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Journal of Neuroscience, Vol 15, 4250-4258, Copyright © 1995 by Society for Neuroscience
V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats
R Landgraf, R Gerstberger, A Montkowski, JC Probst, CT Wotjak, F Holsboer and M Engelmann
Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
To develop and validate a vasopressin (AVP) receptor knockdown strategy, we
infused an antisense oligodeoxynucleotide to the V1 subtype mRNA into the
septum of male rats with osmotic minipumps and measured behavioral,
cellular and molecular parameters. Compared to vehicle and
scrambled-sequence oligo controls, chronic antisense administration for up
to 4 d diminished the ability of the animals to distinguish a previously
exposed juvenile from a novel one and to respond to exogenous AVP (1 ng/5
microliters, intracerebroventricular) with an improved social memory.
Furthermore, anxiety-related behavior was reduced. As measured in the
behaviorally tested rats, antisense treatment resulted in a reduced binding
of radiolabeled AVP in the septum, but not in other limbic brain areas
(receptor autoradiography), and an increased amount of V1 receptor mRNA
(reverse transcriptase PCR), indicating translational arrest and ongoing
transcriptional activity. In sense oligo-treated rats, on the other hand,
both the social and the anxiety-related behavior scores lay between levels
obtained in control and antisense-treated animals. These sense-treated rats
showed a slightly reduced V1 receptor density in the septum and reduced
receptor mRNA levels, indicating hybridization of the sense oligo to the
DNA. The data show the potential of antisense targeting to further reveal
relationships between local gene expression, neuropeptide-receptor
interactions in distinct brain areas, and behavioral performance.
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