Corticotropin-releasing factor and defensive withdrawal: inhibition of monoamine oxidase prevents habituation to chronic stress.

There is growing evidence for a role of extrahypothalamic corticotropin-releasing factor (CRF) in the pathogenesis of anxiety. A modified form of the defensive withdrawal test was used to test the anxiogenic effects of acute administration of intracerebroventricular (1 microg, i.c.v.) CRF in adult male rats. Habituation to the mild stress of daily handling and subcutaneous (s.c.) saline injection over 2-6 weeks abolished the anxiogenic effects of exogenous CRF. At 6 weeks this habituation also resulted in attenuation of baseline withdrawal behavior. CRF receptor binding was significantly decreased in the amygdala of chronically handled animals and may have been responsible for this habituation phenomenon. Comparison of rats treated with the monoamine oxidase (MAO) inhibitor, phenelzine [3 mg/kg, s.c., daily for 2-6 weeks] to the saline-treated groups revealed a failure to habituate to the chronic handling, as the baseline withdrawal (after injection of artificial CSF) by the phenelzine-treated animals was not different from the baseline withdrawal by unhandled rats. In comparison to rats treated chronically with saline, phenelzine treatment enhanced the anxiogenic effect of CRF. In summary, habituation to a mild chronic stress decreased baseline defensive withdrawal. Intraventricular administration of CRF produced an anxiogenic response as measured in the defensive withdrawal test, which was lost through exposure to mild chronic stress. Two or 6 weeks of daily handling and SC saline injection caused a downregulation of CRF receptors in the amygdala, which could account for the behavioral habituation and the loss of CRF-induced defensive withdrawal. Phenelzine treatment concurrent with mild chronic stress prevented habituation and maintained the anxiogenic effect of CRF in spite of the downregulation of CRF receptors in the amygdala.