1. ¹Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Via Madonna delle Carceri, Camerino, Italy
2. ²Laboratory of Clinical and Translational Studies, NIAAA/NIH, Bethesda, MD, USA

Correspondence: Dr R Ciccocioppo, Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy. Tel: +39 0737 403300, Fax: +39 0737 403325, E-mail: roberto.ciccocioppo@unicam.it

³These authors contributed equally to the study

Received 28 November 2008; Revised 19 February 2009; Accepted 19 February 2009; Published online 25 March 2009.

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.