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Psychopharmacology

, Volume 226, Issue 2, pp 347–355 | Cite as

Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat

  • Marsida Kallupi
  • Giordano de Guglielmo
  • Nazzareno Cannella
  • Hong Wu Li
  • Girolamo Caló
  • Remo Guerrini
  • Massimo Ubaldi
  • John J. Renger
  • Victor N. Uebele
  • Roberto CiccocioppoEmail author
Original Investigation

Abstract

Rationale

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.

Keywords

Addiction Drug abuse Neuropeptide S Self-administration Relapse Psychostimulants 

Notes

Acknowledgments

This study was supported by the Compagnia San Paolo Foundation grant (to R.C.). The authors thank Alfredo Fiorelli, Dr. Massimo Nabissi, and Dr. Daniele Tomassoni for expert technical assistance.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Marsida Kallupi
    • 1
  • Giordano de Guglielmo
    • 1
  • Nazzareno Cannella
    • 1
  • Hong Wu Li
    • 1
  • Girolamo Caló
    • 2
  • Remo Guerrini
    • 3
  • Massimo Ubaldi
    • 1
  • John J. Renger
    • 4
  • Victor N. Uebele
    • 4
  • Roberto Ciccocioppo
    • 1
    Email author
  1. 1.School of Pharmacy (Pharmacology Unit)University of CamerinoCamerinoItaly
  2. 2.Department of Experimental and Clinical Medicine, Section of Pharmacology and National Institute of NeuroscienceUniversity of FerraraFerraraItaly
  3. 3.Department of Pharmaceutical Sciences and LTTA (Laboratorio per le Tecnologie delle Terapie Avanzate)University of FerraraFerraraItaly
  4. 4.Department of NeuroscienceMerck Research LaboratoriesWest PointUSA

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