title: Hypothalamic neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat.
abstract: BACKGROUND
  Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)⁵]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.
  
  
  METHODS
  Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)⁵]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.
  
  
  RESULTS
  Intraperitoneal administration of NPSR-QA1 (15-30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15-30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)⁵]NPS (10-30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.
  
  
  CONCLUSIONS
  The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.
authors.affiliation: School of Pharmacy-Pharmacology Unit, University of Camerino, Building of Experimental Medicine, Via Madonna delle Carceri, 62032 Camerino, Italy.
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Cannella
authors.forename: Hong Wu
authors.initials: HW
authors.lastname: Li
authors.forename: Girolamo
authors.initials: G
authors.lastname: Caló
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy; D003042:Cocaine / Q000494:pharmacology*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000187:drug effects*
chemical_list: D000577:Amides; C583306:NPSR-QA1 compound; D009479:Neuropeptides; D015363:Quinolones; D018013:Receptors, Neuropeptide; C535232:neuropeptide S, 5-Cys(tBu)-; C534458:neuropeptide S, rat; D003042:Cocaine