Role of the Neuropeptide S System on alcohol self administration and impulsivity in laboratory rats

Neuropeptide S (NPS) is a 20-amino acid neurotransmitter that exerts both pro-arousal and anxiolytic effects. The NPS system consists of the 20-amino acid neuropeptide S (NPS) and its receptor, the neuropeptide S receptor (NPSR). Previous research has associated the NPS system with Alcohol use disorder (AUD) and impulsivity. AUD is a psychiatric condition caused by the interaction of excessive alcohol consumption with genetically predisposing factors. Impulsivity is a multifaceted behavior characterized by acts that are poorly conceived, prematurely expressed, risky, or inappropriate, often leading to undesirable consequences. In this study, we verified the stimulatory, anxiolytic, and stress-coping roles of NPS in marchigian- sardinian alcohol-preferring (msP) rats using the open-field (OF), elevated plus maze (EPM), and fear conditioning (FC) tests. We investigated the effects of NPS on alcohol self-administration (ASA) in both male and female msP rats, verified whether the anxiolytic effect of NPS alone is sufficient to reduce alcohol seeking, and assessed whether NPS has the ability to suppress stress- induced relapse. We developed two Go/No-Go models of impulsivity, tested the effect of NPS on impulsivity in Wistar and msP rats, and examined the tetrapeptide RTI263—a truncated form of NPS that maintains the anxiolytic properties while being devoid of the stimulatory effect—in Wistar rats. The results showed that NPS reduced ASA in both male and female msP rats through its anxiolytic and stress-coping effects, respectively. However, selective stimulation of the anxiolytic effect of NPS alone was sufficient to reduce alcohol seeking in females but not in males. The Go/No-Go models of impulsivity were validated with predictive validity, as verified by atomoxetine. MsP rats exhibited impulsive-like behavior compared to Wistar controls, which contributes to their heightened motivation for alcohol. NPS exerted an anti-impulsive effect on both msP and Wistar rats. The tetrapeptide RTI263 demonstrated a weaker effect than NPS in the impulsivity model. In conclusion, this study provides novel insights into the role of the NPS system in AUD and impulsivity, highlighting the potential of the NPS system as a valuable target for future therapeutic interventions.