作者: Worthington, John J ; Grajoszek, Aniela ; Piwowarczyk-Nowak, Aneta ; Suszka-Świtek, Aleksandra ; Krzystanek, Marek ; Pałasz, Artur ; Della Vecchia, Alessandra

BACKGROUNDNeuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular relationships between the anxiolytic activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in the context of novel stress-related neuropeptides action. The present work therefore focused on gene expression of novel stress neuropeptides in the rat brain after acute treatment with escitalopram and in combination with neuropeptide S receptor (NPSR) blockade.METHODSStudies were carried out on adult, male Sprague-Dawley rats that were divided into five groups: animals injected with saline (control) and experimental rats treated with escitalopram (at single dose 10 mg/kg daily), escitalopram and SHA-68, a selective NPSR antagonist (at a single dose of 40 mg/kg), SHA-68 alone and corresponding vehicle (solvent SHA-68) control. To measure anxiety-like behavior and locomotor activity the open field test was performed. All individuals were killed under anaesthesia and the whole brain was excised. Total mRNA was isolated from homogenized samples of the amygdala, hippocampus, hypothalamus, thalamus, cerebellum, and brainstem. Real-time PCR was used for estimation of related NPS, NPSR, neuromedin U (NMU), NMU receptor 2 (NMUR2) and nesfatin-1 precursor nucleobindin-2 (NUCB2) gene expression.RESULTSAcute escitalopram administration affects the local expression of the examined neuropeptides mRNA in a varied manner depending on brain location. An increase in NPSR and NUCB2 mRNA expression in the hypothalamus and brainstem was abolished by SHA-68 coadministration, while NMU mRNA expression was upregulated after NPSR blockade in the hippocampus and cerebellum.CONCLUSIONSThe pharmacological effects of escitalopram may be connected with local NPSR-related alterations in NPS/NMU/NMUR2 and nesfatin-1 gene expression at the level of selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.

2021-05-01·Addiction Biology2区 · 医学

Stress induces reinstatement of extinguished cocaine conditioned place preference by a sequential signaling via neuropeptide S, orexin, and endocannabinoid

2区 · 医学

Article

作者: Chou, Yu‐Hsien ; Lee, Hsin‐Jung ; Lee, Ming Tatt ; Chiou, Lih‐Chu ; Hor, Chia Chun ; Calo, Girolamo ; Guerrini, Remo

AbstractNeurons containing neuropeptide S (NPS) and orexins are activated during stress. Previously, we reported that orexins released during stress, via orexin OX1 receptors (OX1Rs), contribute to the reinstatement of cocaine seeking through endocannabinoid/CB1 receptor (CB1R)‐mediated dopaminergic disinhibition in the ventral tegmental area (VTA). Here, we further demonstrated that NPS released during stress is an up‐stream activator of this orexin‐endocannabinoid cascade in the VTA, leading to the reinstatement of cocaine seeking. Mice were trained to acquire cocaine conditioned place preference (CPP) by context‐pairing cocaine injections followed by the extinction training with context‐pairing saline injections. Interestingly, the extinguished cocaine CPP in mice was significantly reinstated by intracerebroventricular injection (i.c.v.) of NPS (1 nmol) in a manner prevented by intraperitoneal injection (i.p.) of SHA68 (50 mg/kg), an NPS receptor antagonist. This NPS‐induced cocaine reinstatement was prevented by either i.p. or intra‐VTA microinjection (i.vta.) of SB‐334867 (15 mg/kg, i.p. or 15 nmol, i.vta.) and AM 251 (1.1 mg/kg, i.p. or 30 nmol, i.vta.), antagonists of OX1Rs and CB1Rs, respectively. Besides, NPS (1 nmol, i.c.v.) increased the number of c‐Fos‐containing orexin neurons in the lateral hypothalamus (LH) and increased orexin‐A level in the VTA. The latter effect was blocked by SHA68. Furthermore, a 30‐min restraint stress in mice reinstated extinguished cocaine CPP and was prevented by SHA68. These results suggest that NPS is released upon stress and subsequently activates LH orexin neurons to release orexins in the VTA. The released orexins then reinstate extinguished cocaine CPP via an OX1R‐ and endocannabinoid‐CB1R‐mediated signaling in the VTA.

2021-04-08·Journal of Medicinal Chemistry1区 · 医学

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

1区 · 医学

Article

作者: Guerrini, Remo ; Amendola, Giorgio ; Calò, Girolamo ; Pacifico, Salvatore ; Ruzza, Chiara ; Reinscheid, Rainer K. ; Cosconati, Sandro ; Fabbri, Martina ; Preti, Delia ; Bernardi, Tatiana ; Sturaro, Chiara ; Ferrari, Federica ; Marzola, Erika ; Fantinati, Anna ; Albanese, Valentina ; Trapella, Claudio

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.

100 项与 SHA-68 相关的药物交易

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