Anorexia and weight loss in male rats 24 h following single dose treatment with orexin-1 receptor antagonist SB-334867.
Acute systemic treatment with the selective orexin-1 receptor antagonist SB-334867 (30 mg/kg, i.p.) has been reported not only to inhibit food intake and to accelerate behavioural satiety in rats, but also to produce a significant loss of bodyweight over the 24 h period post-dosing. The present studies were designed to test the hypothesis that the inhibition of weight gain following acute treatment with SB-334867 is due to a persistent anorectic action of the compound. In Experiment 1, the acute effects of SB-334867 (30 mg/kg, i.p.) on food intake and behaviour in a 1 h test with palatable mash were assessed as a function of injection-test interval. Results confirmed that, when administered 30 min prior to testing, SB-334867 significantly suppressed mash intake and accelerated behavioural satiety. More importantly, significant anorexia and behavioural change were also observed when animals were tested 24 h, but not 48 h, post-dosing. As previously reported, all animals treated with the orexin-1 receptor antagonist lost bodyweight over the 24 h period following acute treatment. The generality of these findings was confirmed in Experiment 2, where acute treatment with SB-334867 (30 mg/kg, i.p.) significantly suppressed home cage chow consumption over the 24 h period post-dosing, an effect also accompanied by a significant loss of bodyweight. The results of Experiment 3 showed that, following i.p. administration of 30 mg/kg, SB-334867 has good CNS penetration, reaches peak plasma and brain concentrations at 30 min, and maintains good exposure over 4 h post-dosing. Overall, current data support the hypothesis that a persistent anorectic action contributes to the significant loss of bodyweight observed 24 h following acute dosing with SB-334867. As the compound is virtually undetectable in plasma or brain beyond 8 h post-dosing, and since nothing is known about potentially active metabolites, we consider the possibility that single dose treatment with SB-334867 results in enduring alterations to the orexin-1 receptor and/or downstream signalling pathways.
Ishii
Y
Y
Behavioural Pharmacology Laboratory, School of Psychology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
Blundell
J E
JE
Halford
J C G
JC
Upton
N
N
Porter
R
R
Johns
A
A
Jeffrey
P
P
Summerfield
S
S
Rodgers
R J
RJ
D000204:Activity Cycles; D000704:Analysis of Variance; D000818:Animals; D000855:Anorexia / Q000139:chemically induced*; D001067:Appetite Depressants / Q000008:administration & dosage*; D001583:Benzoxazoles / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008297:Male; D009287:Naphthyridines; D064446:Orexin Receptors; D051381:Rats; D011919:Rats, Inbred Strains; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014508:Urea / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D015431:Weight Loss / Q000187:drug effects*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001067:Appetite Depressants; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea