title: Orexin-1 receptor mediation of cocaine seeking in male and female rats.
abstract: Previous studies have shown that female rats exhibit enhanced cocaine seeking during multiple phases of cocaine addiction compared with males. The orexin/hypocretin system recently has been implicated in drug addiction in male rats. Based on the known sex differences in cocaine addiction, in the current study we examined orexin-mediated cocaine seeking during self-administration, extinction, and reinstatement in age-matched male (initial weight 250-300 g) and female (initial weight 175-225 g) Sprague-Dawley rats by using the orexin-1 receptor (OX1R) antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB-334867) (10-30 mg/kg). OX1R blockade had no effect on established cocaine self-administration, but attenuated cocaine seeking during extinction in both male and female rats. It is noteworthy that OX1R blockade potently attenuated cue-induced reinstatement in males but had no effect on females. SB-334867 also reduced cocaine seeking during pharmacological stress-induced (yohimbine, 2.5 mg/kg) and yohimbine + cue-induced reinstatement in both sexes. SB-334867 failed to affect reinstatement induced by cocaine (10 mg/kg) in either male or female rats, but selectively reduced cocaine + cue-induced reinstatement only in males. In separate experiments examining basal and cocaine-induced locomotion, SB-334867 attenuated locomotion in both male and female rats. Finally, assessment of plasma and brain levels of SB-334867 showed that estrus females had slightly higher plasma levels than diestrus females, but no overall sex differences or estrous cycle differences were observed in plasma or brain SB-334867 concentrations. These results show that OX1R signaling plays a role in mediating cocaine seeking, but differs between the sexes for cue-induced reinstatement.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Luyi
authors.initials: L
authors.lastname: Zhou
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Ghee
authors.forename: Clifford
authors.initials: C
authors.lastname: Chan
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.forename: Ronald E
authors.initials: RE
authors.lastname: See
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000209:etiology*; D003463:Cues; D005108:Extinction, Psychological; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000502:physiology*; D012646:Self Administration; D012727:Sex Characteristics; D014508:Urea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D015016:Yohimbine / 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; D015016:Yohimbine; D014508:Urea