Enhanced aggressive phenotype of Tph2 knockout rats is associated with diminished 5-HT1A receptor sensitivity

Deborah G A Peeters; Sietse F de Boer; Anneke Terneusen; Adrian Newman-Tancredi; Mark A Varney; Robbert-Jan Verkes; Judith R Homberg

doi:10.1016/j.neuropharm.2019.05.004

Enhanced aggressive phenotype of Tph2 knockout rats is associated with diminished 5-HT_1A receptor sensitivity

Neuropharmacology. 2019 Jul 15:153:134-141. doi: 10.1016/j.neuropharm.2019.05.004. Epub 2019 May 9.

Authors

Deborah G A Peeters¹, Sietse F de Boer², Anneke Terneusen³, Adrian Newman-Tancredi⁴, Mark A Varney⁴, Robbert-Jan Verkes⁵, Judith R Homberg⁶

Affiliations

¹ Dept of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; Dept of Psychiatry, Radboud University Medical Centre, Nijmegen, the Netherlands.
² Dept of Behavioural Neurobiology, Groningen Institute for Evolutionary Life Sciences, Groningen, the Netherlands.
³ Dept of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
⁴ Neurolixis Inc, Dana Point, CA, USA.
⁵ Dept of Psychiatry, Radboud University Medical Centre, Nijmegen, the Netherlands.
⁶ Dept of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands. Electronic address: judith.homberg@radboudumc.nl.

PMID: 31078489
DOI: 10.1016/j.neuropharm.2019.05.004

Abstract

Brain serotonin (5-HT) plays a key role in aggressive behaviours and related psychopathologies, but its precise mechanism of action remains elusive. Genetic animal models may provide a tool to elucidate the relationship between aggression and serotonin. The present study showed that tryptophan hydroxylase 2 (Tph2) knockout (KO) rats, which exhibit profoundly diminished extracellular serotonin levels, display increased aggressiveness compared to their Tph2 wildtype (WT) counterparts. However, the level of aggression in Tph2 KO rats did not equal that of feral wild type Groningen (WTG) rats. To investigate whether enhanced 5-HT_1A receptor functionality may be present in Tph2 KO rats, we tested the acute anti-aggressive potency of the highly selective 5-HT_1A receptor full agonist NLX-112 (a.k.a. befiradol or F13640). Data show that compared to Tph2 WT and WTG rats, the NLX-112 dose-effect curve was shifted to the right in Tph2 KO animals. These results suggest that, unlike previous reports in Tph2 KO mice, Tph2 KO rats have a decreased 5-HT_1A receptor sensitivity compared to both Tph2 WT and WTG animals.

Keywords: 5-HT(1A) receptor; Resident intruder test; Tryptophan hydroxylase 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aggression / drug effects
Aggression / physiology*
Aggression / psychology
Animals
Dose-Response Relationship, Drug
Female
Male
Phenotype*
Random Allocation
Rats
Rats, Transgenic
Receptor, Serotonin, 5-HT1A / genetics
Receptor, Serotonin, 5-HT1A / metabolism*
Serotonin 5-HT1 Receptor Agonists / pharmacology*
Tryptophan Hydroxylase / deficiency*
Tryptophan Hydroxylase / genetics

Substances

Serotonin 5-HT1 Receptor Agonists
Receptor, Serotonin, 5-HT1A
Tryptophan Hydroxylase
tph2 protein, rat