Anxiety states induced by post-weaning social isolation are mediated by CRF receptors in the dorsal raphe nucleus

Abstract

Post-weaning social isolation of rats is utilized as a model of early life stress. We have previously demonstrated that rats exposed to post-weaning social isolation exhibit greater anxiety-like behaviors as adults. Furthermore, these rats exhibit greater density of corticotropin-releasing factor (CRF) type 2 receptors in the dorsal raphe nucleus. Therefore, we examined whether antagonism of CRF2 receptors in the dorsal raphe nucleus reverses the effects of post-weaning social isolation on anxiety states. Male rats were reared in isolation or in groups from day of weaning (postnatal day [PND] 21) to mid-adolescence (PND42) and then allowed to develop to early adulthood housed in groups. At PND62, rats were either infused with vehicle, the CRF1 receptor antagonist antalarmin (0.25-0.5 μg) or the CRF2 receptor antagonist antisauvagine-30 (2 μg) into the dorsal raphe nucleus, 20 minutes prior to being introduced to the elevated plus maze. Isolation-reared rats showed reduced open arm behavior compared to group-reared rats, confirming the anxiogenic effects of post-weaning social isolation. Infusion of the CRF2 receptor antagonist, but not the CRF1 receptor antagonist, into the dorsal raphe nucleus of isolation-reared rats increased open arm behavior when compared to that of group-reared rats. Overall, the findings suggest that CRF2 receptors within the dorsal raphe nucleus mediate anxiety-like states following post-weaning social isolation, and CRF2 receptors may represent an important target for the treatment of anxiety disorders following early life stressors.

Opposite Sex Contact and Isolation: A Novel Depression/Anxiety Model

“…Our results are consistent with this finding. It is well known that social isolation increases anxiety-like behaviors [4,5]. Nevertheless, social isolation paradigms are overwhelmingly modeled by early-life stress.…”

The Role of the Amygdala in Anxiety Disorders

“…A strong body of evidence implicates central CRF in mediating fear and anxiety [12,[121][122][123][124][125][126][127][128], and recent clinical studies suggest an important role for CRF in anxiety disorders [129]. Like anxiogenic and fearful stimuli, central infusion of CRF or CRF receptor agonists increases 5-HT, NE and DA levels in the amygdala [130][131][132][133], and stress-induced increases in monoamine levels in the amygdala are prevented by CRF receptor antagonists [108,111].…”

“…Interestingly, CRF-induced 5-HT release in the amygdala appears to be dependent on CRF2 receptor activation in the dRN [131,133], and CRF2 receptors are known to increase 5-HT neuronal firing rates in the dRN [141]. Importantly, increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused directly into the dRN reduce heightened anxiety-like behavior in rat models of amphetamine withdrawal or early life stress [12,128].…”

“…Importantly, increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused directly into the dRN reduce heightened anxiety-like behavior in rat models of amphetamine withdrawal or early life stress [12,128]. Combined, these findings suggest that CRF2 receptor modulation of 5-HT activity in the amygdala may play an important role in heightened anxiety.…”

“…Furthermore, CRF and its receptors (CRF1 and CRF2) are implicated in fear and anxiety within animal models and in the development of anxiety disorders [12,[121][122][123][124][125][126][127][128][129]. Upon the development of non-peptide CRF1 receptor antagonists that cross the blood-brain barrier, there was great interest in the use of CRF1 receptor antagonist in the treatment of anxiety disorders.…”