Antisense oligonucleotides to corticotropin-releasing factor impair memory retention and increase exploration in rats

Corticotropin-releasing factor is known as a stress peptide which stimulates adrenocorticotropin and corticosterone release. It also has a direct central effect to produce various behavioural activations in rats. In the present study, we have designed and studied the effects of an antisense oligonucleotide directed against the corticotropin-releasing factor gene in rats. Local injection of this antisense oligonucleotide into the hippocampus (1 nmol, five injections) significantly impaired the retention performance of an inhibitory avoidance task in rats. In another experiment, the same injection (1 nmol, four injections) also markedly increased rearing response and total distance travelled by rats in a novel activity chamber. Meanwhile, it markedly decreased grooming behaviour in rats. When directly injected into the hypothalamus in another group of animals (1 nmol, four injections), this antisense oligonucleotide significantly decreased the plasma adrenocorticotropin level. The effectiveness of these antisense oligonucleotide treatments was verified by a significant reduction in the level of corticotropin-releasing factor messenger RNA in specific brain regions as determined by quantitative reverse transcription polymerase chain reaction analysis. These results strengthen the importance of corticotropin-releasing factor in modulating memory processing and exploratory behaviour in rats. This work also provides an important tool for studying other physiological functions that corticotropin-releasing factor may mediate or modulate in mammals.