Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801

Abstract

Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.

Anatomical characterization of the neuropeptide S system in the mouse brain by in situ hybridization and immunohistochemistry

“…Other studies have produced evidence for a role of central NPS neurotransmission in reward and drug abuse (Badia-Elder et al, 2008;Canella et al, 2009;Pañeda et al, 2009;Ruggeri et al, 2010). Finally, we have recently described antipsychotic effects of NPS in animal models of pharmacologically induced psychosis (Okamura et al, 2010) and a possible genetic association of NPSR genotypes with panic disorder (Okamura et al, 2007). In addition, analysis of behavioral phenotypes of NPSR knockout mice demonstrated attenuated arousal, mild alterations in circadian activity, and increased anxiety-like behaviors, suggesting that endogenous NPS signaling might contribute to these brain functions (Duangdao et al, 2009).…”

Orphan GPCRs and Neuromodulation

“…Significant PPI deficits have been observed in patients with schizophrenia and other psychopathological disorders. Three orphan GPCR systems have recently been shown to play a role in regulating PPI (Cardon et al, 2010; Chung et al, 2011; Okamura et al, 2010)…”

Molecular fingerprint of neuropeptide s‐producing neurons in the mouse brain

“…Our own studies have recently uncovered a protective function of NPS in animal models of pharmacologically induced psychosis whereby NPS could reverse neurotoxic, biochemical, and behavioral effects produced by the NMDA receptor antagonist MK-801 (Okamura et al, 2010). Finally, phenotypical analysis of NPSR knockout mice revealed deficits in arousal, circadian activity, and mildly increased anxiety-like behaviors, indicating that endogenous NPS signaling might be involved in these functions (Duangdao et al, 2009).…”