Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice

Abstract

The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient mice is contributed by serotonin 5-HT₂ and glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Indeed, blocking either receptor reduces the aggression of MAOA knockout (KO) mice; however, 5-HT₂ receptor antagonists, such as ketanserin (KET), reduce locomotor activity, while NMDA receptor blockers are typically associated with psychotomimetic properties. To verify whether NMDA receptor blockers induce psychotomimetic effects in MAOA KO mice, here we tested the effects of these compounds on prepulse inhibition (PPI) of the acoustic startle reflex. We found that male MAOA KO mice are hypersensitive to the PPI-disrupting properties of NMDA receptor antagonists, including the non-competitive antagonist dizocilpine (DIZ; 0.1, 0.3 mg/kg, IP) and the NR2B subunit-specific blocker Ro-256981 (5, 10 mg/kg, IP). Since KET has been previously shown to counter the PPI deficits caused by NMDA receptor antagonists, we tested the behavioral effects of the combination of KET (2 mg/kg, IP) and these drugs. Our results show that the combination of KET and DIZ potently reduces aggression in MAOA KO mice without any PPI deficits and sedative effects. While the PPI-ameliorative properties of KET were also observed after infusion in the medial PFC (0.05 μg/side), KET did not counter the PPI-disruptive effects of Ro-256981 in MAOA KO mice. Taken together, these results point to the combination of non-subunit-selective NMDA and 5-HT₂ receptor antagonists as a potential therapeutic approach for aggression and antisocial behavior with a better safety and tolerability profile than each monotherapy.

Keywords: 5-HT2 receptors; NMDA receptors; aggression; monoamine oxidase A; prepulse inhibition.

Figure 1

Effects of the uncompetitive NMDA receptor antagonist dizocilpine (DIZ; 0.1, 0.3 mg/kg, IP) on startle reflex (A) and prepulse inhibition (B) in MAOA KO mice. Data are shown as means ± SEM. Significance levels refer to the results of post hoc comparisons of two-way ANOVA analyses. Main effects are not indicated. * p < 0.05, *** p < 0.001 for comparisons indicated by bracket lines. (SAL, saline; AU, arbitrary units); n = 6–10/group. For further details, see results section.

Figure 2

Effects of the NR2B subunit-specific antagonist Ro-256981 (5, 10 mg/kg, IP) on startle reflex (A) and prepulse inhibition (B) in MAOA KO mice. Data are shown as means ± SEM. Significance levels refer to the results of post hoc comparisons of two-way ANOVA analyses. Main effects are not indicated. * p < 0.05, *** p < 0.001, **** p < 0.0001 for comparisons indicated by bracket lines. (SAL, saline; AU, arbitrary units); n = 6/group. For further details, see results section.

Figure 3

Effects of the systemic administration of ketanserin (KET, 2 mg/kg, IP) on the changes in startle reflex (A) and prepulse inhibition (B) induced by dizocilpine (DIZ, 0.1mg/kg, IP) in MAOA KO mice. Data are shown as means ± SEM. Significance levels refer to the results of post hoc comparisons of three-way ANOVA analyses. Main effects are not indicated. * p < 0.05, **** p < 0.0001 for comparisons indicated by bracket lines. (SAL, saline; VEH, vehicle; AU, arbitrary units); n = 6–8/group. For further details, see results section.

Figure 4

Effects of the medial prefrontal cortex (mPFC) infusion of ketanserin (KET, 0.05 μg/side) on the changes in startle reflex (A) and prepulse inhibition (B) induced by dizocilpine (DIZ, 0.1mg/kg, IP) in MAOA KO mice. Data are shown as means ± SEM. Significance levels refer to the results of post hoc comparisons of three-way ANOVA analyses. Main effects are not indicated. ** p < 0.01 for comparisons indicated by bracket lines. (SAL, saline; VEH, vehicle; AU, arbitrary units); n = 6–10/group. For further details, see results section.

Figure 5

Effects of the medial prefrontal cortex (mPFC) infusion of ketanserin (KET, 0.05 μg/side) on the changes in startle reflex (A) and prepulse inhibition (B) induced by Ro-256981 (5 mg/kg, IP) in MAOA KO mice. Data are shown as means ± SEM. Significance levels refer to the results of post hoc comparisons of three-way ANOVA analyses. Main effects are not indicated. (SAL, saline; VEH, vehicle; AU, arbitrary units); n = 6–7/group. For further details, see results section.

Figure 6

Impact of the systemic injection of ketanserin (KET, 2 mg/kg, IP) on the anti-aggressive effects of dizocilpine in MAOA KO mice. Data are shown as means ± SEM. Significance levels refer to the results of post hoc comparisons of three-way ANOVA analyses. (A): Overall duration of aggressive behavior; (B): Number of attacks; (C): The combination of DIZ and KET in MAOA KO mice had a significantly greater effect on latency than either drug; (D): motor activity within the same experiment revealed a significant three-way interaction. **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05 for comparisons indicated by bracket lines. (SAL, saline; VEH, vehicle; AU, arbitrary units); n = 11–12/group. Main effects are not indicated. For further details, see results section.