Orexin does not work alone.

Although orexin is produced in the lateral hypothalamus and the perifornical hypothalamus, orexin axons project widely throughout the brain.  Receptors are not confined to the lateral hypothalamus.

Orexin excites neurons to secrete other chemicals. Sometimes these are the hormones that actually cause the behavior, but orexin is still important because it alters the amount of these other hormones and can control multiple types of behavior at once.

Orexin can subtly regulate behaviors  by exciting multiple classes of cells at the same time (4). In this way, depending on the other chemicals circulating through the brain that impact these same neurons, orexin may have very different effects. For example, it activates both serotonergic cells and the GABAergic cells that inhibit serotonergic cells, so depending on whether GABA inhibitors are present, it may have opposite effects. Orexins also activates neurons that release hormones that inhibit its own production, which include serotonin and norepinephrine.   

Sometimes the same behaviors that can be regulated by orexin are also controlled by other, unrelated hormones.  Neuropeptide-Y, for instance, is a hormone that also acts in the perifornicular hypothalamus (one of the areas that contains mRNA for orexin) to increase appetite, but appears to be independent of orexin.  

Wakefulness from increased histidine release.

The mechanism for how orexin increases arousal may relate to a role in stimulating the release of histimine to the histaminergic tuberomammillary nucleus (TMN) (1).  The TMN contains a high concentration of the mRNA for one of the orexin receptors, and is involved in promoting wakefulness. When orexin-A was added to the TMN over a period of one hour in rats and mice, the release of histamine to this area increased dose-dependently. Wakefulness increased and both REM and non-REM sleep decreased. The effect on wakefulness was not seen in mice lacking the histamine-1receptor gene, indicating that orexin’s effects on behavior were indeed related to the correlated increase in histamine.

Response to orexin depends on location.

Feeding response to injections of orexin-A and –B, at least in rodents, depends on the particular location of the injection, and on which form of orexin has been injected (3).  Orexin-B does not significantly change feeding response when it is injected into the lateral hypothalamus or the perifornical hypothalamus, while orexin-A does. Injections of either type of orexin have no effect when injected into two other known sites for food intake response—the ventral tegmental area (VTA) or the paraventricular nucleus.  Although orexin does not increase feeding response when injected into the VTA, it has been shown to reinstate drug- seeking behavior in rats when injected into this area rather than into surrounding areas of the brain (2). This effect may be due to its role in excitation of GABA and dopamine-containing neurons, which are involved in the reward system of the brain.