Orexin A administration by lactoferrin- and antitransferrin-modified liposomes potentiate the nucleus accumbens shell dopamine responsiveness to food.

Orexin neurons originate in the hypothalamic region and project to different brain areas. They produce two different neuropeptides: orexin A (Orx A) and orexin B (Orx B) and two receptors for the orexin system has been characterized: OxR1 and OxR2. OxR1 binds orexin A with 30 nM affinity but has much lower affinity for orexin B, whereas OxR2 binds both orexin peptides with similar high affinity. Several studies reported that orexinergic neurons in the lateral hypothalamus (LH) are involved in motivated behavior for drugs of abuse as well as natural rewards. In particular administration of orexin A has been shown to stimulate food consumption, and orexin signaling in VTA is implicated in intake of high-fat food. It has been shown that LH orexin neurons project to the ventral tegmental area (VTA) indicating that the VTA is an important site of action for orexin's role in reward processing. Mesolimbic dopamine (DA) in the nucleus accumbens (NAc) shell is also involved in the rewarding mechanisms of food consumption. Is there a cooperation between DA and Orx A? In our study we investigated by brain microdialysis the responsiveness of NAc shell DA transmission in food consumption after intravenous administration of Orx A encapsulated in different targeted and not-targeted stealth liposomes prepared using film hydration method. Orx A per se produced a later increase of DA in the NAc shell (peaking at 80 min sample) and strengthened the DA responsiveness in this area after sucrose pellets feeding. We registered also an increase of the number of eaten pellets. These effects on DA and on feeding were blocked by intraperitoneally injection of the antagonist of the OxR1 (SB 334867, 30mg/Kg). We can speculate that the strengthening of DA response during food consumption exerted by Orx A administration could increase the rewarding properties of food and could be one of the mechanisms that underlie food addiction. These findings could suggest new targets for a new treatment of eating disorders.