5-HT1A receptor activation reduces fear-related behavior following social defeat in Syrian hamsters

Abstract

Social defeat leads to selective avoidance of familiar opponents as well as general avoidance of novel, non-threatening intruders. Avoidance of familiar opponents represents a fear-related memory whereas generalized social avoidance indicates anxiety-like behavior. We have previously shown that serotonin signaling alters responses to social defeat in Syrian hamsters, although it is unclear whether serotonin modulates defeat-induced fear, anxiety, or both. In this study we focus on 5-HT1A receptors, in part, because their activation had been linked to the acquisition of conditioned fear. We hypothesized that pharmacological activation of 5-HT1A receptors prior to social defeat would reduce avoidance of familiar opponents, impair Arc expression in the basolateral amygdala (BLA), but not alter anxiety-like behavior. We administered 8-OH-DPAT, a 5-HT1A receptor agonist, prior to 3, 5-minute social defeats and 24-hours later exposed hamsters to a social interaction test to measure the conditioned defeat response immediately followed by either a Y-maze test or an open field test. In a separate experiment, we administered 8-OH-DPAT prior to 3, 5-minute social defeats and later removed brains for Arc immunohistochemistry. Social defeat increased the number of Arc immunopositive cells in the central amygdala (CeA), prelimbic cortex (PL), and BLA, and 8-OH-DPAT treatment reduced Arc immunoreactivity in the PL. These results suggest that 5-HT1A receptor activation impairs the fear memory associated with social defeat, but does not alter defeat-induced anxiety. Overall, 5-HT1A receptor activation may impair Arc expression in select brain regions such as the PL and thereby disrupt the development of a fear memory essential for the conditioned defeat response.

Activation of 5-HT2a receptors in the basolateral amygdala promotes defeat-induced anxiety and the acquisition of conditioned defeat in Syrian hamsters

“…Activity-regulated cytoskeletal-associated protein (Arc) is an immediate early gene and a commonly used marker of synaptic plasticity, as it is necessary for the consolidation of long-term memory (Ploski et al, 2008). Recently, we showed that social defeat increases the expression of Arc in the BLA of Syrian hamsters (Bader et al, 2014), which is consistent with other research showing that Arc in the lateral amygdala is necessary for the reconsolidation of auditory fear conditioning (Maddox & Schafe, 2011). Taken together, these findings suggest that the acquisition of conditioned fear and CD is regulated by a similar set of cellular and molecular mechanisms in the BLA.…”

“…On the other hand, social defeat has been shown to increase anxiety-like behavior in an open field test as indexed by reduced locomotion and reduced time spent in the center of the arena (Raab et al, 1986, Meerlo et al, 1996, Kinsey et al, 2007). Also, Syrian hamsters generalize social avoidance to novel intruders suggesting that conditioned defeat involves an increase in anxiety-like behavior (Bader et al, 2014). …”

Dominance status alters restraint-induced neural activity in brain regions controlling stress vulnerability

“…In the social interaction test, one restrained animal briefly showed submissive behavior toward the intruder, and several restrained animals displayed aggressive behavior. These data are similar to agonistic behavior displayed by non-stressed hamsters in a resident-intruder paradigm, and indicate that acute restraint stress does not alter subsequent agonistic behavior [16, 19, 34, 37]. In the other behavioral tests, restrained animals tended to differ from non-restrained controls on some measures, but not always in a direction that would be considered anxiety-like.…”

“…In the learned helplessness model, uncontrollable tail shock sensitizes the caudal DRN, and serotonergic projections from the caudal DRN to the DS and BLA mediate escape deficits and anxiety-like behavior, respectively [65–68]. In the conditioned defeat model, acute social defeat activates the rostral DRN and serotonergic projects to the BLA modulate the changes in agonistic behavior characteristic of the conditioned defeat response [16, 34, 63, 69]. Interestingly, subordinate social status appears to sensitize several DRN subregions such that subsequent social defeat stress leads to elevated neural activity in the rvDRN whereas subsequent restraint stress increases neural activity in the cdDRN.…”

“…A great deal of information indicates that the conditioned defeat response is an ethologically relevant form of conditioned fear. Several cellular and molecular mechanisms that regulate synaptic plasticity within the basolateral amygdala (BLA) are critical for the acquisition of conditioned defeat, including the activity of NMDA receptors, cyclic AMP response element binding protein, brain-derived neurotropic factor, and activity-regulated cytoskeletal-associated protein [13–16]. In addition, neurotransmission in several cortical, limbic, and hindbrain regions modulate both the acquisition and expression of conditioned defeat, including the BLA, central amygdala (CeA), medial amygdala (MeA), bed nucleus of the stria terminalis (BNST), lateral septum (LS), nucleus accumbens (NAcc), ventral hippocampus (vHP), vmPFC, and DRN [17–23].…”