Social instigation and aggression in postpartum female rats: role of 5-Ht1A and 5-Ht1B receptors in the dorsal raphé nucleus and prefrontal cortex

Abstract

Rationale 5-HT1A and 5-HT1B receptor agonists effectively reduce aggressive behavior in males that has been escalated by social instigation. Important sites of action for these drugs are the receptors in dorsal raphé nuclei (DRN) and the ventral–orbital prefrontal cortex (VO PFC). DRN and VO PFC areas are particularly relevant in the inhibitory control of escalated aggressive and impulsive behavior. Objectives The objectives of this study are to assess the anti-aggressive effects of 5-HT1A (8-OH-DPAT) and 5-HT1B (CP-93,129) receptor agonists microinjected into DRN and VO PFC, respectively, and to study the aggressive behavior in postpartum female Wistar rats using the social instigation protocol to increase aggression. Methods and Results 8-OH-DPAT (0.56 µg) in the DRN increased aggressive behavior in postpartum female rats. By contrast, CP-93,129 (1.0 µg) microinjected into VO PFC 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. When 8-OH-DPAT was microinjected into DRN and CP-93,129 was microinjected into VO PFC in female rats at the same time, maternal aggression decreased. Specific participation of 5-HT1B receptors was verified by reversal of the anti-aggressive effects using the selective antagonist SB-224,289 (1.0 µg). Conclusions The decrease in maternal aggressive behavior after microinjections of 5-HT1B receptor agonists into the VO PFC and DRN of female postpartum rats that were instigated socially supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner, due to activation of 5-HT1B receptors at the soma and terminals.

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).…”

“…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.…”

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.…”

“…*p < .05, comparing immobilized and nonimmobilized subjects and comparing 1-day immobilization subjects with 5-and 10-day immobilization subjects day, and 10-day exposure to immobilization stress would affect aggressive behavior. Unlike previous studies where stressed animal subjects were screened on the basis of their aggressive behavior against a random opponent (da Veiga et al, 2011;de Almeida & Miczek, 2002;Fish et al, 1999;Wood et al, 2008;Wood et al, 2003), our study assessed longitudinal changes of aggressive behavior (across stress phase and recovery phase) while controlling for the physical size of opponents, following various lengths of immobilization stress. Consistent with our hypothesis, chronic (10-day) immobilization stress increased aggressive behavior among rats over the course of the experiment.…”

Neuronal serotonin in the regulation of maternal behavior in rodents

“…In this study, rats treated with a 5HT 2 receptor agonist took a much shorter time to initiate contact with pups and retrieve their pups into the nest sites, retrieved more pups and spent more time licking their pups [27] . Similarly, the administration of agonists for the serotonin 5HT 1B receptor caused increased maternal aggression in postpartum rats [33] . Several studies have been carried out to study the influence of serotonin in the regulation of maternal responses, and these include the use of pharmacological manipulations as well as transgenic models designed to target more specific elements within the serotonin system (see table 1).…”