ACUTE, SEQUENCE-SPECIFIC EFFECTS OF OXYTOCIN AND VASOPRESSIN ANTISENSE OLIGONUCLEOTIDES ON NEURONAL RESPONSES

Antisense oligodeoxynucleotides (antisense) are short length single st rands of DNA with base sequences complementary to a length of messenge r RNA of a specific gene. They can be taken up by neurons(7,18) and hy bridize with a complementary messenger RNA to selectively interrupt th e expression of a particular gene. We now describe neuropeptide-specif ic, short-latency (within 2-6 h) effects of antisense infused into the supraoptic nucleus on the responses of rat neurohypophysial neurons, in vivo, to various stimuli. Oxytocin antisense specifically (i) reduc ed the electrophysiological responses of putative oxytocin, but not va sopressin neurons, (ii) inhibited cholecystokinin-induced and electric ally stimulated release of oxytocin from the neurohypophysis, and (iii ) reversibly abolished cholecystokinin-induced expression of Fos withi n the supraoptic nucleus. Vasopressin antisense reduced the excitatory responses of vasopressin neurons, but not of oxytocin neurons. As neu ropeptide content within the supraoptic nucleus and neurohypophysis re mains unaltered at this time, antisense may induce anticipatory, feed- forward alterations in electrical activity in addition to any possible effects on peptide synthesis.