Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2.

Content Provider	Europe PMC
Author	Matzeu, Alessandra Kerr, Tony M. Weiss, Friedbert Martin-Fardon, Rémi
Copyright Year	2016
Abstract	Orexin/hypocretin (Orx/Hcrt) projections from the lateral hypothalamus to the paraventricular nucleus of the thalamus (PVT) are implicated in drug addiction. Specifically, the posterior section of the PVT (pPVT) innervates brain structures that modulate motivated behavior. This study investigated the role of pPVT-Orx/Hcrt transmission in cocaine-seeking behavior. Because the effects of Orx/Hcrt are mediated by two Orx/Hcrt receptors (Hcrt-r1 and Hcrt-r2), we examined the extent to which Hcrt-r1 and Hcrt-r2 are involved in Orx/Hcrt-induced cocaine seeking. Male Wistar rats were made cocaine dependent by self-administering cocaine 6 hours/day (long access) for 21 days. After self-administration training, the rats underwent daily extinction training, during which cocaine was withheld. After extinction, the rats were injected into the pPVT with Orx-A/Hcrt-1 (0–2 µg) alone or, using a single dose of 0.5 µg, in combination with an Hcrt-r1 antagonist (SB334867; 0–15 µg) or an Hcrt-r2 antagonist (TCSOX229; 0–15 µg). Orx-A/Hcrt-1 alone reinstated (primed) cocaine seeking. Unexpectedly, coadministration of Orx-A/Hcrt-1 with SB334867 did not have any effects on Orx-A/Hcrt-1-induced reinstatement, whereas when coadministered with Orx-A/Hcrt-1, TCSOX229 prevented cocaine-seeking behavior. These results indicate that Hcrt-r2 in the pPVT mediates the reinstating effect of Orx-A/Hcrt-1 in animals with a history of cocaine dependence and further identify Hcrt-r2 as a possible molecular target that can guide future therapeutic approaches for the prevention of drug-seeking behavior.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC5074483&blobtype=pdf
Page Count	7
ISSN	00223565
Volume Number	359
DOI	10.1124/jpet.116.235945
PubMed Central reference number	PMC5074483
Issue Number	2
PubMed reference number	27540003
Journal	The Journal of Pharmacology and Experimental Therapeutics [J Pharmacol Exp Ther]
e-ISSN	15210103
Language	English
Publisher	The American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2016-08-18
Publisher Place	Bethesda, MD
Access Restriction	Open
Rights License	Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
Content Type	Text
Resource Type	Article
Subject	Pharmacology Molecular Medicine