Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex

Abstract

Rationale Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior. Objectives The objectives of the study are to assess the anti-aggressive effects of 5-HT1A and 5-HT1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and CP-93,129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT1A and 5-HT1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects. Results 8-OH-DPAT (0.56 and 1.0 μg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 μg) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 μg) and SB-224,289 (1.0 μg). Conclusions The decrease in aggressiveness observed with microinjections of 5-HT1A and 5-HT1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner.

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…(Parsey et al, 2002). Consistently, local infusion of 5-HT 1A and 5-HT 1B receptor agonists into the ventral OFC decreases aggressive behavior in rodents (Centenaro et al, 2008;da Veiga et al, 2011). Local infusion of a 5-HT 1A receptor agonist into median raphe nucleus, the corticomedial amygdaloid nucleus, or the dorsal PAG also reduces aggressive behavior, whereas conversely local infusion of a 5-HT 1A receptor agonist into the medial septal area increases aggressive behavior (De Almeida and Lucion, 1997).…”

“…Furthermore, manipulations that lower 5-HTergic signaling, such as PCPA injections, increase impulsivity and aggression, whereas increasing 5-HT signaling using 5-HT precursors or SSRIs can reduce aggressive behavior in rodents (Chiavegatto et al, 2001;Di Chiara et al, 1971;Hodge and Butcher, 1974;Koe and Weissman, 1966;Miczek et al, 2001). Pointing at a critical role for 5-HT 1 receptor subtypes in mediating the antiaggressive effects of increased 5-HT signaling, systemic administration of drugs activating 5-HT 1A and 5-HT 1B receptors exert antiaggressive effects (Bannai et al, 2007;Centenaro et al, 2008;de Boer and Koolhaas, 2005;Miczek et al, 1989;Olivier et al, 1995;Sijbesma et al, 1991). The link between 5-HT and aggression has been further established using genetically modified mouse models.…”

“…Intriguingly, it overlaps with circuitry controlling fear, anxiety, and mating behavior at the neuroanatomical and even cellular level (Canteras and Graeff, 2014 Monoaminergic afferents target the central nodes of this aggression circuitry, and thereby confer modulatory and regulatory consequences on behavior (Figure 3). However, monoaminergic action in target regions depends on several factors ranging from the neuroanatomical connectivity map at the cellular level and the receptor complement present on Sweidan et al, 1991Schwartzer and Melloni, 2010Parsey et al, 2002Rosell et al, 2010Centenaro et al, 2008da Veiga et al, 2011 Local infusion: 5-HT1AR agonist Figure 3. Monoaminergic modulation of aggression circuitry.…”

HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory

“…Finally, animal models suggest a specific role of HTR1B in socially relevant behaviors such as rearing and grooming; the microinjection of HTR1B agonist into the prefrontal cortex of mice resulted in increased rearing and grooming behavior along with an increased aggressiveness after social instigation. Intriguingly, HTR1A agonist threat was associated with a similar effect on social aggressiveness, but a reversed effect on rearing and grooming [32]. That is, HTR1B stimulation in the prefrontal cortex of animals may lead to an enhanced behavioral reactivity to the external stimuli, which results in an association with both disruptive and social promoting activities, this being decided likely according to the cognitive interpretation the animal carries out of the environmental conditions.…”

Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT1B/ striatal dopamine D2 receptor density

“…Thus, if the stimulation of 5-HT1Br (acted by 5-HT1Br agonists) inhibits aggressive behavior, it is reasonable to expect that the blockage of 5-HT1Br, which may be analogous to low availability of 5-HT1Br or low 5-HT1Br densities, increases aggressive behavior. More interestingly, the microinjection of 5-HT1Br agonists into the PFC decreases aggressive behavior (Centenaro et al, 2008;da Veiga et al, 2011;De Almeida et al, 2006;Veiga, Miczek, Lucion, & Almeida, 2007). Therefore, our findings suggest the possibility that chronic stress down-regulates 5-HT1Br densities in the prelimbic and orbitolateral cortices of the right hemisphere, which, in turn, escalates aggressive behavior (Lopez et al, 1997), although further research is needed to test this hypothesis.…”