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.
Highlights
We previously showed that low doses of DIZ and Ro 25-6981 potently reduced aggression in monoamine oxidase A (MAOA) KO, but not WT mice
The results of this study showed that MAOA KO mice are highly susceptible to the detrimental effects of NMDA receptor antagonism on prepulse inhibition (PPI)
These results collectively extend previous evidence from our group and others, indicating that NMDA and 5-HT2 receptors in the prefrontal cortex (PFC) are critically important in the abnormal aggressive behavior of MAOA-deficient mice [13,25]
Summary
Antisocial behavior is characterized by aggressive and non-aggressive rule-breaking, violation of societal norms, disregard for the rights and properties of others, and violence [1]. The robust association between pathological aggression, antisocial behavior, and delinquency imposes a hefty burden on society [2], preventive and therapeutic interventions for these problems remain highly challenging. No drug has been approved for its treatment [3,4]. Several studies have investigated the biological underpinnings of pathological aggression and antisocial behavior. The best-characterized molecular factor associated with these disorders is monoamine oxidase A (MAOA), the key enzyme
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