Holmes et al, 2005;Swanson et al, 2005).…”

Section: Effect Of Chronic Fluoxetine Treatment On Hippocampal Gene Ementioning

confidence: 99%

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

Miller

Schultz

Gulati

et al. 2007

Neuropsychopharmacol

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Despite widespread use of antidepressants, the factors underlying the behavioral response to antidepressants are unknown. It has been shown that antidepressant treatment promotes the proliferation and survival of neurons in the adult hippocampus via enhanced serotonergic signaling, but it is unclear whether hippocampal neurogenesis is responsible for the behavioral response to antidepressants. Furthermore, a large subpopulation of patients fails to respond to antidepressant treatment due to presumed underlying genetic factors. In the present study, we have used the phenotypic and genotypic variability of inbred mouse strains to show that there is a genetic component to both the behavioral and neuronal effects of chronic fluoxetine treatment, and that this antidepressant induces an increase in hippocampal cell proliferation only in the strains that also show a positive behavioral response to treatment. Furthermore, the behavioral and neuronal responses are associated with an upregulation of genes known to promote neuronal proliferation and survival. These results suggest that inherent genetic predisposition to increased serotonin-induced neurogenesis may be a determinant of antidepressant efficacy.

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“…[117,118] This is also supported by the phenotypic analysis of anxietyand depression-related behaviours in genetically GALR-modified mice strains. [119][120][121][122][123] Taken together, these preclinical data suggest that GALRs could serve as targets of antidepressant therapy, using either GALR1/GALR3 antagonists or GALR2 agonists. GALR3 antagonists (figure 5) are being tested in clinical trials for the treatment of depression and patents have already been issued on their use for MDD treatment.…”

Section: Galanin Receptorsmentioning

confidence: 87%

Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

2009

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Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.

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Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior

Cited by 41 publications

References 44 publications

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

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

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

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