ICV ADMINISTRATION OF ANTI-NPY ANTISENSE OLIGONUCLEOTIDE - EFFECTS ONFEEDING-BEHAVIOR, BODY-WEIGHT, PEPTIDE CONTENT AND PEPTIDE RELEASE

Neuropeptide-Y (NPY) is a potent stimulator of feeding, and chronic ad ministration of the peptide has been shown to increase body weight. Th is study determined the chronic effects of repeated daily injections o f an antisense phosphorothioate oligonucleotide complementary to the r at mRNA for NPY (aNPY) on food intake, feeding behavior and body weigh t change in rats. Five mu g of the aNPY oligonucleotide in ten mu l of vehicle or a missense control oligonucleotide were administered intra cerebroventricularly (ICV) for seven consecutive days. Cumulative food intake, meal size and meal duration were significantly lowered in aNP Y-treated animals. Body weight change of aNPY-injected animals was sig nificantly lower than controls, and the effect was reversed after trea tments ceased. A two-bottle taste aversion paradigm was employed to de termine the behavioral specificity of the anorectic effect, and the ph osphorothioate oligonucleotide was found not to be aversive at the dos age used. Following an additional five day injection period, animals w ere killed and paraventricular nuclei (PVN) were dissected. In vitro r elease and tissue content of NPY from this brain area were evaluated b y heterologous radioimmunoassay. Content of NPY was unchanged in this brain area. Paradoxically, in vitro release of NPY was increased in aN PY-treated animals.