Introduction
Aggressiveness is considered a social behavior since it requires at least two subjects, and it can be either defensive or offensive. Among primates, humans and rodents there are similarities in aggressive neurobiology (Takahashi et al., 2011; Niederkofler et al., 2016). The aggressive spectrum displayed depends on the specie, the sex, the stimuli, and the contextual contingency (Niederkofler et al., 2016; Takahashi et al., 2011; Takahashi & Miczek, 2014). According to the qualitative and quantitative features aggressiveness in rodents, could be considered as adaptive or maladaptive (Muroy et al., 2016). In their natural environment, rodents are strongly aggressive to defend their food resources, reproductive possibilities and territory (Takahashi et al., 2012). The resident vs. intruder test (RVI) is the most validated paradigm to measure this kind of interaction (Takahashi & Miczek, 2014).
Serotonin (5-HT) plays an important role in social behavior. Among others, modulates several behaviors, such as copula, postnatal care, adolescent social playing, maternal and territorial aggressiveness (Berger et al., 2009; Buhot et al., 2000; Mittal et al., 2017; Strüder & Weicker, 2001; Takahashi et al., 2012). Many systems are involved in aggressive behavior (Chamero et al., 2011; Carrillo et al., 2009; Duke at al., 2013) Although, serotonergic deficiency hypothesis establish an inverse relationship between the serotonergic system activity and aggressive behavior (Cervantes & Delville, 2009; Kravitz & Huber, 2003; Miczek et al., 2004; Mongillo et al., 2014; Takahashi et al., 2011; Niederkofler et al., 2016; van Erp & Miczek; 2000). In rodent models, there are several ways to generate aggressiveness by decreasing 5-HT: neurotoxicity, olfactory bulbectomy, social isolation, and pharmacological depletion (Hritcu et al., 2007; Jéquier et al., 1967; Koe & Weissman, 1966; Vergnes et al., 1988). Para-chlorophenylalanine (pCPA) is an irreversible TPH enzyme inhibitor. An intraperitoneal pCPA administration causes an acute decrease within the central serotonergic system (Jáquier, 1967; Hritcu et al., 2007) and it has been used to generate aggression models (Jáquier, 1967; Keleta et al., 2007; Kubala et al., 2008).
5-HT producing neurons in the raphe complex project their axons to the cortex, amygdala, hippocampus, basal ganglia, thalamus, hypothalamus, and olfactory bulb (OB) (Lesch & Waider, 2012; Mazerolle et al., 2016). OB is an important serotonergic innervated structure (Huang et al., 2017; McLean & Shipley, 1987; Steinfeld et al., 2015) and the main sensory information used by rodents to start social interactions, such as aggressive behavior, is olfaction (Guillot & Chapouthier, 1996). Moreover, Lucki (1998) showed that 5-HT synthesis inhibition in OB rats caused increased aggressiveness, whereas enhancement transmission suppressed aggressive behavior. First sensory center that processes odor information is the OB, a structure that has been considered when studying territorial aggression (Bester-Meredith et al., 2022). ​​Nonetheless, the relationship between OB and aggression in a pCPA 5-HT depletion model has not been studied.
5-HT is synthesized through the tryptophan hydroxylase (TPH) enzyme (Khan & Thomas, 2004). TPH gene has two isoforms (Walther et al., 2003), while the TPH1 isoform is mostly expressed outside the blood-brain barrier, the TPH2 isoform is expressed in the cerebral tissue and its mRNA expression has so far been mostly described in raphe complex neurons (Malek et al., 2005; Patel et al., 2004; Pelosi et al., 2015; Walther et al., 2003). A human brain post-mortem study, showed TPH2 expression in the cortex, thalamus, hypothalamus, hippocampus, amygdala, cerebellum, and raphe nuclei (Zill et al., 2007). A study using catfishes (Raghuveer et al.; 2011) reported TPH2 mRNA expression in OB. Furthermore, Patel et at., (2004) showed that TPH2 mRNA expression in rat brain revealed a very weak signal in the OB.
Principal neurons and local interneurons in OB have GABAA receptors with different subunit components (Panzanelli, 2005). Particularly, the presence of GABAA receptor subunit α1 mRNA in the OB has been described (Zhang et al., 1991) and is the most common GABAA α subunit in adult rodent neurons (Bosman et al., 2002). In addition, it has been reported that 5-HT depletion could affect GABAA receptor expression in different brain areas (Si et al., 2022; Wang et al., 2020).
Our aim was to evaluate aggressive behavior, serotonergic activity in the OB, TPH2, and GABAA α1 mRNA expression in the OB, after a single pCPA i.p administration in male rats.