## 3 Orexins and Food Intake in Experimental Animal Models
### Rat
Lateral hypothalamic neurons expressing orexin send projections to the medial prefrontal cortex, and it was demonstrated that for a cue-potentiated feeding, it is necessary the activation of the orexin 1 receptors located in the medial prefrontal cortex, the connectivity of the latter region with the lateral hypothalamus and the development of the medial prefrontal cortex neural plasticity [97]. The data show the involvement of the medial prefrontal cortex in the cognitive motivation to eat, suggesting that this cortical region is a potential target for the treatment of excessive appetite/overeating. It was reported that the administration of orexin A into the hindbrain increased both meal size and feeding; these effects were inhibited with the orexin 1 receptor antagonist SB-334,867; and hypothalamic neurons containing orexin send projections to hindbrain centers (e.g., area postrema, and nucleus of the solitary tract) in which the expression of the orexin 1 receptor was reported [87]. The study showed that, via the hindbrain orexin 1 receptors, hypothalamic neurons expressing orexin decrease the sensitivity to gastrointestinal nutrient load and hence, more food is consumed [87] (Table 3). In female rats, it was reported that a cafeteria diet promoted changes in the hypothalamic mechanisms involved in food consumption at different periods (short-, medium- and long-term) [78]. A short-term period (4 weeks of cafeteria diet) did not affect the expression of orexin in the hypothalamus; a medium-term period (11 weeks) increased the expression of orexin and body weight, and a long-term period (20 weeks) increased more such expression [78]. The alteration in mRNA orexin level was associated to epigenetic modifications in the promoter region. Thus, the data indicate that during the development of obesity, the expression of orexin varies, and hence the alterations observed show the differential roles played by orexin in food consumption at different feeding periods (Table 3). Moreover, the administration of sea buckthorn seed oil was studied regarding the cisplatin-induced vomiting and the role played by orexin A [88]. The plasma level of orexin A and mRNA/protein expressions of the orexin 1 receptor were measured in the brainstem/hypothalamus as well as the expression of orexin A in the lateral hypothalamus. In all cases, the administration of sea buckthorn seed oil increased significantly all the parameters studied and prevented cisplatin-induced vomiting. Thus, it seems that this prevention was mediated by an increase in the central and peripheral levels of orexin A and in the expression of the orexin 1 receptor in both the hypothalamus and brainstem [88] (Table 3). A high-fat diet activates neurons expressing orexin, which in turn, increases the consumption of a high-fat diet by activating the mesolimbic reward pathway [79] (Table 3). It was reported that under a palatable high-fat Western diet (short-term), excitatory synapses to orexin neurons became amenable to long-term depression after one week of high-fat diet feeding; the effect was re versed after four weeks of a high-fat diet [79]. It seems that this mechanism is a homeostatic response that occurs to prevent the overactivation of such neurons and to decrease high-fat diet consumption and obesity. The long-term depression depends on the retrograde endocannabinoid signaling and on the postsynaptic metabotropic glutamate receptor 5 [79]. In free-feeding animals, it was demonstrated that the administration into the median raphe nucleus of prazosin (\(\alpha\)1-adrenoacceptor antagonist) increased food intake and the expression of fos in the lateral hypothalamic neurons containing orexin [91]. It was also demonstrated that the latter neurons are targeted by axons arising from cell bodies located in the median raphe nucleus [91]. The findings suggest that prazosin, through the orexinergic system, promotes a motivational response regarding food consumption (Table 3).