Corticotropin-releasing factor receptor antagonism within the dorsal raphe nucleus reduces social anxiety-like behavior after early-life social isolation

Abstract

Social isolation of rats during the early part of development increases social anxiety-like behavior in adulthood. Furthermore, early-life social isolation increases the levels of corticotropin-releasing factor (CRF) receptors in the serotonergic dorsal raphe nucleus (dRN) of adult rats. Interactions between serotonin and CRF systems are thought to mediate anxiety behavior. Therefore, we investigated the effects of CRF receptor antagonism within the dRN on social anxiety-like behavior after early-life social isolation. Male rats were reared in isolation or in groups from weaning until midadolescence, and rehoused in groups and allowed to develop into adulthood. Adult rats underwent surgery to implant a drug cannula into the dRN. After recovery from surgery and acclimation to the testing arena, rats were infused with vehicle or the CRF receptor antagonist d-Phe-CRF((12-41)) (50 or 500 ng) into the dRN before a social interaction test. Isolation-reared rats pretreated with vehicle exhibited increased social anxiety-like behavior compared with rats reared in groups. Pretreatment of the dRN with d-Phe-CRF((12-41)) significantly reduced social anxiety-like behaviors exhibited by isolation-reared rats. Overall, this study shows that early-life social stress results in heightened social anxiety-like behavior, which is reversed by CRF antagonism within the dRN. These data suggest that CRF receptor antagonists could provide a potential treatment of stress-related social anxiety.

Figure 1.

Cannula placements in the dRN. Schematic representations of drug infusion cannulae placements in the dRN (gray dots) or outside the dRN (gray stars) for control pair-housed (A), group-reared (B), and isolation-reared (C) rats. Figures were adapted from Paxinos and Watson (1997).

Figure 2.

Infusion of d-Phe-CRF into the dRN does not differentially affect locomotion. All rats, regardless of dRN drug infusion, showed reduced levels of distance moved over the testing session. *p < 0.05 compared with the first 5 min for all three drug treatments. The figure inset shows no significant difference in the total amount of distance moved between drug treatment groups. Error bars indicate SEM.

Figure 3.

CRF receptor antagonism within the dRN reduced social anxiety-like behavior of isolates. A, Isolation-reared rats exhibited increased latency to approach an unfamiliar conspecific (aCSF treatment) compared with group-reared rats during a 30 min social interaction test, which was significantly decreased after pretreatment of the dRN with 50 and 500 ng of d-Phe-CRF. B, Isolation-reared rats exhibited decreased duration of social contact compared with group-reared rats, which was increased to group-reared rat levels by pretreatment of the dRN with d-Phe-CRF. C, Isolation-reared rats also showed increased duration of fear behavior compared with group-reared rats, which was reduced to group-reared rat levels by pretreatment of the dRN with d-Phe-CRF. *p < 0.05 between group- and isolation-reared rats. ^#p < 0.05 compared with aCSF infusion. ^δp < 0.05 compared with 50 ng of d-Phe-CRF infusion. Error bars indicate SEM.