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SB‐334867, a selective orexin‐1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin‐A in rats
Author(s) -
Rodgers R. J.,
Halford J. C. G.,
Nunes de Souza R. L.,
Canto de Souza A. L.,
Piper D. C.,
Arch J. R. S.,
Upton N.,
Porter R. A.,
Johns A.,
Blundell J. E.
Publication year - 2001
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.0953-816x.2001.01518.x
Subject(s) - orexin , orexin receptor , orexin a , medicine , endocrinology , antagonist , sniffing , neuropeptide , lateral hypothalamus , receptor antagonist , psychology , receptor , hypothalamus , neuroscience
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 µg 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.