Nicotine up-regulates expression of orexin and its receptors in rat brain

Orexins are two recently discovered neuropeptides that can stimulate food i ntake. As the chronic use of tobacco typically leads to a reduction in body weight, it is of interest to determine whether nicotine, the major biologi cally active tobacco ingredient, has an effect on orexin metabolism in the brain. Using a semiquantitative RT-PCR technique, the levels of messenger R NA (mRNA) for prepro-orexin, orexin A (OX1-R) and orexin B (OX2-R) receptor s were 20-50% higher in rats receiving nicotine for 14 days at the level of 2-4 mg/kg day compared with rats receiving saline solvent alone. In animal s treated with nicotine at 4 mg/kg-day, the expression levels of mRNA for p repro-orexin, OX1-R, and OX2-R were significantly higher compared with thos e in either the free-feeding control or pair-fed saline control rats. RIA d ata indicated that both orexin A and orexin B peptide levels were significa ntly elevated (45-54%; P < 0.01) in the dorsomedial nucleus (DMH) of the ni cotine-treated rats compared with either solvent-only or pair-fed controls. Additionally, orexin B was significantly elevated (83%; P < 0.01), over le vels in both types of the control animals, in the paraventricular nucleus ( PVN) region. In summary, we demonstrated that an inverse association betwee n nicotine and food intake as well as body weight held with doses comparabl e to those consumed by average human smokers. Moreover, our data indicated that chronic exposure to nicotine can induce a long-term increase in the ex pression levels of prepro-orexin and their receptor mRNA in the rat hypotha lamus and in the levels of orexin A in the DMH and orexin B in the DMH and PVN among the six hypothalamic regions that we examined.