title: Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward.
abstract: Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users.
authors.affiliation: Department of Biology, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hutcheson
authors.forename: Davide
authors.initials: D
authors.lastname: Quarta
authors.forename: Briac
authors.initials: B
authors.lastname: Halbout
authors.forename: Aurélie
authors.initials: A
authors.lastname: Rigal
authors.forename: Enzo
authors.initials: E
authors.lastname: Valerio
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D003913:Dextroamphetamine / Q000008:administration & dosage*; D004193:Discrimination Learning / Q000187:drug effects; D008297:Male; D009287:Naphthyridines; D064446:Orexin Receptors; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012201:Reward; 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; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea; D003042:Cocaine; D003913:Dextroamphetamine