Neuropeptide S Induces Acute Anxiolysis by Phospholipase C-Dependent Signaling within the Medial Amygdala

Abstract

Neuropeptide S (NPS) is an important anxiolytic substance of the brain. However, the signaling pathways downstream of NPS receptor (NPSR) activation, underlying the behavioral effect of NPS, remain largely unknown. Here, we show that bilateral microinfusion of NPS (0.2 nmol/0.5 μl) into the medial amygdala (MeA) of male adult Wistar rats reduced anxiety-related behavior on both the elevated plus-maze and the open field. Moreover, as shown in amygdala tissue micropunches intracerebroventricular infusion of NPS (1 nmol/5 μl) (1) evoked phosphorylation and synthesis of CaMKIIα in relation to reference protein β-tubulin representing Ca influx, and (2) induced phosphorylation of mitogen-activated protein kinase ERK1/2. The NPS-induced anxiolysis was prevented by local inhibition of phospholipase C signaling using U73122 (0.5 nmol/0.5 μl) in the MeA, indicating the behavioral relevance of this pathway. Conversely, local pharmacological blockade of adenylyl cyclase signaling using 2',5'-dideoxyadenosine (12.5 nmol/0.5 μl) failed to inhibit the anxiolytic effect of NPS infused into the MeA. Hence, NPS promotes acute anxiolysis within the MeA dependent on NPSR-mediated phospholipase C signaling. Taken together, our study extends the knowledge about the intracellular signaling mechanisms underlying the potent anxiolytic profile of NPS.

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis

“…The NPS effects on intracellular Ca 2ϩ also studied in NPSR1-transfected HEK293T and CHO cells are most likely mediated by NPSR-induced G q signaling (Reinscheid et al, 2005;Liao et al, 2016;Clark et al, 2017). In vivo, it has recently been demonstrated that NPS promotes anxiolysis in a phospholipase C-dependent manner and increases intracellular Ca 2ϩ levels characterized by increased phosphorylation and synthesis of Ca 2ϩ /calmodulin-dependent kinase II within the rat medial amygdala (Grund and Neumann, 2017).…”

Pharmacological profile of the neuropeptide S receptor: Dynamic mass redistribution studies

“…Additionally, the complexity of NPSR signaling has been recently underlined by the identification of NPSR biased agonists, such as NPS (1‐10) and SFKN‐NH 2, that preferentially signal through IP 3 ‐DAG‐Ca 2+ second messengers. This class of NPSR ligands may be useful as innovative anxiolytics . Despite this NPSR signaling complexity, structure‐activity relationship studies and drug discovery programs targeting NPSR have been conducted so far only with classical single end‐point assays (for reviews see and ).…”

“…This class of NPSR ligands may be useful as innovative anxiolytics. 36,37 Despite this NPSR signaling complexity, structure-activity relationship studies and drug discovery programs targeting NPSR have been conducted so far only with classical single end-point assays (for reviews see 4 and 5). This approach may be reductionist and incomplete.…”

Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease

“…The hyperlocomotor effects of NPS are robust and have been replicated by several laboratories around the world ( Table 1 ). The pioneer study of Xu and collaborators [ 2 ] showed that central administration of NPS increases locomotor activity in mice at lower doses (0.1 nmol), and this effect lasts for about 1 h. These findings were largely replicated [ 4 , 19 , 20 , 26 , 27 , 67 ] and extended to rats [ 33 , 34 , 35 , 36 ]. Distinct from classical psychostimulant drugs (i.e., amphetamines), repeated NPS injections did not lead to locomotor sensitization [ 34 ].…”