ANTISENSE OLIGONUCLEOTIDES IN NEUROENDOCRINOLOGY - ENTHUSIASM AND FRUSTRATION

Antisense oligodeoxynucleotides (ODN) offer the potential advantage to manipulate neuropeptide or neuropeptide receptor expression within th e brain transiently and site-specifically, thus providing a tool for n euroendocrinological research into the physiological function of a par ticular neuropeptide system. In this study, various approaches are int roduced which reveal that antisense ODN may exert acute, short-term ef fects on neuronal responsiveness to afferent stimuli, as well as long- term effects on neuropeptide/receptor protein availability in a given system depending on the duration of treatment. Short-term effects were seen in that oxytocin (OXT) and vasopressin (AVP) antisense ODN affec ted electrophysiological and secretory parameters of oxytocinergic and vasopressinergic neurons, respectively, as well as their ability to e xpress the Fos protein in response to afferent stimulation a few hours after a single infusion into the hypothalamic supraoptic nucleus. In this study, two methodological approaches to study long-term effects o f the antisense ODN are exemplified, in which antisense ODN directed a gainst the mRNA coding for the neuropeptide itself or its receptor wer e used. The repeated infusion of corticotropin releasing hormone (CRH) antisense ODN into the paraventricular nucleus resulted in reduced im munoreactive CRH, but not AVP, in the external zone of the median emin ence; Furthermore, in order to evaluate the receptor-mediated effects of CRH and AVP released locally within the paraventricular nucleus on adrenocorticotropin (ACTH) release from the pituitary, CRH receptor (a nd also AVP receptor) antisense ODN were repeatedly infused into the h ypothalamic nuclei; this treatment resulted in an elevation of stimula ted, but not basal, ACTH release into the blood. However, in addition to these obvious antisense effects, results are discussed which demons trate sequence-unspecific effects of phosphorothioated ODN, suggesting that some of their mechanisms of action are not yet understood. (C) 1 997 Elsevier Science Ltd.