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

Corticotropin releasing factor (CRF) is an important regulator of the endocrine, behavioral, autonomic and immune responses to stress, Two high affinity CRF receptors have been identified, which are distributed in distinct anatomical regions. CRF1 receptors have been relatively well characterized and antagonists to this receptor effectively block stress-induced behaviors in rodents. The function of CRF2 receptors, which are highly expressed in limbic brain regions, is less well understood. Therefore, an antisense oligonucleotide approach was used to study the role of CRF2 receptors in the lateral septum in rats. An antisense oligonucleotide directed against the CRF2 receptor mRNA reduced expression of CRF2 receptors by 60-80%. in shock-induced freezing tests, animals administered the antisense oligonucleotide exhibited a significant reduction in freezing duration. However, pain sensitivity and locomotor activity were unaltered. A four-base mismatch of the antisense sequence had no significant effects on CRF2 receptor density and on freezing behavior. These data support the involvement of CRF2 receptors in fear conditioning. CRF1, receptor antagonists also reduce freezing in this test. Additional studies to determine the effects of simultaneous inhibition of both receptor subtypes show that rats receiving both CRF2 receptor antisense oligonucleotide and CRF1 receptor antagonist frets significantly less than animals treated with either agent alone. These results provide additional evidence for the role of CRF2 receptors in mediating the stress-induced actions of endogenous CRF. (C) 2001 Dupont pharmaceuticals Company. Published by Elsevier Science B.V. Ail rights reserved