Relaxin-3 systems in the brain—The first 10 years

Smith, Craig; Ryan, Phil; Hosken, Ihaia T.; Ma, Sherie; Gundlach, Andrew L.

doi:10.1016/j.jchemneu.2011.05.013

Cited by 97 publications

(99 citation statements)

References 104 publications

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“…Furthermore, our studies have revealed that the modulation of anxiety-like behaviours via RXFP3 occurs in both rats and mice, suggesting this action is conserved and that both species are suitable for the investigation of relaxin-3/RXFP3 targeted therapeutics for anxiety disorders in humans. However, due to the extensive nature of this peptidergic system [18,20,36] Table 1 …”

Section: Resultsmentioning

confidence: 99%

“…The largest population of relaxin-3 expressing neurons is located within the tegmental area known as the nucleus incertus (NI), and these neurons project broadly throughout the brain [15][16][17][18][19]. The neuroanatomy of the relaxin-3/RXFP3 system suggests a broad role as an ascending neuromodulatory network [20,21], akin to the monoamine systems including serotonin, and noradrenaline [22][23][24][25]. Anatomical and functional data [15][16][17][18] suggest that relaxin-3/RXFP3 systems may interact directly with monoamine [19,26] and other peptide systems [27][28][29], and/or act at shared downstream limbic and hypothalamic target areas to modulate 'anxiety' and other stress-related responses [30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

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Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Zhang

Chua

Yang

et al. 2015

Behavioural Brain Research

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Zhang

Chua

Yang

et al. 2015

Behavioural Brain Research

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“…Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11)(12)(13)(14)(15)(16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels of RXFP3 (11,15,(17)(18)(19)(20)(21)(22).…”

Section: Addiction | Dependencementioning

confidence: 99%

Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

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

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114

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Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased selfadministration of alcohol in a dose-related manner and attenuated cue-and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/ RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of rewardseeking. addiction | dependenceA lcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed "alcohol addiction") (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6-8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7-10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11-16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels ...

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“…Accordingly, expression of relaxin and RXFP1 is widely distributed in the central and peripheral tissues including the brain, heart, skin, liver, ovaries, and testes [26] . Conversely, the expression of relaxin-3 and its cognate receptor RXFP3 is almost exclusively confined to the brain [24,25,34,[43][44][45] .…”

Section: Relaxin Family Peptides and Elaxin Family Peptides And Its Rmentioning

confidence: 99%

“…Histochemistry, in situ hybridization, and autoradiography have shown that distribution of RXFP3 mRNA largely overlaps the binding sites of relaxin-3 and distribution of relaxin-3-positive axonal terminals [44][45][46][47] . Thus, the density of relaxin-3 fibers as well as RXFP3 mRNA and binding sites is high in the brainstem and hypothalamic regions such as the nucleus of the solitary tract (NTS), NI,PVN, SON, the periventricular and lateral hypothalamic areas as well as in the septum, hippocampus, central and medial amygdala, and paraventricular thalamic nucleus (PVT) [43] . This large brain distribution of the relaxin-3/RXFP3 system suggests multiple functional implications for relaxin-3.…”

Section: Expression Of Relaxin-3 and Rxfp3 In The Brainmentioning

confidence: 99%

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Lenglos

Calvez

Timofeeva

2014

Receptor Clin Invest

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Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it development in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in thead libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitumfed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype.

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Relaxin-3 systems in the brain—The first 10 years

Cited by 97 publications

References 104 publications

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Relaxin-3/RXFP3 system regulates alcohol-seeking

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

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