Testosterone, cortisol, and serotonin as key regulators of social aggression: A review and theoretical perspective

As there is growing evidence that T and CRT together regulate social aggression, the question how this neurobiological mechanism operates becomes inevitable. CRT and T are the end products of the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) axes, respectively. The HPA axis consists of three levels, beginning with the paraventricular nucleus (PVN) of the hypothalamus, which produces corticotropin-releasing hormone (CRH) in response to stress. CRH, in turn, promotes the release of adrenocorticotropic hormone (ACTH) by the pituitary; the second level of the HPA axis. ACTH then stimulates the adrenal cortex, which ultimately leads to the synthesis and release of glucocorticoids (corticosterone in rodents and cortisol in humans). The HPG axis also consists of three levels of which the two first levels are the hypothalamus and the pituitary gland, where gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) together with follicle stimulating hormone (FSH) are released respectively. LH and FSH are transported to the third level of the HPG axis, the gonads, where they are responsible for the production of T, the end product of the HPG axis. Critically for explaining the apparent interplay of T and CRT in the studies described above (Dabbs et al. 1991; Glenn et al. 2011; Pajer et al. 2006; Popma et al. 2007), is evidence that the adrenal and gonadal systems interact antagonistically, that is the HPG axis inhibits the HPA axis and vice versa (Viau 2002). CRT inhibits HPG axis activity at all levels, and T inhibits HPA axis activity at the level of the hypothalamus (Johnson et al. 1992; Tilbrook et al. 2000; Viau 2002). Such an interaction would in itself bias the neurobiological profile toward imbalance, i.e. either high T and low CRT, or high CRT and low T. It is important to note here that due to differences in androgen production between females and males, the interaction of the HPG and HPA axes may be different between the sexes. This is because while in males androgen production mainly originates from the HPG axis, the relative contribution of the HPG axis on T secretion in females is lower, as approximately half of the androgen production comes from the adrenal cortex, the final component of the HPA axis (Burger 2002). Therefore, although the HPA and HPG axes have a mutual inhibitory relationship in both sexes, the magnitude of this relationship might be different between males and females.

The T/CRT ratio hypothesis (Terburg et al. 2009; van Honk et al. 2010) states that the predisposition for social aggression develops from such an imbalance of the hormones CRT and T. This imbalance is indicated by T/CRT ratio (T:CRT), in which a high ratio reflects high T levels in relation to CRT levels, and a low ratio reflects low T relative to CRT levels. These circulating steroids are suggested to exert long-term (genomic) influence on social aggression by up-regulating neuropeptide gene expression (van Honk et al. 2010). On the one hand, T elevates vasopressin gene expression at the amygdala, which facilitates aggressive approach (Schulkin 2003). Furthermore, T can regulate aggressive behavior by its conversion to estradiol (E) by the enzyme aromatase, which in rats promotes aggression [as discussed in (Trainor et al. 2006)]. On the other hand, excess of CRT and CRH promotes CRH gene expression in the amygdala, which facilitates fear/anxiety and behavioral withdrawal (Schulkin 2007; Schulkin et al. 1998). As we shall see in the remainder of this review, these different action mechanisms at the amygdala seem to cause diametrically opposite effects at the behavioral level, influencing the way an individual will react aggressively (fight) or fearful (flight) in social confrontations.

Causal evidence for effects of CRT and T on social aggressive tendencies comes from hormone administration studies that utilize psychological paradigms, which index motives for aggressive approach and fearful withdrawal.

Besides the genomic effects that were discussed earlier (Schulkin 2003, 2007; Schulkin et al. 1998), animal studies have shown that CRT and T administration have direct effects on the excitability of neurons within the amygdala (Karst et al. 2010; Sarkey et al. 2008). With functional neuroimaging it is possible to gain insights about the neural mechanisms by which these steroids alter aggression circuitry in the human brain. Starting with T effects, Hermans et al. (2008) used functional Magnetic Resonance Imaging (fMRI) to investigate this issue. These researchers showed participants angry facial expressions to probe the reactive aggression circuitry of the brain consisting of the hypothalamus, amygdala, orbital frontal cortices (OFC) and periaqueductal grey (PAG) in the brainstem [for a review on the neuroanatomy of the aggression system see (Nelson and Trainor 2007)]. It was found that exogenous T increased neural responses towards angry faces within this network. The amygdala is a key structure in the signaling of threat stimuli such as the angry and fearful face, and is supposed to regulate the processing thereof (Phelps and LeDoux 2005). Furthermore, amygdala and hypothalamus are known to have a rich androgen receptor distribution in animals (Sarkey et al. 2008), which supports the notion that this network is under strong mediation of T. Interestingly, in the study of Hermans and colleagues, T/CRT ratio correlated positively with activity in the amygdala-hypothalamus-PAG aggression network (Hermans et al. 2008). Recent correlative work is in line with this, showing that activity in amygdala in response to fearful and angry faces is positively correlated to serum and salivary T concentrations (Derntl et al. 2009; Manuck et al. 2010).

