CRITICAL ISSUES IN THE ANTISENSE INHIBITION OF BRAIN GENE-EXPRESSION IN-VIVO - EXPERIENCES TARGETING THE 5-HT1A RECEPTOR

There have been many recent reports of receptor down-regulation in the brain by antisense oligodeoxynucleotides (ODNs) administered in vivo. However, the literature is inconsistent regarding the experimental cr iteria that are necessary or sufficient to demonstrate a true antisens e effect. Here we review some of the critical conceptual and methodolo gical issues. We highlight the problems of specificity and toxicity en countered in our attempts to down-regulate the 5-HT1A receptor using a phosphorothioate-modified ODN. We also present preliminary data sugge stive of a decreased hippocampal 5-HT1AR expression induced by the ant isense ODN, but it is a reduction which is of limited extent and which does not provide unequivocal evidence for an antisense-mediated effec t. We conclude that antisense ODNs are not yet suitable as tools for r outine in vivo neuropharmacological use, although they show considerab le promise. (C) 1997 Elsevier Science Ltd.