Antagonism of NPY-induced feeding by pretreatment with cyclic AMP responseelement binding protein antisense oligonucleotide

Although second messenger systems subserving neuropeptide Y (NPY)-mediated behaviors have been identified for a variety of receptors in several tissue s, downstream signaling events are not well known. The nuclear binding prot ein, cyclic AMP response element binding protein (CREB) appears to be a tra nscription factor that is activated following injection of NPY into rat hyp othalamus. To allow determination of the functional nature of CREB mediatio n of NPY-induced feeding, injection cannulae were implanted into the perifo rnical hypothalamus of 18 rats. Treatment of seven rats with CREB antisense oligonucleotide (15 ug) significantly antagonized NPY feeding for up to on e week after treatment, while similar injections of CREB sense oligonucleot ide (15 ug) had no significant effect on NPY-induced feeding. Two weeks aft er the antisense oligonucleotide treatment, feeding was once again elicited by the injection of NPY. Hypothalamic CREB protein was also reduced signif icantly two days after the CREB antisense oligonucleotide treatment. These results suggest that activation of CREB, probably through phosphorylation, may be a necessary event for the signal transduction of NPY stimulation int o feeding behavior. (C) 2000 Harcourt Publishers Ltd.