Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression

Abstract

Rationale Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. Objective We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. Results New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Conclusions Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment.

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

“…Low 5-HT levels are associated with increased impulsivity and aggression, and manipulations that increase 5-HT activity are associated with reduced aggression (Takahashi et al, 2011). BDNF promotes 5-HT neuron development and function (Eaton and Whittemore, 1996;Mamounas et al, 1995), and BDNF deficiency is correlated with enhanced aggression and 5-HT dysfunction, including impaired 5-HT release, altered expression of 5-HT receptors, and deficits in 5-HT2A-mediated excitatory neurotransmission (Chan et al, 2006;Lyons et al, 1999;Rios et al, 2006).…”

“…The 5-HT neurochemical signaling system has been consistently associated with control of aggressive behavior (Takahashi et al, 2011). PFC circuits are thought to provide an important regulatory role by providing inhibitory control over aggression (Takahashi and Miczek, 2014).…”

Comparing mechanisms of host manipulation across host and parasite taxa

“…However, the details of the specific mechanisms of action for OA, 5-HT and DA in shaping behavior are dependent on specific receptor types and their locations in different brain and CNS regions (Adamo, 2013;Demas et al, 2011;Fabre-Nys, 1998;Takahashi et al, 2011;Winberg and Nilsson, 1993), and should be accounted for when interpreting mechanistic studies. For example, 5-HT receptors can reduce or increase aggression depending on their location in the vertebrate brain (Summers and Winberg, 2006;Takahashi et al, 2011).…”

“…However, the details of the specific mechanisms of action for OA, 5-HT and DA in shaping behavior are dependent on specific receptor types and their locations in different brain and CNS regions (Adamo, 2013;Demas et al, 2011;Fabre-Nys, 1998;Takahashi et al, 2011;Winberg and Nilsson, 1993), and should be accounted for when interpreting mechanistic studies. For example, 5-HT receptors can reduce or increase aggression depending on their location in the vertebrate brain (Summers and Winberg, 2006;Takahashi et al, 2011). Despite the extensive research described herein, it remains unknown whether parasites alter host neuromodulators by secreting neurochemicals to produce changes in host neurochemical activity, or by secreting chemicals that trigger a host response, leading to altered neurochemical activity (Adamo, 2013;de Jong-Brink et al, 2001;Thomas et al, 2005).…”

Serotonin revisited

“…5-HT 6 receptors are associated with cognition (Kendall et al 2011), as well as antidepressant and anxiolytic effects , while 5-HT 4 receptors are linked to appetite suppression (Francis et al 2011). New roles for serotonin receptor subtypes and modulators of serotonin transmission are suggested in animal models of aggressive behaviour (Takahashi et al 2011).…”