Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice

• Aggression testing occurred in mice with mutations in the TLX gene.
• TLX homozygotes were uniformly aggressive, while heterozygotes showed a mixed aggressive phenotype.
• Clozapine and ketanserine reduced aggression in all TLX mice.
• (+) DOI increased aggression in all TLX mice.

Deleting the tailless (TLX) gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacological control over aggression and study the role of serotonin (5-HT)2A/C receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous (+/−) or homozygous (−/−) for the TLX gene and wild-types (+/+) using a resident-intruder paradigm. No +/+ mice were aggressive, 36% of +/− TLX and 100% of −/− TLX mice showed aggression. Dose-effect functions were established for clozapine (0.1–1.5 mg/kg, ip), ketanserin (0.3–1.25 mg/kg, ip), and (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI] (0.5–2.0 mg/kg, ip). Injecting clozapine decreased the frequency and duration of attacks for +/− TLX and −/− TLX mice. Clozapine did not decrease grooming in either +/− TLX or −/− TLX mice but may have increased locomotion for −/− TLX mice. Injecting ketanserin, a 5-HT2A/C receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting (±)DOI, a 5-HT2A/C receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/− and −/− TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT2A/C receptors.