Behavioral characterization of escalated aggression induced by GABAB receptor activation in the dorsal raphe nucleus

Abstract

Rationale Pharmacological activation of GABAB receptors in the dorsal raphé nucleus (DRN) can escalate territorial aggression in male mice. Objectives We characterized this escalated aggression in terms of its behavioral and environmental determinants. Methods Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 μl) or vehicle (saline) was microinjected into the DRN ten minutes before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment. Results Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts. Conclusions For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat.

Stress and the social brain: behavioural effects and neurobiological mechanisms

“…In rodents, acute stress -elicited, for example, by 'frustration' caused by omission of scheduled reinforcement or instigation by pre-exposure to a physically inaccessible intruder -typically leads to reduced social behaviors and increased aggression, including antisocial behaviours such as bite counts that exceed species-typical levels 11,12 . This fits with the concept of acute stress as a 'flight or fight' response 6 and implies that brief acute stressors mobilize resources to cope with the situation.…”

“…A fourth model -post-weaning social isolation -is characterized by normal basal HPA-axis activity, but enhanced autonomic and glucocorticoid responses to stress 65 , which may drive the increased-stress induced aggression seen in adults in this model 11,12 . Alterations in the glucocorticoid response to stress could result from molecular and cellular adaptations within different components of the HPA-axis as well as in the brain regions that regulate HPA-axis activity.…”

“…Corticosterone treatment in neonates 66 mimicked the diminished adult social exploration and increased submissiveness observed in maternally deprived mice 31,32,42 . Corticosterone treatment in juvenile rats 67 diminished social exploration as did exposure to peripuberty stress 35, 68-70 and acute glucocorticoid treatments in adulthood 71 increased aggressive behavior as did acute stress elicited by frustration 11,12 . Other studies have mimicked the long-term effects of early stress exposure on HPA-axis function.…”

Raphe GABAergic Neurons Mediate the Acquisition of Avoidance after Social Defeat

“…The mechanism by which silencing DRN GABA neurons impaired the socioaffective encoding without influencing the execution of social avoidance response remains uncertain. Increases in 5-HT output in the vmPFC after GABA-B receptor activation in the DRN and disinhibition of 5-HT neurons has been shown consistently to promote social approach and offensive behaviors of defeated mice (Takahashi et al, 2010;Takahashi et al, 2012). This is in general agreement with data linking enhancement of forebrain 5-HT output with resilience to social stress and maintenance of dominant social status in various species (Raleigh et al, 1991;Malatynska et al, 2005;Alekseyenko et al, 2010;Penn et al, 2010;Bruchas et al, 2011).…”

“…Local GABAergic neurons in the DRN are thought to provide an inhibitory relay for converging inputs that exert top-down control over 5-HT function (Freedman et al, 2000;Celada et al, 2001;Chiba et al, 2001;Varga et al, 2001;Varga et al, 2003;Amat et al, 2005). Pharmacological evidence further suggests that modulating GABA activity in the DRN has a dramatic impact on affiliative or aggressive behaviors (Takahashi et al, 2010;Takahashi et al, 2012); however, our understanding of these mechanisms on a microcircuit level remains limited.…”