Abstract
Hypothalamic orexin neurons project to many brain areas, including hindbrain structures such as the nucleus of the solitary tract (NTS) and area postrema (AP), where orexin 1 receptors (OX1Rs) are expressed. Hindbrain administration of orexin-A increases feeding and meal size, and blockade of hindbrain OX1Rs with the selective antagonist SB334867 has the opposite effect. Here we asked whether hindbrain OX1R stimulation or blockade alter rats' sensitivity to gastrointestinal satiety signals. Rats received 4th intracerebroventricular (icv) injections of vehicle or orexin-A, at a dose with no effect on its own, prior to an intragastric (IG) infusion of saline or a satiating volume of Ensure. IG Ensure suppressed subsequent chow intake, but orexin-A pretreatment significantly attenuated this IG nutrient-induced satiety at 2 h into the dark phase. In a second experiment, rats received NTS injections of vehicle or orexin-A before intraperitoneal (IP) injection of vehicle or the satiation hormone cholecystokinin (CCK). NTS orexin-A pretreatment completely blocked the intake-suppressive effect of CCK on dark-phase chow intake. Finally, we investigated the role of endogenous hindbrain OX1R activation by pretreating rats with 4th-icv injection of vehicle or SB334867 followed by IG infusion of saline or Ensure just before a chocolate Ensure licking test session. IG nutrient infusion suppressed Ensure intake, and blockade of hindbrain OX1Rs significantly prolonged that intake-suppressive effect. We conclude that hindbrain OX1Rs are a mechanism though which hypothalamic orexin neurons can reduce animals' sensitivity to gastrointestinal nutrient load, allowing them to consume more food.