Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

Abstract

Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT 1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT 1B agonist anpirtoline (0.125-1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression "instigated" or primed by prior exposure to the opponent, and (3) aggression heightened by "frustration" caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT 1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT 1Bagonists 253, zolmitriptan) The development of valid experimental protocols that model clinically relevant, excessive levels of aggressive behavior is a continuing challenge for pre-clinical research on aggression (Miczek 2001). The leading neurobiological hypothesis attributes such intense aggressive behavior, often related to expressions of impulsivity, to a deficit in brain serotonin (Linnoila et al. 1983;Virkkunen et al. 1989;Coccaro 1989). An early example of this research strategy was the demonstration that mice would exhibit intense aggressive behavior after prolonged isolated housing, and this isolation-induced aggression is associated with lower serotonin turnover in the brainstem ). Long-standing concerns with the validity and reliability of isolation-induced aggression and its limited species generality prompt the search for alternate approaches (Brain 1975;Krsiak 1975). Similarly, correlation of aggressive behavior with a single tissue or CSF measurement of serotonin or its metabolite need to be reconciled with the anti-aggressive effects of agonist NO . 2 and antagonist treatment of specific serotonin receptor subtypes (Olivier et al. 1995;de Almeida et al. 2001).The exposure of an experimental subject to a potential rival for a short time prior to the actual confrontation engenders intense levels of aggression, as originally described in mice (Lagerspetz 1969;Tellegen and Horn 1972). For example, mice, rats, and hamsters initiate attacks with very short latency and at high frequency when tested with an intruder in their home cage or in an unfamiliar locale after having been provoked previously by an opponent (Potegal 1992;Fish et al. 1999). Instigation or priming is specific for increasing aggressive behavior and does not activate locomotion, feeding, or sexual behavior (Lagerspetz and Hautojarvi 1967;Potegal and Tenbrink 1984;Potegal 1992). Even after removal of the instigating or priming stimulus, high levels of aggression persist in fish and rodents, presumably from increased "aggressive arousal" or "attack readiness" (Heiligenberg 1974;Potegal and Tenbrink 1984;Potegal 1992). At the neurochemical level, animals that have been instigated to fight are characterized by a long-lasting decrease in serotonin in hypoth...

The Influence of Early Weaning on Aggressive Behavior in Mice

“…This finding implies that the level of aggression may have been heightened by the early weaning manipulation but we could not detect the attack bite behavior in isolation-induced aggression tests. One possible explanation for why the laboratory mice were not very aggressive in the isolation-induced aggression test was the fact that sexually naive mice were used in the previous study, and such mice have been reported to show low levels of aggression [2,15]. The purpose of the present study was to investigate the effects of early weaning on aggressive behavior exhibited in adulthood after the males were paired with females for 3 weeks.…”

Interaction of nitric oxide and serotonin in aggressive behavior

“…Both male and female mice that lack functional expression of the 5-HT 1B receptor gene (5-HT 1B Ϫ/Ϫ ) are more aggressive (Saudou et al, 1994;Bouwknecht et al, 2001), consistent with the anti-aggressive effect of several 5-HT 1B agonists including eltoprazine (Olivier et al, 1990), CP-94,253 (Fish et al, 1999;Chiavegatto et al, 2001), zolmitriptan , and anpirtoline (Rilke et al, 2001;Miczek and de Almeida, 2001;de Almeida and Miczek, 2002). Although agonists at 5-HT 1A receptors also decrease aggression in rodents (Olivier et al, 1995;Miczek et al, 1998), the mutant mice lacking 5-HT 1A receptors are more anxious, less reactive, and possibly less aggressive (Zhuang et al, 1999).…”

Effect of 5-HT1B receptor agonists injected into the prefrontal cortex on maternal aggression in rats

“…CP-94,253, anpirtoline and zolmitriptan, all 5-HT 1B receptor agonists, when administered systemically have anti-aggressive effects under conditions that induce moderate or escalated levels of aggression such as social instigation, self-administration of alcohol or frustration, without impairing non-aggressive activities (2,3). This 5-HT receptor subtype received considerable attention when mutant 129/Sv mice lacking the gene for the 5-HT 1B receptor were found to display more aggressive behavior (4,5).…”

“…Stimulation of 5-HT 1B receptors in the VO PFC proved to effectively reduce aggressive behavior in resident male mice confronting an intruder without discernible side effects (12). From a clinical perspective, it is important to study animal aggression that escalates above the species-typical level (2,3). One experimental approach used to escalate aggressive behavior is to provoke an animal by exposing it to a rival, and this procedure is often referred to as social instigation (17)(18)(19).…”

“…One experimental approach used to escalate aggressive behavior is to provoke an animal by exposing it to a rival, and this procedure is often referred to as social instigation (17)(18)(19). Most individuals engage in aggressive behavior at twice the usual level after being instigated than without such provocation (2,3). Nearly all evidence about 5-HT 1B receptors and escalated aggression has been obtained from experiments with males, and there is an urgent need to investigate this neurobiological mechanism in female aggression.…”