A Role for the Neuropeptide S System in the Mechanisms of Alcohol Addiction

The present study sought to determine whether the NPS system might have a role in the regulation of alcohol related behaviours. In fact, back ground information indicates that in alcohol-prefering female rats, ICV treatment with NPS was able to decrease ethanol intake in a two bottle choice paradigm (Badia-Elder et al., 2008); in addition NPS blocked both acquisition and expression of morphine conditioned place preference in mice implanted ICV (Li W et al., 2009). In addition to this, NPSR mRNA is abundantly expressed in brain regions (i.e., amygdala, hippocampus and lateral hypothalamus) that are known to play a significant role in the regulation of alcohol drinking and reinstatement of alcohol-seeking (Heilig and Koob, 2007; Le and Shaham, 2002). Moreover, the arousing effects of NPS together with its ability to activate the HPA axis system may represent a condition that resembles the patho-physiogical state associated with excessive alcohol use or preceding relapse (Adinoff et al., 2005; Cleck and Blendy, 2008). Altogether these observations prompted us to investigate the significance of the NPS receptor system in the modulation of alcohol abuse related behaviors. In our studies we first investigated the effects of ICV NPS injection on ethanol self administration using both genetically selected alcohol-preferring rats and heterogeneous Wistars (from which the msP rats were derived). Secondly we studied the effect of NPS in the modulation of craving and relapse using several well validated animal models of relapse. Recently it has been reported that ICV injection of NPS induce Fos expression in the lateral hypothalamus (LH) hypocretinergic neurons (Niimi, 2006). Based on these findings, and in light of the significant role of the Hcrt-1/Ox-1 system in the regulation of relapse to drug seeking (Boutrel et al., 2005; Harris et al., 2005; Lawrence et al., 2006), we used the Hcrt-1/Ox-A receptor selective antagonist SB334867 to investigate the possibility that an interaction exists between the NPS and the hypocretin systems in the LH. Finally the ability of NPS to induce conditioned place preference was evaluated. [....] The present study sought to determine whether ethanol intoxication would result in changes in NPS system expression and activity in laboratory animal. Two main reasons prompted us to hypothesize the involvement of the NPS system in withdrawal subsequent ethanol intoxication. First, NPSR mRNA is abundantly expressed in brain regions (i.e. amygdala, thalamus and hypothalamic regions) that are known to be involved in anxiety and is consistent with a possible role of the NPS system in modulating behavioural response to stress (Xu et al., 2007). In addition, NPS is known to possess anxiolytic properties in rodents (Badia-Elder et al., 2008; Leonard et al., 2008; Rizzi et al., 2008; Vitale et al., 2008; Xu et al., 2004) and, as described previously, it regulates several alcohol-related behaviours. To address this hypothesis, we first investigated the variations of NPSR mRNA expression in rats exposed to 6 days of intermittent ethanol intoxication. The study was carried out on tissue samples obtained from rats killed 12 hours after intoxication, when the physical signs of withdrawal were detected and 7 days after intoxication, when only the psychological signs of withdrawal, such as anxiety, were present. Furthermore, seven days after intoxication, we tested anxiolityc-like properties of 0.3 and 1 nmole of NPS in non-dependent and post-dependent rats in two different paradigms, elevated plus maze (EPZ), and defensive burying (DB).