Activation of 5-HT1A autoreceptors in the dorsal raphe nucleus reduces the behavioral consequences of social defeat

Abstract

In animal models, serotonin (5-HT) activity contributes to stress-induced changes in behavior. Syrian hamsters (Mesocricetus auratus) exhibit a stress-induced change in behavior in which social defeat results in increased submissive and defensive behavior and a complete loss of normal territorial aggression directed toward a novel, non-aggressive opponent. We refer to this defeat-induced change in agonistic behavior as conditioned defeat. In this study we tested the hypothesis that 5-HT activity in the dorsal raphe nucleus (DRN) contributes to the acquisition and expression of conditioned defeat. We investigated whether injection of the selective 5-HT1A agonist flesinoxan (200 ng, 400 ng, or 800 ng in 200 nl saline) into the DRN would reduce the acquisition and expression of conditioned defeat. Additionally, we investigated whether injection of the selective 5-HT1A antagonist WAY 100635 (400 ng in 200 nl saline) into the DRN would enhance the acquisition and expression of conditioned defeat following a sub-optimal social defeat experience. We found that injection of flesinoxan into the DRN before exposure to a 15-min social defeat reduced the amount of submissive and defensive behavior shown at testing. We also found that injection of flesinoxan into the DRN before testing similarly reduced submissive and defensive behavior. In addition, we found that WAY 100635 enhanced conditioned defeat when injected either before social defeat or before testing. These data support the hypothesis that the activity of 5-HT cells in the DRN, as regulated by 5-HT1A autoreceptors, contributes to the formation and display of conditioned defeat. Further, our results suggest that 5-HT release in DRN projection regions augments defeat-induced changes in social behavior.

Figure 1

The location of DRN injection sites are shown. a) A representative photomicrograph is shown of a hamster coronal brain section injected with India ink and stained with neutral red. The needle tract and ink injection are clearly visible and indicate an injection site approximately 5.4 mm behind bregma. b) Schematic representations are shown of hamster coronal brain sections adapted from the atlas of Morin and Wood (2001), and coordinates are reported from bregma. The illustrations represent injections from all four experiments and circles indicate the location of multiple injections. Black circles indicate the approximate site of accurately placed injections within the DRN, and open circles indicate injections placed outside the DRN. DRN – dorsal raphe nucleus, 4V – fourth ventricle, PAG – periaqueductal grey, xscp – decussation of the superior cerebellar peduncle.

Figure 2

Durations (mean ± SE) of submissive and defensive, aggressive, social, and nonsocial behavior are shown for a 5-min test with a novel, non-aggressive opponent. Defeated animals received an injection of flesinoxan (200 ng, N = 11; 400 ng, N = 10; 800 ng, N =11) or vehicle (N = 10) into the dorsal raphe nucleus (DRN) 10 min before defeat training. Likewise, no defeat controls received an injection of flesinoxan (800 ng, N = 10) or vehicle (N = 9) into the DRN 10 min before exposure to a resident aggressor’s empty cage. These data demonstrate reduced submissive and defensive behavior with increasing doses of flesinoxan given prior to training (asterisk indicates p < 0.05 compared to vehicle controls). Flesinoxan given prior to defeat training did not alter the behavior of no defeat controls. See the text for significant differences between defeated animals and no defeat controls.

Figure 3

Durations (mean ± SE) of submissive and defensive, aggressive, social, and nonsocial behavior are shown for a 5-min test with a novel, non-aggressive opponent. Defeated animals received an injection of flesinoxan (200 ng, N = 8; 400 ng, N = 9; 800 ng, N = 9) or vehicle (N = 9) into the dorsal raphe nucleus (DRN) 10 min before conditioned defeat testing. Likewise, no defeat controls received an injection of flesinoxan (800 ng, N = 8) or vehicle (N = 8) into the DRN 10 min before testing. These data demonstrate reduced submissive and defensive behavior with increasing doses of flesinoxan given prior to testing (asterisk indicates p < 0.05 compared to vehicle controls). Flesinoxan given prior to testing did not alter the behavior of no defeat controls. See the text for significant differences between defeated animals and no defeat controls.

Figure 4

Durations (mean ± SE) of submissive and defensive (sub/def), aggressive, social, and nonsocial behavior are shown for a 5-min test with a novel, non-aggressive opponent. Animals received an injection of WAY 100635 (400 ng, N = 11) or vehicle (N = 10) into the dorsal raphe nucleus 10 min before sub-optimal social defeat training. Administration of WAY 100635 prior to social defeat significantly increased submissive and defensive behavior compared to vehicle controls (asterisk indicates p < 0.05).

Figure 5

Durations (mean ± SE) of submissive and defensive (sub/def), aggressive, social, and nonsocial behavior are shown for sub-optimally defeated animals during a 5-min test with a novel, non-aggressive opponent. Animals received an injection of WAY 100635 (400 ng, N = 10) or vehicle (N = 9) into the dorsal raphe nucleus 10 min before conditioned defeat testing. Injection of WAY 100635 prior to testing significantly increased submissive and defensive behavior compared to vehicle controls (asterisk indicates p < 0.05).