title: The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization.
abstract: Orexin-expressing neurons are present in hypothalamic nuclei and send projections toward mesolimbic regions such as the nucleus accumbens (NAc), a key brain region implicated in the processing of the motivational significance of reinforcers. Recent evidence found that activation of the orexin system can lead to a state of hyperarousal that may facilitate drug craving or contribute to vulnerability to drug relapse. This study aimed at assessing the effects of the orexin-1 receptor antagonist SB-334867 [1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride] on amphetamine-induced dopamine (DA) release in the shell subregion of the NAc by means of in vivo microdialysis in freely moving rats. Since behavioral sensitization is thought to play a role in the maintenance of compulsive drug use, we also tested the effect of SB-334867 on the expression of sensitization to the locomotor activating effects of amphetamine. Acute administration of SB-334867 (30 mg/kg SC) significantly reduced the acute effects of amphetamine (1 mg/kg IP) on extracellular DA levels in the NAc shell. The expression of amphetamine sensitization was also significantly reduced by acute SB-334867 treatment. Altogether our findings show that selective orexin-1 antagonism both reduces the acute effects of amphetamine on DA outflow in the NAc shell and decreases the expression of locomotor sensitization to the repeated, intermittent administration of amphetamine.
authors.affiliation: Department of Biology, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy. davide.2.quarta@gsk.com
authors.forename: Davide
authors.initials: D
authors.lastname: Quarta
authors.forename: Enzo
authors.initials: E
authors.lastname: Valerio
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hutcheson
authors.forename: Gael
authors.initials: G
authors.lastname: Hedou
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
mesh_terms: D000661:Amphetamine / Q000037:antagonists & inhibitors*; D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009287:Naphthyridines; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009479:Neuropeptides / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012201:Reward; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D018765:Dopamine Uptake Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea; D000661:Amphetamine; D004298:Dopamine