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Serotonin₂A/C receptors mediate the aggressive phenotype of TLX gene knockout mice
Pablo Juárez1, Maria G Valdovinos, Michael E May
1Department of Special Education, Vanderbilt University, Nashville, TN, USA.
Abstract:
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 (0.1-1.5mg/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-HT(2A/C) receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting (±)DOI, a 5-HT(2A/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-HT(2A/C) receptors.
Insights
Deleting the tailless (TLX) gene causes aggression in mice. Serotonin (5-HT)(2A/C) receptors are involved in this aggression, with drugs affecting these receptors altering aggressive behaviors.
Area of Science:
- Neuroscience
- Behavioral Genetics
- Pharmacology
Background:
- The tailless (TLX) gene deletion in mice results in aggressive phenotypes.
- The role of heterozygous TLX gene status and specific neurotransmitter systems in aggression remains uncharacterized.
Purpose of the Study:
- To investigate the pharmacological control of aggression in TLX gene-modified mice.
- To elucidate the involvement of serotonin (5-HT)(2A/C) receptors in mediating aggression.
Main Methods:
- Resident-intruder paradigm was used to analyze aggression in wild-type, heterozygous (+/-), and homozygous (-/-) TLX mice.
- Dose-effect functions for clozapine, ketanserin (5-HT(2A/C) antagonist), and (±)DOI (5-HT(2A/C) agonist) were established.
- Behavioral responses including aggression, grooming, and locomotion were quantified.
Main Results:
- Aggression was observed in 36% of +/- TLX and 100% of -/- TLX mice, but not in wild-type mice.
- Clozapine administration decreased aggression frequency and duration in TLX mice.
- Ketanserin differentially affected aggression and locomotion based on genotype, while (±)DOI increased aggression and decreased locomotion.
Conclusions:
- Aggression in TLX null and heterozygous mice is mediated by serotonin (5-HT)(2A/C) receptors.
- Pharmacological modulation of 5-HT(2A/C) receptors can impact aggression levels in these mouse models.
