Attenuation of fear conditioning by antisense inhibition of brain corticotropin releasing factor-2 receptor

Corticotropin releasing factor (CRF) is an important regulator of the endoc rine, behavioral, autonomic and immune responses to stress, Two high affini ty CRF receptors have been identified, which are distributed in distinct an atomical regions. CRF1 receptors have been relatively well characterized an d antagonists to this receptor effectively block stress-induced behaviors i n rodents. The function of CRF2 receptors, which are highly expressed in li mbic brain regions, is less well understood. Therefore, an antisense oligon ucleotide approach was used to study the role of CRF2 receptors in the late ral septum in rats. An antisense oligonucleotide directed against the CRF2 receptor mRNA reduced expression of CRF2 receptors by 60-80%. in shock-indu ced freezing tests, animals administered the antisense oligonucleotide exhi bited a significant reduction in freezing duration. However, pain sensitivi ty and locomotor activity were unaltered. A four-base mismatch of the antis ense sequence had no significant effects on CRF2 receptor density and on fr eezing behavior. These data support the involvement of CRF2 receptors in fe ar conditioning. CRF1, receptor antagonists also reduce freezing in this te st. Additional studies to determine the effects of simultaneous inhibition of both receptor subtypes show that rats receiving both CRF2 receptor antis ense oligonucleotide and CRF1 receptor antagonist frets significantly less than animals treated with either agent alone. These results provide additio nal evidence for the role of CRF2 receptors in mediating the stress-induced actions of endogenous CRF. (C) 2001 Dupont pharmaceuticals Company. Publis hed by Elsevier Science B.V. Ail rights reserved