Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system - PubMed (original) (raw)

. 2010 Nov 9;107(45):19567-72.

doi: 10.1073/pnas.1004100107. Epub 2010 Oct 25.

Nazzareno Cannella, Daina Economidou, Massimo Ubaldi, Barbara Ruggeri, Friedbert Weiss, Maurizio Massi, Juan Marugan, Markus Heilig, Patricia Bonnavion, Luis de Lecea, Roberto Ciccocioppo

Affiliations

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

Marsida Kallupi et al. Proc Natl Acad Sci U S A. 2010.

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 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

(Upper) Effect of ICV treatment with NPS (0.0, 1.0, and 2.0 nmol/rat) or with the NPS antagonist SHA 68 (0.0, 30, and 60 mg/kg) on cocaine self-administration under an FR5 schedule of reinforcement. One group of rats (n = 8) was treated with NPS and another group (n = 7) with SHA 68. (A and C) Active lever; (B and D) inactive lever. (Lower) Effects of ICV injection of NPS (0.0, 1.0, and 2.0 nmol/μL/rat) or IP injection of SHA 68 on cue-induced reinstatement of cocaine seeking (n = 8/group). Reinstatement responses in rats exposed to S+ and S− condition (in the absence of reward delivery) compared with the mean number of lever presses of the last 3 d of extinction (EXT). (E and G) Mean (±SEM) number of responses at the cocaine active lever. (F and H) Mean (±SEM) number of responses at the cocaine inactive lever. Different from extinction, ##P < 0.01. Different from vehicle-treated rats (controls), *P < 0.05.

Fig. 2.

Fig. 2.

Dual labeling of c-Fos and Hcrt-1/Ox-A immunoreactivity in: (A) the lateral hypothalamus (LH); (B) the central amygdala (CeA); (D) the perifornical area (PeF); (F) the dorsomedial hypothalamic nucleus (DMH) of rats (n = 4) injected with NPS (2 nmol) ICV. Coronal sections were taken at AP coordinates identical to those used for intra-LH, -CeA, -PeF, and -DMH NPS injections. c-Fos and Hcrt-1/Ox-A were visualized with biotinylated antibodies leading, respectively, to black and brown immunoreactive products. Arrows indicate colocalization of c-Fos (dark nuclei) with Hcrt-1/Ox-A (brown). (C) Depiction of coronal sections used for analysis of the LH, CeA, PeF, and DMH; (E) magnified detail of D, showing that in the LH and PeF, c-Fos and Hcrt-1/OX-A immunoreactivity are coexpressed in about 40% of the counted cells. In the DMH, coexpression was found in about 20% of the counted neurons. In the CeA, a detectable expression of c-Fos was also found but in the absence of Hcrt-1/OX-A immunoreactivity. [Scale bars, 50 μm (A, B, D, and F) and 20 μm (E).]

Fig. 3.

Fig. 3.

Effect of intracranial bilateral injection of NPS (0.1 and 0.5 nmol/0.6 μL/rat) or its vehicle (0.0) on cue-induced reinstatement of cocaine seeking. Reinstatement responses in rats (n = 7–8/group) exposed to S+ and S− conditions (in the absence of cocaine or saline) compared with the mean number of lever responses during the last 3 d of the extinction period (EXT). Mean (± SEM) number of responses at the (A) cocaine active and (B) inactive levers in rats with cannulae aimed at the LH. Mean (± SEM) number of responses at the (C) cocaine active and (D) inactive levers in rats with cannulae aimed at the PeF. Mean (± SEM) number of responses at the (E) cocaine active and (F) inactive levers in rats with cannulae aimed at the DMH. Mean (± SEM) number of responses at the (G) cocaine active and (H) inactive levers in rats with cannulae aimed at the CeA. Different from extinction, ##P < 0.01 and #P < 0.05. Different from vehicle-treated rats (controls), *P < 0.05 and **P < 0.01.

Fig. 4.

Fig. 4.

Effect of treatment with the Hcrt-1/Ox-A antagonist SB-334867 (10 mg/kg, i.p.) or its vehicle (0.0) on the consequences of intra-LH injection of NPS (0.5 nmol/0.6 μL/rat) or its vehicle (0.0) on cue-induced reinstatement of cocaine seeking in rats (n = 7). Reinstatement responses in rats exposed to the S+ and S− conditions (in the absence of cocaine or saline) compared with the mean number of lever responses during the last 3 d of extinction (EXT). (A) Mean (±SEM) number of responses at the active lever. (B) Mean (±SEM) number of responses at the inactive lever. Different from extinction, ##P < 0.01. Different from vehicle-treated rats (controls), *P < 0.05.

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