Turning to functional neuroimaging studies with CRT administration, similar paradigms have been conducted as with T administration. However, it seems that while T sensitizes the amygdala selectively towards angry faces, exogenous CRT seems to dampen amygdala reactivity in general. A recent study of Henckens et al. (2010) showed that acute hydrocortisone reduced left amygdala reactivity toward both fearful and happy faces. Desensitization of the amygdala in the resting brain following hydrocortisone administration has also been reported (Lovallo et al. 2010) and could explain the anxiolytic effects found in the administration behavioral studies (Buchanan et al. 2001; Putman et al. 2007a, b; van Peer et al. 2010). It remains to be scrutinized if CRT administration could alter amygdala responses selectively towards angry faces as to the best of our knowledge no fMRI study with CRT administration has included angry faces yet.

In sum, acute exogenous CRT reduces amygdala-mediated emotional processing, while acute exogenous T increases amygdala-mediated anger processing. When translating these findings towards the behavioral findings, it seems that T promotes vigilant responses to angry faces through inducing amygdala-hyperreactivity for angry faces and that exogenous CRT is anxiolytic, probably through inducing desensitization of the amygdala towards threat (fearful faces). What remains to be scrutinized, is which neural mechanisms are responsible for T effects on fearful faces and CRT effects on angry faces.

As discussed earlier in this review, CRT and T affect decision-making. The parameter within these paradigms that is manipulated by hormone administration is reward versus punishment sensitivity. To date, only one study examined neural responses towards reward following steroid administration. With fMRI and a reward anticipation task, Hermans et al. (2010) studied the effect of exogenous T on the neural circuitry implicated in reward anticipation. Behavioral studies previously showed that exogenous T was related to a reward-driven decision-making strategy (van Honk et al. 2004). Hermans et al. (2010) showed that administration of T increased the neural response in ventral striatum, the ‘reward network’ of the brain, during the expectation of reward on a monetary incentive delay task. Hyperreactivity of this reward network following exogenous T could well explain the increased reward sensitivity observed on the behavioral paradigms following T administration. A neurobiological mechanism that could be involved in this T-reward link is the dopamine system. Androgens are known to modify the activity of dopaminergic neurons, which regulate the reward network, as are glucocorticoids [for a review on androgens, see (Wood 2008); for a review on glucocorticoids, see (Piazza and Le Moal 1997)]. Adrenal, as well as gonadal systems might thus interact with the brain’s mesolimbic reward system to exert their effects on reward behavior.

In sum, exogenous T seems to induce hyperreactivity of neural circuitry involved in aggression and reward, while exogenous CRT seems to dampen neural responses towards fearful faces. A field that warrants further investigation is how T and CRT interact with the dopaminergic system to influence reward-sensitivity.

Serotonin’s role in impulsivity is well-established (Bevilacqua et al. 2010; Virkunnen and Linnoila 1993), and it is therefore a likely candidate to differentiate between impulsive and instrumental aggression in a person that already is prone to social aggression. Low 5-HT is related to impulsivity (Bevilacqua et al. 2010; Virkunnen and Linnoila 1993), and a large body of animal literature suggests that 5-HT is also causally involved in aggression. The majority of these studies suggest an inhibitory effect of 5-HT on aggression (Carrillo et al. 2009; Francesco Ferrari et al. 2005; Huber et al. 1997). Thus low 5-HT is related to impulsivity and aggression, leading to the hypothesis that high T/CRT ratio, in combination with low 5-HT facilitates impulsive aggression in particular (Terburg et al. 2009; van Honk et al. 2010). Indeed, low levels of the 5-HT metabolite 5-Hydroxyindoleacetic acid have been reported in males with antisocial personality traits and impulsive aggression (Linnoila et al. 1983; Soderstrom et al. 2001). Another study used the serotonin-releasing agent fenfluramine (Siever et al. 1999), which increases glucose metabolism in the OFC and cingulate cortices of healthy subjects, brain regions that are implied in the inhibition of impulsive aggression (Blair 2004). In impulsive aggressive males (intermittent explosive disorder), fenfluramine did not alter glucose metabolism in these brain regions, indicative of reduced 5-HT modulation (Siever et al. 1999). In line with this, a more recent study showed reduced 5-HT transporter availability in the anterior cingulate cortex (ACC) in impulsive aggressive males (Frankle et al. 2005). In females, the same relationship between low 5-HT and impulsive aggression in patient groups has been reported (Rosell et al. 2010). Overall, correlative human data does support the notion that 5-HT transmission, in prefrontal regions OFC and ACC, is attenuated in impulsive aggressive individuals. Causal data is scarce, but in line with the above. A study that experimentally lowered and elevated 5-HT via tryptophan depletion and enhancement found that high trait, but not low trait aggressive males changed their behavior on the Taylor paradigm (Cleare and Bond 1995): a widely used aggression paradigm (Taylor 1967). Following tryptophan depletion high trait-aggressive subjects behaved more aggressive than following tryptophan enhancement (Cleare and Bond 1995). Another study illustrated that 5-HT enhancement led to a decrease in rejections on the Ultimatum Game and increased morality on moral scenario decision-making in males and females (Cima and Raine 2009; Crockett et al. 2010). Finally, a study by Crockett and colleagues showed that tryptophan depletion led to higher rejection rates on the Ultimatum Game in males and females (Crockett et al. 2008). Thus, while low 5-HT is related to impulsive aggression, high 5-HT is related to increased moral and prosocial behavior. In combination with a T/CRT induced aggression predisposition however, high 5-HT could lead to an instrumental aggressive style. The hypothesis that high 5-HT levels would accompany instrumental aggression however is purely speculative and needs to be investigated. However, a remarkable pattern in the literature on low 5-HT transmission and aggression is that the majority of these studies include patients with antisocial personality disorder and not patients with psychopathy, the latter being defined more profoundly by instrumental aggression (Cima and Raine 2009).

