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. CRF 1 receptors have been relatively well characterized a...

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Bibliographic Details
Published in:Brain research. Molecular brain research. 2001-04, Vol.89 (1), p.29-40
Main Authors: Ho, Siew Peng, Takahashi, Lorey K, Livanov, Valentin, Spencer, Karen, Lesher, Treena, Maciag, Carla, Smith, Mark A, Rohrbach, Kenneth W, Hartig, Paul R, Arneric, Stephen P
Format: Article
Language:English
Subjects:
Animals
Antisense oligonucleotide
Behavioral psychophysiology
Biological and medical sciences
CHO Cells
Conditioning (Psychology) - physiology
Corticotropin releasing factor
corticotropin releasing factor l
corticotropin releasing factor receptors
CRF 2 receptor
Cricetinae
Electroshock
Fear - physiology
Fear conditioning
Fundamental and applied biological sciences. Psychology
Hormones and behavior
Injections, Intraventricular
Male
Oligonucleotides, Antisense - pharmacology
Pain Threshold - physiology
Psychology. Psychoanalysis. Psychiatry
Psychology. Psychophysiology
Rats
Rats, Sprague-Dawley
Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors
Receptors, Corticotropin-Releasing Hormone - genetics
Receptors, Corticotropin-Releasing Hormone - metabolism
Reflex, Startle - physiology
Septal Nuclei - physiology
Shock-induced freezing
Stress
Stress, Physiological - physiopathology
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Summary: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. CRF 1 receptors have been relatively well characterized and antagonists to this receptor effectively block stress-induced behaviors in rodents. The function of CRF 2 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 CRF 2 receptors in the lateral septum in rats. An antisense oligonucleotide directed against the CRF 2 receptor mRNA reduced expression of CRF 2 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 CRF 2 receptor density and on freezing behavior. These data support the involvement of CRF 2 receptors in fear conditioning. CRF 1 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 CRF 2 receptor antisense oligonucleotide and CRF 1 receptor antagonist froze significantly less than animals treated with either agent alone. These results provide additional evidence for the role of CRF 2 receptors in mediating the stress-induced actions of endogenous CRF.
ISSN:0169-328X
1872-6941
DOI:10.1016/S0169-328X(01)00050-X