Hypothalamic orexin and pro-opiomelanocortin activities are essential for the anorexic effects of m-chlorophenylpiperazine in mice.

Hypothalamic pro-opiomelanocortin (POMC) activity is reportedly essential for satiety signalling downstream of serotonin (5-HT). Here we show that food-restricted wild-type mice, which exhibited decreased hypothalamic POMC expression and increased hypothalamic orexin expression, were responsive to m-chlorophenylpiperazine (m-CPP), a 5-HT(2C/1B) receptor agonist, leading to anorexia, whereas food-restricted A(y) mice with decreased hypothalamic POMC and orexin expression, were not. Injection of POMC small interfering RNA (siRNA) oligonucleotide+orexin siRNA oligonucleotide into the third cerebral ventricle was unresponsive to mCPP-induced anorexia, whereas a single injection of POMC or orexin siRNA oligonucleotides elicited a response. The injection of POMC siRNA oligonucleotides suppressed the anorexic effects of sibutramine, a serotonin and noradrenaline re-uptake inhibitor. The injection of orexin siRNA oligonucleotides suppressed the hyperphagia induced by the injection of POMC siRNA oligonucleotides. These findings suggest that functional hypothalamic POMC and orexin activity has a critical role in satiety signalling of mCPP in mice.