SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats.
Intracerebroventricular (i.c.v.) administration of the novel hypothalamic neuropeptide orexin-A stimulates food intake in rats, and delays the onset of behavioural satiety (i.e. the natural transition from feeding to resting). Furthermore, preliminary findings with the selective orexin-1 receptor antagonist, SB-334867, suggest that orexin-A regulation of food intake is mediated via the orexin-1 receptor. At present, however, little is known about either the intrinsic effects of SB-334867 on the normal structure of feeding behaviour, or its effects upon orexin-A-induced behavioural change. In the present study, we have employed a continuous monitoring technique to characterize the effects of SB-334867 (3-30 mg/kg, i.p.) on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Administered alone, SB-334867 (30 mg/kg, but not lower doses) significantly reduced food intake and most active behaviours (eating, grooming, sniffing, locomotion and rearing), while increasing resting. Although suggestive of a behaviourally nonselective (i.e. sedative) action, the structure of feeding behaviour was well-preserved at this dose level, with the reduction in behavioural output clearly attributable to an earlier onset of behavioural satiety. As previously reported, orexin-A (10 microg per rat i.c.v.) stimulated food intake, increased grooming and delayed the onset of behavioural satiety. Pretreatment with SB-334867 dose-dependently blocked these effects of orexin-A, with significant antagonism evident at dose levels (3-10 mg/kg) below those required to produce intrinsic behavioural effects under present test conditions. Together, these findings strongly support the view that orexin-A is involved in the regulation of feeding patterns and that this influence is mediated through the orexin-1 receptor.
Rodgers
R J
RJ
School of Psychology, University of Leeds, UK. johnr@psychology.leeds.ac.uk
Halford
J C
JC
Nunes de Souza
R L
RL
Canto de Souza
A L
AL
Piper
D C
DC
Arch
J R
JR
Upton
N
N
Porter
R A
RA
Johns
A
A
Blundell
J E
JE
D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology*; D001835:Body Weight; D002352:Carrier Proteins / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D006963:Hyperphagia / Q000139:chemically induced / Q000378:metabolism*; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D011919:Rats, Inbred Strains; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012528:Satiety Response / Q000187:drug effects*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D002352:Carrier Proteins; 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