Anti-aggressive effects of the selective high-efficacy 'biased' 5-HT₁A receptor agonists F15599 and F13714 in male WTG rats

Abstract

Background: The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmacological data showing robust anti-aggressive effects of 5-HT1A receptor agonists in dose ranges that concomitantly inhibit 5-HT neurotransmission. Hence, an adequate interpretation of the role of 5-HT activity in regulating aggression depends on elucidating the predominant site of action, i.e., raphe presynaptic autoreceptors versus forebrain postsynaptic heteroreceptors, of these 5-HT1A receptor agonists.

Objectives: The present experiments investigated the anti-aggressive properties of the selective 5-HT1A receptor agonists F15599 that preferentially target postsynaptic 5-HT1A heteroreceptors in the frontal cortex and F13714 that more preferentially activates raphe somatodendritic 5-HT1A autoreceptors.

Methods: Both 'biased' agonists were acutely administered intraperitoneally in aggressive resident male WTG rats confronting an intruder.

Results: Systemic administration of F15599 and F13714 exerted very potent (ID50 = 0.095 and 0.0059 mg/kg, respectively) anti-aggressive effects. At 4.5-fold higher dose ranges, the anti-aggressive effects were accompanied by concomitant motor inactivity and/or reduction of social engagement. Pretreatment with WAY-100635 counteracted the behavioural effects of both agonists.

Conclusions: Overall, the qualitatively similar but quantitatively different anti-aggressive profiles of F15599 and F13714 largely correspond to their distinct 5-HT1A receptor binding/activation potencies. Moreover, the marked anti-aggressive potency of F13714 adds additional support for a critical role of raphe somatodendritic 5-HT1A autoreceptors, and hence phasic 5-HT neuron activity, in the initiation/execution of aggressive actions.

Keywords: 5-HT1A; Aggressive behaviour; Autoreceptors; Dorsal Raphe; F13714; F15599; Heteroreceptors; Serotonin.

Fig. 1

Effect of acute systemic (IP) F15599 on the attack latency time (ALT; insert) and different behavioural categories of resident wild-type Groningen rats in the offensive aggressive resident-intruder test. One-way ANOVA revealed significant effects of drug-dose for ALT [F(5,58) = 17.586; p < 0.0001], offensive behaviour [F(5,58) = 20.579; p < 0.0001], total social interaction [F(5,58) = 13.626; p < 0.0001], non-social exploration [F(5,58) = 3.381; p < 0.01] and inactivity [F(5,58) = 7.664; p < 0.0001]. Asterisk indicates that values are significantly (p < 0.05; Dunnett’s test) different from the vehicle value.

Fig. 2

Effect of acute systemic (IP) F13714 on the attack latency time (ALT; insert) and different behavioural categories of resident wild-type Groningen rats in the offensive aggressive resident-intruder test. One-way ANOVA revealed significant effects of drug-dose for ALT [F(7,69) = 28.31; p < 0.0001], offensive behaviour [F(7,69) = 29.11; p < 0.0001], total social interaction [F(7,69) = 2.75; p < 0.002], non-social exploration [F(7,69) = 2.33; p < 0.01 and inactivity [F(7,69) = 17.86; p < 0.0001]. Asterisk indicates that values are significantly (p < 0.05; Dunnett’s test) different from the vehicle value

Fig. 3

Antagonism of the anti-aggressive effects of F15599 and F13714 by pretreatment with WAY-100,635. One-way ANOVA revealed significant effects of treatment for ALT [F(5,34) = 6.32; p < 0.0001], offensive behaviour [F(5,34) = 4.36; p < 0.005] and total social interaction [F(5,34) = 2.70; p < 0.05]. Each treatment group consisted of 6–8 subjects. Asterisk indicates that values are significantly (p < 0.05; Dunnett’s test) different from the vehicle/vehicle values

Fig. 4

Comparative potency of different 5-HT_1A receptor agonists to inhibit offensive aggression (top panel) and to enhance motor inactivity (bottom panel) in the rat resident-intruder offensive aggression test. In the legend, the numbers in between the parentheses indicate the ED₅₀ values of the drug’s anti-aggressive and inactivity-enhancing potency, respectively