Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system.
Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. Environmental conditioning factors are among the major determinants of relapse in abstinent cocaine users. Here we describe a role of the neuropeptide S (NPS) system in regulating relapse. In rats with a history of cocaine self-administration, presentation of stimuli predictive of drug availability reinstates drug seeking, triggering relapse. Intracerebroventricular (ICV) injection of NPS increased conditioned reinstatement of cocaine seeking, whereas peripheral administration of the NPS receptor antagonist SHA 68 reduced it. Manipulation of the NPS receptor system did not modify cocaine self-administration. We also found that ICV NPS administration activates c-Fos expression in hypocretin-1/orexin-A (Hcrt-1/Ox-A) immunoreactive neurons in the lateral hypothalamus (LH) and in the perifornical area (PeF). Of note, intra-LH and intra-PeF administration of NPS increased conditioned reinstatement of cocaine responding, an effect that was selectively blocked with the Hcrt-1/Ox-A receptor selective antagonist SB334867. Finally, results showed that intra-LH injection of the NPS antagonist [D-Cys(tBu) (5)]NPS blocked cue-induced cocaine seeking, indicating a role for this system in the pathophysiology of drug relapse.
School of Pharmacy (Pharmacology Unit), University of Camerino, 62032 Camerino, Italy.
Marsida
M
Kallupi
Nazzareno
N
Cannella
Daina
D
Economidou
Massimo
M
Ubaldi
Barbara
B
Ruggeri
Friedbert
F
Weiss
Maurizio
M
Massi
Juan
J
Marugan
Markus
M
Heilig
Patricia
P
Bonnavion
Luis
L
de Lecea
Roberto
R
Ciccocioppo
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000209:etiology*; D003463:Cues; D004333:Drug Administration Routes; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009474:Neurons; D009479:Neuropeptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D018377:Neurotransmitter Agents; D000068797:Orexins; D051381:Rats; D020318:Rats, Long-Evans; D012008:Recurrence
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins; C534458:neuropeptide S, rat; D003042:Cocaine