Neuropeptide S reduces mouse aggressiveness in the resident/intruder test through selective activation of the neuropeptide S receptor

Ruzza, Chiara; Asth, Laila; Guerrini, Remo; Trapella, Claudio; Gavioli, Elaine C.

doi:10.1016/j.neuropharm.2015.05.002

Cited by 15 publications

(10 citation statements)

References 32 publications

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“…In addition to robust anxiolytic actions, NPS and OXT share various other behavioral and physiological effects, such as the reversal of social fear (Zoicas et al, 2014;Zoicas et al, 2016), the attenuation of aggressive-like behavior (Beiderbeck et al, 2014;de Jong et al, 2014;Ruzza et al, 2015), as well as anorexic (Olson et al, 1991;Beck et al, 2005;Smith et al, 2006) and antinociceptive effects (Li et al, 2009;Eliava et al, 2016). Moreover, both NPS and OXT neurons are responsive to acute stress (Neumann, 2007;Ebner et al, 2011;Jüngling et al, 2012;Torner et al, 2017) and have the capacity to regulate the physiological activity of the hypothalamo-pituitary-adrenal axis (Neumann et al, 2006;Smith et al, 2006;Jurek et al, 2015;Torner et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis

Grund

Goyon

et al. 2017

J. Neurosci.

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Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus. Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.

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Section: Introductionmentioning

confidence: 99%

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis

Grund

Goyon

et al. 2017

J. Neurosci.

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“…The binding initiates a second-message cascade unique for each receptor and results in a distinct molecular response (Hökfelt et al, 2003). It has been revealed that neuropeptides can induce plasticity in a series of behavioral processes, including sensory detection (Shankar et al, 2015), signal integration (Grammatopoulos, 2012), and behavioral responsiveness (Ruzza et al, 2015) by acting either individually or in concert with other neuromodulators (Dölen et al, 2011; Flores et al, 2015; Maroun and Wagner, 2016). Therefore, neuropeptides and their downstream components may act as vital parts of the regulatory network underlying behavioral plasticity in swarming animals.…”

Section: Introductionmentioning

confidence: 99%

The neuropeptide F/nitric oxide pathway is essential for shaping locomotor plasticity underlying locust phase transition

Yang

Jiang

et al. 2017

eLife

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Behavioral plasticity is widespread in swarming animals, but little is known about its underlying neural and molecular mechanisms. Here, we report that a neuropeptide F (NPF)/nitric oxide (NO) pathway plays a critical role in the locomotor plasticity of swarming migratory locusts. The transcripts encoding two related neuropeptides, NPF1a and NPF2, show reduced levels during crowding, and the transcript levels of NPF1a and NPF2 receptors significantly increase during locust isolation. Both NPF1a and NPF2 have suppressive effects on phase-related locomotor activity. A key downstream mediator for both NPFs is nitric oxide synthase (NOS), which regulates phase-related locomotor activity by controlling NO synthesis in the locust brain. Mechanistically, NPF1a and NPF2 modify NOS activity by separately suppressing its phosphorylation and by lowering its transcript level, effects that are mediated by their respective receptors. Our results uncover a hierarchical neurochemical mechanism underlying behavioral plasticity in the swarming locust and provide insights into the NPF/NO axis.DOI: http://dx.doi.org/10.7554/eLife.22526.001

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“…In particular, we introduced side chains containing thiourea ( 12 ), N-substituted acetamide ( 13 , 14 ) and guanidine ( 15 , 16 ) functions. In this subset of molecules, compounds 13–16 have been specifically designed to modulate the hydrophilic/lipophilic balance of 1 , which might be important for its in vivo effectiveness as suggested in different studies. , In particular, it has been demonstrated that 1 , at the high dose of 50 mg/kg, can only partially counteract NPS effects, with different levels of efficacy, depending on the assay used. − These findings have been hypothetically attributed to suboptimal physicochemical properties of the compound, in particular, its high lipophilicity . Thus, in a first attempt to overcome these limits, the acetamide derivatives 13 and 14 have been synthesized as possible bioisosteres of 1 in which a methylene spacer was interposed between the piperazine nitrogen and the carbonyl function of the 7-side chain.…”

Section: Resultsmentioning

confidence: 99%

“…The in vivo pharmacological profile of 1 has been explored in various animal models in which considerably variable effectiveness was observed according to different assays, which has been interpreted as due to suboptimal pharmacokinetic properties of the molecule. − As a first attempt to overcome these limits, Hassler et al developed the piperidine derivative RTI-118 ( 2 , Figure ) that exhibited lower potency (hNPSR-Asn 107 p A 2 = 6.31; hNPSR-Ile 107 Ca 2+ pA 2 = 6.96) in vitro but a slightly improved in vivo effectiveness in reducing cocaine self-administration and seeking behavior in rats; these results were ascribed to the higher water solubility of the molecule . Nonetheless, there is a generally recognized need for further optimizing the pharmacological profile and, above all, the drug-likeness properties of oxazolo[3,4- a ]pyrazine ligands to obtain even more potent NPSR antagonist tools to be employed in vivo in preclinical studies.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on Oxazolo[3,4-a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent In Vivo Activity

et al. 2021

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Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4- a ]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68 , a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure–activity relationships and provide an updated model of ligand/NPSR interactions.

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Neuropeptide S reduces mouse aggressiveness in the resident/intruder test through selective activation of the neuropeptide S receptor

Cited by 15 publications

References 32 publications

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis

The neuropeptide F/nitric oxide pathway is essential for shaping locomotor plasticity underlying locust phase transition

Structure–Activity Relationship Studies on Oxazolo[3,4-a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent In Vivo Activity

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