The effect of a corticotropin-releasing factor receptor 1 antagonist on the fear conditioning response in low- and high-anxiety rats after chronic corticosterone administration.

This study aimed to test the hypothesis that high-anxiety (HR) rats are more sensitive to the effects of chronic corticosterone administration and antalarmin (corticotropin-releasing factor (CRF) receptor 1, CRF1 antagonist) injections than low-anxiety (LR) rats, and this effect is accompanied by changes in CRF system activity in brain regions involved in the control of emotions and the hypothalamic-pituitary-adrenal (HPA) axis. Male rats were divided into LR (n = 25) and HR (n = 30) groups according to the duration of conditioned freezing in a contextual fear test. Chronic corticosterone administration (by injection, 20 mg/kg) for 21 d (except weekends) increased freezing duration and number of GR (glucocorticoid receptor)-immunoreactive nuclei in the basal amygdala (BA) and decreased GR-immunoreactive nuclei in the infralimbic cortex (IL), dentate gyrus (DG), and CA3 area, only in the HR group. Moreover, in this group, corticosterone administration decreased number of CRF-immunoreactive neurons of the parvocellular paraventricular hypothalamic nucleus (pPVN), DG, and CA1. Antalarmin (10 mg/kg, i.p., 2 injections) significantly attenuated conditioned fear responses, increased plasma corticosterone concentration, and decreased GR-immunoreactive nuclei in the BA, only in the HR group. Moreover, in this group, antalarmin increased number of GR-immunoreactive nuclei in the IL, DG, and CA3 and increased number of CRF-immunoreactive cells in the pPVN, DG, and CA1. Hence, antalarmin attenuated the fear response and restored HPA axis function in HR rats, which were more sensitive to corticosterone exposure. These data suggest that individual differences in central local CRF system activity may determine the neurobiological mechanisms related to mood and emotional disorders.