Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System

Abstract

The association of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor for relapse risk in alcoholism. This study examined in rats the effects of a newly deorphanized neuropeptide receptor and its cognate ligand, Neuropeptide S (NPS), on ethanol consumption and reinstatement of ethanol-seeking by environmental cues previously associated with ethanol availability. In the self-administration experiments, the stable response rates observed for ethanol reinforcement were not modified by intracerebroventricular (ICV) injection of NPS (1.0 and 2.0 nmol per rat). In the reinstatement experiments, ethanol-associated cues induced robust rates of ethanol seeking, which were highly resistant to extinction over repeated sessions of reinstatement testing. ICV NPS treatment (1.0, 2.0 and 4.0 nmol per rat) resulted in a significant increase of ethanol seeking elicited by ethanol-associated cues. In contrast, NPS did not affect the reinstatement of responding to water-paired stimuli. Site-specific NPS injection (0.1 and 0.5 nmol per rat) into the lateral hypothalamus also reinstated extinguished responding to ethanol. This effect was selectively blocked by pre-treatment with the hypocretin-1/orexin-A antagonist SB-334867 (10 mg/kg, i.p.). At the dose tested, SB-334867 did not modify alcohol reinstatement per se. These results provide the first demonstration that activation of NPS receptors in the LH intensifies relapse to ethanol-seeking elicited by environmental conditioning factors. This effect is selective, and is mediated by activation of LH hypocretin neurones. Based on the present findings, we also predict that antagonism at NPS receptors could represent a novel pharmacological approach to alcohol relapse treatment.

Chronic Ethanol Potentiates the Effect of Neuropeptide S in the Basolateral Amygdala and Shows Increased Anxiolytic and Anti-Depressive Effects

“…The genetic make up of this selectively bred alcohol-preferring rat strain is not completely clear, but could presumably include effects on NPS, NPSR, or effector systems downstream of the receptor. In line with Badia-Elder's data in EtOH non-preferring rats, Cannella et al (2009) showed that NPS had no effect on EtOH consumption in wistar rats. Thus, genetic factors clearly influence the effect of NPS both on reward and EtOH consumption.…”

Neuropeptide S Receptor Gene Expression in Alcohol Withdrawal and Protracted Abstinence in Postdependent Rats

“…Given that in postdependent rats protracted abstinence is associated with increased HPA axis activity and higher peripheral corticosteroids levels (Rasmussen et al, 2000;Zorrilla et al, 2001), we may speculate that facilitation of NPS function in the PaV may contribute to this hormonal dysregulation. Previous studies conducted in our laboratory have also shown that central activation of NPS receptors facilitates relapse to alcohol seeking; thus, considering that postdependent rats are more inclined to relapse, one could speculate that higher NPS neurotransmission levels following alcohol intoxication history may contribute to exacerbate this behavior (Cannella et al, 2009;Liu and Weiss, 2002). At present, it is unclear how to reconcile the NPS anxiolytic-like profile with its ability to facilitate reinstatement of alcohol seeking as previously described in our laboratory (Cannella et al, 2009).…”

“…Previous studies conducted in our laboratory have also shown that central activation of NPS receptors facilitates relapse to alcohol seeking; thus, considering that postdependent rats are more inclined to relapse, one could speculate that higher NPS neurotransmission levels following alcohol intoxication history may contribute to exacerbate this behavior (Cannella et al, 2009;Liu and Weiss, 2002). At present, it is unclear how to reconcile the NPS anxiolytic-like profile with its ability to facilitate reinstatement of alcohol seeking as previously described in our laboratory (Cannella et al, 2009). One would, however, speculate that neurocircuitary associated with relapse behavior and anxiety could be different.…”

“…In this respect, it would be highly interesting to study the possible link between the NPS system, alcohol withdrawal, and anxiety, given that on the one hand, NPS is related to anxiolytic-like actions (Leonard et al, 2008;Vitale et al, 2008), while on the other, it activates the HPA axis and increases relapse to alcohol and cocaine seeking elicited by conditioning factors and drug priming, respectively (Cannella et al, 2009;Paneda et al, 2009). …”

Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system

“…ICV injection of NPS has also been shown to stimulate hypothalamic-pituitary-adrenal axis (HPA) activity, enhancing plasma adrenocorticotropic hormone (ACTH) and corticosterone levels (3). Our group has recently found that intra-LH injections of NPS facilitate conditioned reinstatement of alcohol seeking (4). In addition, Pañeda and coworkers reported that ICV NPS itself increased relapse-like behavior in mice previously trained to self-administer cocaine.…”