Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety.
Two brain-derived corticotropin-releasing hormone receptors have been cloned, termed corticotropin-releasing hormone receptors type I and type 2. Antisense oligodeoxynucleotides targeted to the cloned rat and mouse corticotropin-releasing hormone receptors type I messenger RNA reduced the binding of the natural ligand of the corticotropin-releasing hormone receptors type I and also the release of adenocorticotrophic hormone in primary rat anterior pituitary cells and in clonal mouse pituitary cells (AtT-20) by up to 60% in an application time-dependent manner. Studies on intracellular uptake of fluorescence-labelled oligodeoxynucleotides indicated a cytoplasmic accumulation starting within two to four hours after application of oligodeoxynucleotides in vitro. In vivo, antisense oligodeoxynucleotides infused intra-cerebroventricularly reduced binding of radiolabelled corticotropin-releasing hormone receptors in central sites of the rat brain. Anxiety induced by i.c.v. administration of corticotropin-releasing hormone was attenuated by corticotropin-releasing hormone receptors type I antisense treatment as determined in the elevated plus maze and in the novel open field test. The corticotropin-releasing hormone-induced behavioural changes were absent in corticotropin-releasing hormone receptors type I antisense-pretreated animals. These results show that the selected antisense probes used were able to suppress corticotropin-releasing hormone receptors type I function in vitro as well as in vivo and suggest that the development of drugs blocking this specific receptor might lead to a novel class of anxiolytics.
Skutella
T
T
Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Probst
J C
JC
Renner
U
U
Holsboer
F
F
Behl
C
C
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D001007:Anxiety / Q000503:physiopathology*; D002470:Cell Survival; D002531:Cerebellum / Q000737:chemistry / Q000166:cytology; D002540:Cerebral Cortex / Q000737:chemistry / Q000166:cytology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005239:Fear; D007031:Hypothalamus / Q000737:chemistry / Q000166:cytology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D010902:Pituitary Gland / Q000737:chemistry / Q000166:cytology; D010911:Pituitary Neoplasms; D012333:RNA, Messenger / Q000235:genetics; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism*; D013315:Stress, Psychological / Q000503:physiopathology; D014407:Tumor Cells, Cultured
D016375:Antisense Elements (Genetics); D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone