Hypothalamic orexin-A binding sites are downregulated by chronic nicotine treatment in the rat

Chronic nicotine treatment (4 mg/kg per day; 14 days) significantly reduced the affinity and density of orexin-A binding sites in the anterior hypothalamus of rat brain. There was a significantly lower sensitivity of orexin-A binding to orexin peptides, to the related secretin and pituitary adenylate cyclase activating peptide, and to unrelated neuropeptide Y (NPY). This change correlated with selective downregulation of a fraction of hypothalamic NPY Y-1 receptors. In previous studies, we have demonstrated an increase in the levels of orexin-A peptide and NPY in discrete hypothalamic areas upon nicotine treatment. This finding contradicts an expected increase in the production of these orexigenic peptides in a model where an inverse relationship is observed between food consumption and nicotine treatment. This study provides a possible explanation to this inconsistency in that a decrease in affinity of orexin-A binding could reduce neural orexin signaling, which may contribute to decreased food intake observed in smokers and animals chronically treated with nicotine. (C) 2001 Published by Elsevier Science Ireland Ltd.