In sum, we propose that the T/CRT ratio modulates the biobehavioral balance between aggression and fear, and that in individuals with high T/CRT ratio, who thus have an aggressive disposition, low 5-HT induces impulsive aggression.

We have reviewed evidence suggesting that high T together with low CRT predisposes toward social aggression and that 5-HT could modulate the balance between impulsive and instrumental aggression. There are very few studies on aggression that take T, CRT and 5-HT into account simultaneously. One study by Kuepper et al. (2010) used a S-citalopram challenge, which increases 5-HT, to assess 5-HT availability in relation to T levels and self-reported measures of aggression. S-citalopram induces CRT release and therefore CRT response was measured as indicator of responsiveness to S-citalopram (Kuepper et al. 2010), nicely illustrating the tight positive relationship between 5-HT function and CRT. The authors however found that 5-HT availability and T levels were unrelated in males and females. Interestingly, an interaction was found between 5-HT, T, and aggression. Males, and not females, with low 5-HT availability and high T levels reported higher levels of aggression. This is the only study showing this interaction thus it needs to be replicated and investigated in females. Nonetheless, the study of Kuepper et al. (2010) does suggest that the combination of high T levels together with low 5-HT function facilitates aggression. This is in line with earlier work showing positive effects of high T levels together with low 5-HT function on impulsive aggression (Higley et al. 1996). This is an interesting finding because although there is evidence from the animal literature that T affects 5-HT function (Fink et al. 1999), correlations between T and cerebrospinal fluid or plasma 5-HT levels in humans are not found (Kuepper et al. 2010). However animal research also suggests that T does have an effect on 5-HT function, but via aromatization to E (Fink et al. 1999). More research needs to be done to elucidate the relationship between T and 5-HT function in humans, but it is clear that an imbalance in levels of these chemicals could potentiate impulsive aggression.

Together, these findings give rise to a dual-hormone serotonergic (DHS) hypothesis in which high T/CRT ratio predisposes to aggression in general, and low prefrontal 5-HT transmission, through promoting impulsivity and lowering fear, predisposes to impulsive aggression (see Fig. 1). In terms of neural mechanism, such a neurobiological profile enhances reactivity of the neurocircuitry of reactive aggression of which the key structure is the amygdala. Indeed, high T/CRT ratio is positively correlated with activity in the amygdala-hypothalamus-PAG aggression system in response to threat (Hermans et al. 2008). Furthermore, low 5-HT transmission in prefrontal cortex (PFC) might be related to reduced inhibitory prefrontal control over this reactive aggression network, leading to hyper-responsiveness. Indeed, impulsive aggressive patients have reduced amygdala-PFC connectivity (Decety et al. 2009; Marsh et al. 2008). Neuroimaging studies are also in line with this, showing that the impulsive aggressive individual is characterized by amygdala hyper-responsiveness, while the instrumental aggressive individual shows amygdala hypo-responsiveness towards threat (Blair 2010). Finally, gender differences in T levels, and their relation to 5-HT transmission should be studied further, but the antagonistic properties of T and CRT, as well as the relation between 5-HT and impulsivity are reliably observed in both sexes. Our dual-hormone serotonergic hypothesis with high T, low CRT, and low 5-HT transmission, provides therefore a plausible framework for the study of impulsive aggression in both men and women.

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