To evaluate the role of neuropeptide Y (NPY), a potent appetite stimulant, in controlling food intake and body weight, we investigated the use of antisense oligodeoxynucleotides (ODNs) to inhibit NPY gene expression in the hypothalamus. We compared the hypothalamic distribution of fluorescein-labelled ODNs administered intracerebroventricularly, and effects on food intake and NPY gene expression, of three different structural modifications of an antisense ODN sequence against NPY. Rats had either the antisense or missense ODNs (24 micrograms/day) or saline infused into the third ventricle by osmotic minipumps for 7 days. The unmodified phosphodiester ODN was not detectable in the hypothalamus after 7 days and had no effects on food intake. The phosphorothioate ODN was widely distributed throughout the hypothalamus but had nonselective effects, with similar changes in food intake and NPY mRNA levels in the antisense and missense groups, and was severely toxic. The propyl-protected ODN appeared to penetrate the hypothalamus well but had no antisense-selective effects on NPY mRNA levels or food intake. Antisense ODNs are increasingly used to inhibit gene expression in vitro and in intact animals. These negative findings underline the need for rigorous evaluation of any effects of antisense ODNs administered into the central nervous system, and raise doubts about the validity of this approach in physiological or pharmacological studies.

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