Behavioral and Pharmacogenetics of Aggressive Behavior

Abstract

Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT1A receptor) can often result in inconsistent results on aggression, due to “phasic” effects of pharmacological agents vs “trait”-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT1A and 5-HT1B) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene × environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters (e.g., MAO A) or rate-limiting synthetic and metabolic enzymes of 5-HT determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate, and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g. BDNF, nNOS, αCaMKII, Neuropeptide Y). The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior.

Role of 5-HT2A Receptors in Immunomodulation in Animal Models of Aggressive Behavior

“…Therefore, it can be assumed that the sensitivity of 5-HT 2A receptors to their ligands, and particularly to the antagonists, depends on different contribution of this receptor subtype to aggressive behaviors, and may explain dissimilar effects of ketanserin on immunity in aggressive rats and mice, observed in our experiments. It should also be considered that application of both agonists and antagonists of 5-HT 2A receptors in patients with various neuropsychiatric disorders and in several animal species is associated with the side effects of these compounds, such as the cognitive deficits, sedation or hypolocomotion [4] [5] [34], that, in turn, may differently affect immune reactivity in animals.…”

“…Among several types of 5-HT receptors, 5-HT 2A receptors have long been implicated in the pathophysiology of aggressive behaviors [1]- [6]. Moreover, a number of atypical antipsychotic drugs and antidepressants, targeting 5-HT 2A receptors, have been successfully used in patients with various neuropsychiatric disorders [4], which are known to be associated with abnormal aggression and altered immune function [7]- [9]. A number of studies have also demonstrated that 5-HT receptor subtypes are involved in the 5-HTergic mechanisms of immunomodulation [10]- [18].…”

Maternal alterations in the proteome of the medial prefrontal cortex in rat

“…The highest, cortical control influencing maternal responses implies the involvement of the medial prefrontal cortex (mPFC) in maternal adaptations [6][7][8]. In addition, the mPFC is part of the limbic system and is associated with emotional changes, including anxiety, stress responses, and depression, as well as aggression [9][10][11][12][13][14][15]. Impaired maternal responsiveness in human mothers suffering from postpartum depression (PPD) has been shown to be associated with reduced activity in brain areas corresponding to the mPFC [16][17][18].…”

The Role of Serotonin in Aggression and Impulsiveness

“…An implusive temperament is associated with clinical conditions, such as pathological gambling, eating disorders, and borderline personality disorder as well as being a risk factor for self-harm, suicide, and emotional liability [3,7]. Brain imaging and pharmacogenetic studies have demonstrated that serotonin dysfunction is associated with impulsive behaviors [8]. Aggression is not a personality trait like impulsivity, but it is the behavior of harm or injury to others [9].…”