ICV administration of anti-NPY antisense oligonucleotide: effects on feeding behavior, body weight, peptide content and peptide release.

Neuropeptide-Y (NPY) is a potent stimulator of feeding, and chronic administration of the peptide has been shown to increase body weight. This study determined the chronic effects of repeated daily injections of an antisense phosphorothioate oligonucleotide complementary to the rat mRNA for NPY (aNPY) on food intake, feeding behavior and body weight change in rats. Five micrograms of the aNPY oligonucleotide in ten microliters of vehicle or a missense control oligonucleotide were administered intracerebroventricularly (ICV) for seven consecutive days. Cumulative food intake, meal size and meal duration were significantly lowered in aNPY-treated animals. Body weight change of aNPY-injected animals was significantly lower than controls, and the effect was reversed after treatments ceased. A two-bottle taste aversion paradigm was employed to determine the behavioral specificity of the anorectic effect, and the phosphorothioate oligonucleotide was found not to be aversive at the dosage used. Following an additional five day injection period, animals were killed and paraventricular nuclei (PVN) were dissected. In vitro release and tissue content of NPY from this brain area were evaluated by heterologous radioimmunoassay. Content of NPY was unchanged in this brain area. Paradoxically, in vitro release of NPY was increased in aNPY-treated animals.

ICV administration of anti-corticotropin-releasing factor antisense oligonucleotide: effects on feeding behavior and body weight.

Corticotropin-releasing factor (CRF) has been reported to reduce food intake and body weight, and numerous studies suggest a role for CRF in putative mechanisms for the regulation of body energy. This study investigated the effects of ICV-administered antisense phosphorothioate oligonucleotides, directed against the CRF mRNA, on feeding behavior and body weight in rats. Sixteen male HSD rats were cannulated in the lateral ventricle, and given ad libitum access to tap water and a ground chow diet. Feeding behavior was recorded by computer, and meal patterns were assessed. Rats were given 3 micrograms each of two anti-CRF oligonucleotides (aCRF) or two control oligos in the hour before the onset of the nocturnal cycle for ten consecutive days. Cumulative food intake was assessed at 3, 6, 12 and 24 h after each injection, as well as over the 10-day injection period. Compared to missense controls, rats receiving the antisense oligonucleotides ate significantly more at 6 h (P = 0.01), but not at 3, 12, 24 h, or during the entire 10-day injection period (P > 0.05). There was no effect on body weight change, meal size, or meal interval (P > 0.05). These data indicate that daily administration of anti-CRF oligonucleotides has a significant short-term stimulatory effect on feeding behavior, but does not have a long-term effect on feeding or body weight gain.