Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system

Abstract

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 selfadministration, 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. I n 2004, Xu and colleagues reported the deorphanization of a novel neuropeptide system named neuropeptide S (NPS). NPS binds to Gs and Gq protein-coupled receptors, previously identified as GPR154 and now referred to as NPSR (1, 2). NPS peptide transcript is expressed predominantly in a small group of neurons located between the locus ceruleus (LC), the Barrington nucleus, and the parabrachial nuclei. NPSR mRNA is expressed throughout the central nervous system with the highest concentration in olfactory structures, the amygdaloid complex, the paraventricular thalamic nucleus, the subiculum, and the lateral (LH), dorsomedial (DMH), and ventromedial hypothalamus (VMH) (1, 2).Activation of NPSR by intracerebroventricular (ICV) injection of NPS stimulates locomotor activity, increases arousal, and suppresses all stages of sleep (1). ICV injection of NPS has also been shown to stimulate hypothalamic-pituitary-adrenal axis (HPA) activity, enhancing plasma adrenocorticotropic hormone (ACTH) and corticosterone levels (3). Our group has recently found that intra-LH injections of NPS facilitate conditioned reinstatement of alcohol seeking (4). In addition, Pañeda and coworkers reported that ICV NPS itself increased relapse-like behavior in mice previously trained to self-administer cocaine. This latter effect was blocked by CRF1R antagonism and was absent in CRF1 receptor KO mice, suggesting a stress-like effect of NPS under the experimental conditions used (5).In the present study, to examine further the significance of the NPS system in the pathophysiology of cocaine craving and relapse, we studied the effect of NPS and of the selective NPSR antagonists SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-ca...

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

“…When administered into the LH, NPS enhances reinstatement of alcohol and cocaine seeking triggered by environmental conditioning factors. This effect is blocked by peripheral administration of the OX1 antagonist SB334867, which suggests an important interaction between these two peptidergic systems (15,16,19). In addition, NPS facilitates cocaine reinstatement with mechanisms mimicking, at least in part, the effect of stress and that may involve the corticotropin releasing factor and the Hcrt-1/Ox-A systems as well (20)(21)(22).…”

“…In previous studies, we demonstrated that the proreinstatement activity of Hcrt-1/Ox-A can be triggered by upstream activation of the neuropeptide S (NPS) system (14)(15)(16). NPS is a neurotransmitter produced in the pericoerulear zone of the brainstem and is released in the lateral hypothalamus (LH) where it activates its cognate G q/s protein-coupled receptor named neuropeptide S receptor (NPSR) (17,18).…”

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

“…Animals were then trained to self-administer cocaine (0.125, 0.25, and 0.5 mg/0.1 ml) or heroin (20 μg/ 0.1 ml) under a fixed ratio 1 (FR1) with 20 s time-out (TO) schedule of reinforcement, in which each response at the drug-paired active lever resulted in the IV delivery of 0.1 ml of fluid, whereas responses at the inactive lever resulted in no fluid delivery (Kallupi et al, 2010). Rats received 2 h daily sessions for 13-14 consecutive days.…”

Neuropeptide-S Evoked Arousal with Electroencephalogram Slow-Wave Compensatory Drive in Rats

“…Orexin peptide is known to promote wakefulness and suppresses sleep [27]. Central infusion of NPS activates orexin-containing neuron such as orexin-A [28] to facilitate dopamine neurotransmission in the nucleus accumbens [29], which might promote waking and inhibit sleep. Therefore, stimulation of NPS receptors in the lateral hypothalamic area might result in the activation of orexin-A neurons to mediate its effects through the dopamine circuits.…”