High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

Abstract

Aggression frequently coincides with specific dimensions of emotionality, such as impulsivity, risk-taking, and drug abuse. Serotonergic (5-HTergic) neurotransmission contributes to the regulation of numerous neurobiological functions, and is thought to play a key role in modulating aggressive responses. The current study uses selectively-bred High (bHR) and Low (bLR) Responder rats that exhibit differences in emotionality and behavioral control, with bHRs exhibiting heightened novelty-induced exploration, impulsivity, and increased sensitivity to drugs of abuse, and with bLRs characterized by exaggerated depressive- and anxiety-like behaviors. Based on this behavioral profile we hypothesized that bHR rats exhibit increased aggression along with changes in testosterone and corticosterone secretion characteristic of aggression, and that these changes are accompanied by alterations in the expression of key genes that regulate 5-HTergic neurotransmission (Tph2 and Sert) as well as in the activation of 5-HTergic cell groups following aggressive encounter. Our data demonstrate that when compared to bLR rats, bHRs express increased baseline Tph2 and Sert in select brainstem nuclei, and when tested on the resident-intruder test they exhibited: 1) increased aggressive behavior; 2) potentiated corticosterone and testosterone secretion; and 3) diminished intrusion-induced c-fos expression in select 5-HTergic brainstem cell groups. The most prominent gene expression differences occurred in the B9 cell group, pontomesencephalic reticular formation, median raphe, and the gigantocellular nucleus pars α. These data are consistent with the notion that altered 5-HT neurotransmission contributes to bHRs’ heightened aggression. Furthermore, they indicate that a specific subset of brainstem 5-HTergic cell groups contributes to the regulation of intrusion-elicited behavioral responses.

The neurobiology of offensive aggression: Revealing a modular view

“…Interestingly, these fibers ascend just alongside the HAA [82]. These fibers contain 5-HT (serotonin) and activation of 5-HT 1A/B or 5-HT 2A/C receptors in the brain has strong modulatory but mainly inhibitory effects on aggression [56,[102][103][104][105]. To what extent this serotonergic influence is effectuated directly on HAAneurons or indirectly via the PFC and/or other brain areas, remains open for future research (see also the Neurochemistry/pharmacology section below).…”

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

“…21-23). Relative to bLRs, bHRs are more impulsive (19), more aggressive (20), and more likely to signtrack to food-and drug-associated cues (19). Although we have previously shown that these selectively bred rats also differ in their initial propensity to take cocaine (24), the present study assesses individual differences in cocaine addiction liability by exposing bHR and bLR rats to a prolonged self-administration procedure ( Fig.…”

“…particular, bHR rats exhibit a constellation of traits relevant to addiction (18)(19)(20) that are not necessarily apparent in outbred HR rats (e.g., refs. 21-23).…”

The novelty-seeking phenotype modulates the long-lasting effects of adolescent MDMA exposure

“…MDMA has a unique pharmacology which, unlike that of other drugs of abuse, preferentially enhances synaptic 5-HT when administered acutely [76]. Although the novelty response has been attributed to DAergic mechanisms [77], serotonin has also been shown to play a role in the response to novelty-seeking [33,78]. High novelty-seeking appears to be a risk factor for drug addiction in general, as it tends to increase the risk of early experimentation with drugs and seems to modulate long-term MDMA-induced effects in adulthood.…”