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Review
. 2011 Feb;213(2-3):183-212.
doi: 10.1007/s00213-010-2000-y. Epub 2010 Sep 3.

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

Aki Takahashi  1 , Isabel M Quadros, Rosa M M de Almeida, Klaus A Miczek
Affiliations
Review

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

Aki Takahashi et al. Psychopharmacology (Berl). 2011 Feb.

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-HT(1A), 5-HT(1B) and 5-HT(2A/2C) receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT(1A) and 5-HT(1B) 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-HT(1B), 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-HT(1) family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT(2) family expression may cause escalated aggression, whereas the phasic increase of 5-HT(2) 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.

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Figures

Figure 1
Figure 1. Mouse agonistic behavior
Behaviors of resident and intruder mice engaged in an aggressive confrontation: (a) the resident leaps and bites the intruder as the intruder attempts to escape; (b) the resident (right) threatens as the intruder (left) holds a defensive upright posture; (c) the resident investigates the intruder’s anogenital region; (d) the resident pursues the fleeing intruder; (e) both resident and intruder engage in a mutual upright defensive posture. Reprinted with permission from Miczek and O’Donnell (1978).
Figure 2
Figure 2. Dopamine and serotonin during aggression
Measurements of extracellular dopamine and serotonin via in vivo microdialysis in resident male rats before, during, and after a confrontation with an intruder. (a) In the nucleus accumbens (top panel), dopamine levels (gray circles) rise and remain elevated after the confrontation, while serotonin levels (black diamonds) do not significantly change. (b) In the prefrontal cortex (bottom panel), dopamine levels rise after the confrontation, while serotonin decline and remain lower after the confrontation. Samples were collected every 10 min and levels are expressed as mean percent of baseline ± SEM. Baseline was measured for 50 min before the fight. The vertical light gray bar indicates the occurrence of the 10-min fight. * and ** represent significant differences from baseline (dashed line) at the p < 0.05 and p < 0.01 levels, respectively. Reprinted with permission from Van Erp and Miczek (2000).
Figure 3
Figure 3
A. Effects of social instigation on aggressive behavior by a resident mouse toward a male intruder. Bars represent the mean frequency ±SEM (vertical lines) of attack bites under control (light gray) and instigated (dark gray) conditions. Asterisks denote statistical significance from control (**P<0.01). B. Preferential reduction of instigated aggressive behavior by the 5-HT1B agonist anpirtoline (left panel, filled circles) and CP-94,253 (right panel, filled squares). Symbols represent the mean frequency of attack bites, expressed as a percentage of vehicle (V) baseline, ±SEM. Light gray symbols represent non-instigated fighting and dark gray symbols represent instigated levels of fighting. Asterisks denote significance from vehicle baseline (P<0.05). Adapted from Fish et al. (1999) and de Almeida and Miczek (2002).
Figure 4
Figure 4
Effects of repeated, twice daily administration of the SSRI citalopram (10 mg/kg, i.p.) on aggressive behavior in mice after drinking 1.0 g/kg alcohol in operant self-administration panels. Frequency of aggressive acts (± SEM) is defined as sum of attack bites, threats, pursuits and tail rattles, and was analyzed in 5 min confrontations against a male intruder, during the course of fours weeks of citalopram (or saline control) treatment. + symbols represent differences from baseline (++ p<0.01; +++ p<0.001); * symbols represent group (citalopram vs. saline-controls) differences (** p<0.01; *** p<0.001). Adapted from Caldwell & Miczek (2008).
Figure 5
Figure 5
Means on the composite index of antisocial behavior as a function of MAOA activity and a childhood history of maltreatment. MAOA activity is the gene expression level associated with allelic variants of the functional promoter polymorphism, grouped into low and high activity; childhood maltreatment is grouped into 3 categories of increasing severity. The antisocial behavior composite is standardized (z score) to a M = 0 and SD = 1; group differences are interpretable in SD unit differences (d). Reprinted with permission from Caspi et al. (2002).
Figure 6
Figure 6. Extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) of mice after GABAB receptor activation in the dorsal raphe nucleus (DRN)
(A) Baclofen microinjected into the DRN increased the 5-HT level in the mPFC whereas saline injection did not change the 5-HT level. Twenty minutes samples were collected 5 samples for baseline, 3 samples after saline injection, and 6 samples after baclofen (0.06 nmol) injection. Data are expressed as percentage of baseline (n=7). * p<.05 compared to the baseline. (B) The effect of 0.06 nmol baclofen on attack bites after the different interval (10, 40 and 100 min, corresponding to the time period of fraction 9, 11, and 14 in the microdialysis, respectively). Escalated attack bites were observed both 10 and 40 minutes after the intra-DRN baclofen injection. * p<.05 compared to corresponding vehicle control.
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