title: Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats.
abstract: The orexin/hypocretin system has been implicated in multiple phases of drug addiction. Acute orexin receptor blockade with the orexin-1 receptor (OX1R) antagonist, SB-334867, has been found to reduce cocaine seeking after cocaine self-administration. As repeated drug dosing can have differential effects and is more clinically relevant than acute dosing, in the current study we examined the effects of repeated SB-334867 on cocaine self-administration, extinction, and reinstatement to cocaine seeking in Sprague-Dawley rats. We found that repeated SB-334867 (10 mg/kg/day) had no effect on established cocaine self-administration. Repeated SB-334867 (both 10 and 20 mg/kg) attenuated cocaine seeking during extinction; however, this effect was only observed when animals had no prior experience with SB-334867 and when SB-334867 was administered prior to, but not after, daily extinction sessions. Notably, daily treatment with SB-334867 (10 mg/kg) during extinction increased subsequent cue-induced reinstatement, whereas repeated SB-334867 (20 mg/kg) administration during extinction enabled acute SB-334867 to reduce cue-induced reinstatement. Repeated SB-334867 treatment (10 or 20 mg/kg) failed to affect reinstatement induced by priming injections of cocaine (10 mg/kg). These results show that repeated inhibition of OX1R-mediated signaling exerts a lasting and specific role in mediating environmentally activated cocaine seeking.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 416B, Charleston, SC 29425, USA.
authors.forename: Luyi
authors.initials: L
authors.lastname: Zhou
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Smith
authors.forename: Phong H
authors.initials: PH
authors.lastname: Do
authors.forename: Gary
authors.initials: G
authors.lastname: Aston-Jones
authors.forename: Ronald E
authors.initials: RE
authors.lastname: See
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects*; D008297:Male; D009287:Naphthyridines; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012646:Self Administration; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; C578627:Hcrtr1 protein, rat; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea; D003042:Cocaine