Rj. Rodgers et al., SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats, EUR J NEURO, 13(7), 2001, pp. 1444-1452
Intracerebroventricular (i.c.v.) administration of the novel hypothalamic n
europeptide orexin-A stimulates food intake in rats, and delays the onset o
f behavioural satiety (i.e. the natural transition from feeding to resting)
. Furthermore, preliminary findings with the selective orexin-1 receptor an
tagonist, SB-334867, suggest that orexin-A regulation of food intake is med
iated via the orexin-1 receptor. At present, however, little is known about
either the intrinsic effects of SB-334867 on the normal structure of feedi
ng behaviour, or its effects upon orexin-A-induced behavioural change. In t
he present study, we have employed a continuous monitoring technique to cha
racterize 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 a
lone, SB-334867 (30 mg/kg, but not lower doses) significantly reduced food
intake and most active behaviours (eating, grooming, sniffing, locomotion a
nd rearing), while increasing resting. Although suggestive of a behavioural
ly nonselective (i.e. sedative) action, the structure of feeding behaviour
was well-preserved at this dose level, with the reduction in behavioural ou
tput clearly attributable to an earlier onset of behavioural satiety. As pr
eviously reported, orexin-A (10 mug per rat i.c.v.) stimulated food intake,
increased grooming and delayed the onset of behavioural satiety. Pretreatm
ent with SB-334867 dose-dependently blocked these effects of orexin-A, with
significant antagonism evident at dose levels (3-10 mg/kg) below those req
uired to produce intrinsic behavioural effects under present test condition
s. Together, these findings strongly support the view that orexin-A is invo
lved in the regulation of feeding patterns and that this influence is media
ted through the orexin-1 receptor.