Sulfur modification of oligodeoxynucleotides produces nuclease resistance but also leads to toxic effects when these compounds are administered in vivo. To assess their potential as viable alternatives to full phosphorothioate derivatives, we have used rotational behavior and immunohistochemistry to investigate the efficacy and longevity of phosphorothioate, end-capped antisense oligodeoxynucleotides in suppression of c-fos and ngfi-a in the striatum of adult rats. Our results suggest that, despite having a limited duration of action, these end-capped, chimeric oligodeoxynucleotides are capable of specifically inhibiting gene expression in vivo and may, therefore, possess broader application potential in chronic suppression models as the reduction of sulfur content is likely to greatly minimize their toxic effects.