Satiety enhancement by selective orexin-1 receptor antagonist SB-334867: influence of test context and profile comparison with CCK-8S.

Acute systemic treatment with the selective orexin-1 (OX1R) antagonist SB-334867 reduces food intake in rats, an effect associated with an acceleration in behavioural satiety and unrelated to gross behavioural disruption, alterations in palatability, or toxicity. However, as enhanced satiety is behaviourally indexed by an earlier-than-normal transition from eating to resting, and since orexin-A has been implicated in mechanisms of arousal, it remains possible that sedation contributes to the anorectic effect of acute OX1R blockade. Previous work has shown that, when treated with SB-334867 (30 mg/kg, i.p.) 30 min before a 1h test with palatable food, rats begin to show appreciable levels of resting 10-15 min earlier than under control conditions (i.e. around 20 min versus 30-35 min into the session). The present results demonstrate that a 20 min increase in the injection-test interval (i.e. 50 min) had no significant impact on the anorectic, behavioural or weight gain effects of SB-334867 in non-deprived male rats. Most importantly, this altered treatment regimen led to a temporal profile of resting virtually identical to that previously observed with the more conventional 30 min injection-test interval. Although parallel studies indicated that the OX1R antagonist accelerated the onset of resting (and suppressed most active behaviours) even in the absence of food, an equianorectic dose of the natural satiety-related signal cholescystokinin octapeptide (CCK-8S; 5 microg/kg, i.p.) also produced very similar behavioural effects regardless of the presence of food. Together with evidence that SB-334867 preserves the structural integrity of natural feeding behaviour, does not induce nausea/illness or alter taste/palatability and fails to influence EEG measures of arousal/sleep, the present findings are consistent with the view that acute OX1R antagonism selectively enhances satiety. However, unlike the immediate short-circuiting of the satiety sequence induced by CCK-8S, the slower response to SB-334867 implies a more indirect mechanism of action.