SB‐334867, a selective orexin‐1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin‐A in rats

Abstract

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.

Insular hypocretin transmission regulates nicotine reward

“…Importantly, however, responding for food and nicotine rewards was similar under the PR schedule, in which SB-334867 selectively decreased nicotine intake without altering responding for food. Previously, it was shown that low doses of SB-334867 similar to those used in the present study did not alter arousal (20), sleep-wake cycles (20), food intake (21), or behavioral satiety (21) in rats. However, at higher doses (Ն10 mg/kg), SB-334867 decreased consumption of palatable high-fat food (22) and baseline food intake (21).…”

A Commentary on the Neurobiology of the Hypocretin/Orexin System

“…Finally, hypocretin agonists and antagonists are also badly needed to assess the potential therapeutic value of this pathway for sleep and other disorders. Only one compound with moderate affinity and bioavailability, SB-334867, a Hcrtr1 antagonist, is available (Rodgers et al 2001). The phenotype of the system knockout, narcolepsy, indicate important and non redundant effects of this peptide system in the area of wake regulation, sleep consolidation and the cohesion of REM sleep.…”

Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways

“…Although the exact mechanisms of MCH and orexin action are not yet known, treatment with either neuropeptide induces food intake in rodents, and their respective receptor antagonists ablate this response. 26,27 Leptin inhibits the expression of MCH and OX in leptin-deficient animals and blocks the fastinginduced activation of orexin neurons, although it does not affect the activation state of MCH neurons, suggesting that leptin regulates these two populations through separate mechanisms and/or through distinct populations of LepRb neurons. As OX regulates arousal as well as food intake (both of which are modulated by metabolic state fasting promotes the waking state, but food intake reduces alertness), 28 leptin may regulate OX neurons differently than it does MCH neurons to balance metabolic need and arousal.…”