Critical issues in the antisense inhibition of brain gene expression in vivo: experiences targetting 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 criteria that are necessary or sufficient to demonstrate a true antisense effect. Here we review some of the critical conceptual and methodological issues. We highlight the problems of specificity and toxicity encountered in our attempts to down-regulate the 5-HT1A receptor using a phosphorothioate-modified ODN. We also present preliminary data suggestive of a decreased hippocampal 5-HT1AR expression induced by the antisense ODN, but it is a reduction which is of limited extent and which does not provide unequivocal evidence for an antisense-mediated effect. We conclude that antisense ODNs are not yet suitable as tools for routine in vivo neuropharmacological use, although they show considerable promise.
Le Corre
S M
SM
Department of Psychiatry, University of Oxford, U.K.
Burnet
P W
PW
Meller
R
R
Sharp
T
T
Harrison
P J
PJ
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D007276:Injections, Intraventricular; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*
D016376:Oligonucleotides, Antisense; D011985:Receptors, Serotonin