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

Abstract

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...

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

“…Thus the changes in GAL mRNA and methylation likely occur in nonserotonin cells. Interestingly, the up-regulation of GALR1 mRNA in the ventral periaqueductal gray is in agreement with two recent experimental studies on male rats that showed an increase in GALR1 mRNA levels (likely not in 5-HT neurons) after mild, blast-induced traumatic brain injury (84) and chronic mild stress (85). For a discussion of medullary raphe nuclei, see SI Discussion, Medullary Raphe Nuclei.…”

<p>Galanin Receptors as Drug Target for Novel Antidepressants: Review</p>

“…Galanin receptors (GALRs) belong to G-protein-couple receptor (GPCR) superfamily that consists of three subfamilies namely GalR1, GalR2 and GalR3. 21 All the three receptors are classified under rhodopsin like (class A) GPCRs, 17,22,23 alternatively named as seven trans membrane receptors or 7TM based on the notion that seven membrane spanning proteins are constituted in their general structure. 23 Their structure is composed of three intercellular loops (ICLs), an extracellular N-terminus, three intracellular loops and three extracellular loops (ECLs).…”

“…21 All the three receptors are classified under rhodopsin like (class A) GPCRs, 17,22,23 alternatively named as seven trans membrane receptors or 7TM based on the notion that seven membrane spanning proteins are constituted in their general structure. 23 Their structure is composed of three intercellular loops (ICLs), an extracellular N-terminus, three intracellular loops and three extracellular loops (ECLs). 21,24 The helix eight at the C-termini which is located parallel to the membrane is present in all models; 21 it is found in the structure of three receptors and acts as a conformational switch.…”

“…GAL's action on GalR1 in ventral periaqueductal gray area was associated with depressive like behavior, possibly representing a novel target for antidepressant therapy. 23 Moreover, it modulates the function of serotonin receptor (5-HT1AR) at autoreceptor and postsynaptic levels in the brain areas. 53,[55][56][57][58][59] As to previous studies, investigations were underway to confirm the mechanism through which receptors mediate signal transductions.…”

Disruption of Neurosynaptic Physiology and Neuron Network Dysfunction in Brain Disorders: An Environmental and Occupational Health Perspective

“…Animal models of disease make poor extrapolative sense. However, endophenotypic components of disease and their reactivity to exposure are scientifically more relevant to study [201]. Genotype-environmental exposure response can be examined on functional neuroimaging [202], neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, emotional or neuropsychological measures, as resultant phenotypes.…”