Neuropeptide S system mediates nicotine-induced reward-facilitatory behavior

Neuropeptide S (NPS), a 20-amino acid bioactive molecule has emerged as a promising treatment target for substance abuse in preclinical research. However, its role in nicotine reward, a major contributor to tobacco addiction, remains unexplored. This study investigated the involvement of the NPS system in reward-related effects of nicotine using the intracranial self-stimulation (ICSS) procedure in operant chamber. Adult male Wistar rats were implanted with bipolar electrode targeting the lateral hypothalamus-medial forebrain bundle and trained under a fixed-ratio 1 schedule across a range of brain stimulation frequencies (165-33 Hz). Under control conditions, the trained rats displayed a frequency-dependent increase in lever-press activity. Intracerebroventricular (i.c.v.) infusion of NPS (0.5-2 nmol) facilitated ICSS behaviour, while NPS receptor antagonist SHA-68 (0.1-10 nmol) was not effective. However, SHA-68 pretreatment (i.c.v.) dose dependently blocked the ICSS-facilitatory action of nicotine (0.25 mg/kg; subcutaneous, s.c.). A single nicotine injection (s.c.) activated NPS-containing neurons in the pericoerulear area (peri-LC), and increased NPS protein levels in the lateral hypothalamus (LH). Repeated nicotine administration (s.c.) elevated NPS mRNA expression in the peri-LC, and increased protein levels in the LH, paraventricular thalamus and peri-LC. However, these changes seem region specific since the nicotine treatment, in single or multiple doses, ensued no response in parabrachial nucleus, amygdala or ventral tegmental area. In sum, we suggest that the endogenous NPS system plays a critical role in reward-related effects of nicotine.