title: Activation of Hypocretin-1/Orexin-A Neurons Projecting to the Bed Nucleus of the Stria Terminalis and Paraventricular Nucleus Is Critical for Reinstatement of Alcohol Seeking by Neuropeptide S.
abstract: BACKGROUND
  Environmental conditioning is a major trigger for relapse in abstinent addicts. We showed that activation of the neuropeptide S (NPS) system exacerbates reinstatement vulnerability to cocaine and alcohol via stimulation of the hypocretin-1/orexin-A (Hcrt-1/Ox-A) system.
  
  
  METHODS
  Combining pharmacologic manipulations with immunohistochemistry techniques, we sought to determine how NPS and Hcrt-1/Ox-A systems interact to modulate reinstatement of alcohol seeking in rats.
  
  
  RESULTS
  Intrahypothalamic injection of NPS facilitated discriminative cue-induced reinstatement of alcohol seeking. This effect was blocked by the selective Hcrt-1/Ox-A antagonist SB334867 microinjected into the hypothalamic paraventricular nucleus (PVN) or into the bed nucleus of the stria terminalis (BNST) but not into the ventral tegmental area or the locus coeruleus. Combining double labeling and confocal microscopy analyses, we found that NPS-containing axons are in close apposition to hypothalamic Hcrt-1/Ox-A positive neurons, a significant proportion of which express NPS receptors, suggesting a direct interaction between the two systems. Retrograde tracing experiments showed that intra-PVN or intra-BNST red fluorobead unilateral injection labeled bilaterally Hcrt-1/Ox-A somata, suggesting that NPS could recruit two distinct neuronal pathways. Confirming this assumption, intra-BNST or PVN Hcrt-1/Ox-A injection enhanced alcohol seeking similarly to hypothalamic NPS injection but to a lesser degree.
  
  
  CONCLUSIONS
  Results suggest that the Hcrt-1/Ox-A neurocircuitry mediating the facilitation of cue-induced reinstatement by NPS involves structures critically involved in stress regulation such as the PVN and the BNST. These findings open to the tempting hypothesis of a role of the NPS system in modulating the interactions between stress and environmental conditioning factors in drug relapse.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
authors.affiliation: Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, School of Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, School of Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Severi
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruggeri
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Serena
authors.initials: S
authors.lastname: Stopponi
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino; Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.. Electronic address: nazzareno.cannella@zi-mannhem.de.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Cannella
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior; D000431:Ethanol / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D012686:Septal Nuclei / Q000378:metabolism*; D013788:Thalamus / Q000378:metabolism
chemical_list: C000596232:Hcrt protein, rat; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; C534458:neuropeptide S, rat; D000431:Ethanol
keywords: Addiction; Cue; Hypocretin; Neuropeptide S; Orexin; Relapse; Stress