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 CRF(2) 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 CRF(1) receptor antagonist antalarmin (0.25-0.5 μg) or the CRF(2) receptor antagonist antisauvagine-30 (2 μg) into the dorsal raphe nucleus, 20 min 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 CRF(2) receptor antagonist, but not the CRF(1) 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 CRF(2) receptors within the dorsal raphe nucleus mediate anxiety-like states following post-weaning social isolation, and CRF(2) receptors may represent an important target for the treatment of anxiety disorders following early life stressors.

Figure 1

Behavior on the elevated plus maze (EPM) of young adult rats reared in isolation or group conditions. Isolation-reared rats showed (A) reduced number of open arm entries and (B) reduced time spent in open arms of the EPM, indicative of increased anxiety-like behavior. (C) Total distance moved in the EPM did not differ between rearing conditions. *P < 0.05. N = 12 per group.

Figure 2

Cannula placements within and surrounding the dorsal raphe nucleus (dRN) for (A) group-reared and (B) isolation-reared rats. Circles indicate placements within the dRN and stars indicate placements within 0.5 mm of the dRN. Figures adapted from [28].

Figure 3

Effects of corticotropin-releasing factor (CRF) receptor antagonists infused into the dorsal raphe nucleus (dRN) on behavior in the elevated plus maze (EPM) of young adult rats reared in isolation or group conditions. (A) Isolation-reared rats showed reduced number of open arm entries that was reversed by dRN infusion of either the CRF₂ receptor antagonist antisauvagine-30 (ASV-30) or 0.25 μg of the CRF₁ receptor antagonist antalarmin (Ant). (B) Isolation-reared rats showed reduced time spent in open arms of the EPM, which was reversed by dRN infusion of the CRF₂ receptor antagonist ASV-30. (C) Total distance moved in the EPM did not differ between rearing conditions or dRN infusion treatment groups. *Significantly different from vehicle-treated group-reared rats; ^#significantly different from vehicle-treated isolation-reared rats; P < 0.05. N = 6-8 per group.