Influence of Central Serotonin Availability on Social and Repetitive Behavior in Mice
Authors: Gould Georgianna G. , Witt Nasriya , Allen Jonathan , Sanchez Alicia , Javors Martin A. , Daws Lynette C. 
Published: November 2023

Impaired social behavior is a core symptom of autism that also manifests in other psychiatric disorders such as schizophrenia, bipolar disorder and depression. It is among the most treatment‐resistant of psychiatric disorder symptoms. Serotonin (5‐HT) is a monoamine neurotransmitter that regulates mood balance in the brain and it is also a strong shaper of social behavior. For example, in some patients and mouse models of impaired sociability, social behavior deficits worsen with decreased 5‐HT availability, but improve following pharmacological enhancement of 5‐HT neurotransmission by administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. The objective of this study was to determine if increasing serotonin availability in the brain would correspond with improvements in sociability. Conversely, we predicted that reducing serotonin availability in the brain would worsen sociability in either gregarious or socially‐deficient mice.

Methods

To test this hypothesis, we performed social interaction, social novelty, locomotor and repetitive behavioral tests on BTBR mice, a socially deficient inbred strain, and C57BL/6 mice, which display normal social behaviors. Before testing, adult males of both strains were given either a single injection of 100 mg/kg pargyline, a monoamine oxidase inhibitor, to block the metabolic breakdown of 5‐HT in the brain, or 300 mg/kg over 3 days of para‐chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor to block 5‐HT synthesis in the brain. Controls were treated with vehicle on the same schedule with the drug treatments. The behavioral tests employed were mouse three‐chamber sociability and marble burying, which is a murine index of repetitive behavior.

Results

We observed in social interaction preference tests that PCPA treatment increased locomotor activity in C57BL/6, but not in BTBR mice. More critically, PCPA significantly reduced social interaction preference in C57BL/6, but not in BTBR mice. Pargyline enhanced social interaction preference in C57BL/6 and social novelty preference in both strains. On the other hand, PCPA had little effect on social novelty preference. Marble burying behavior in both strains was unchanged by either PCPA or pargyline treatments.

Conclusions

Findings from our study demonstrate that acute pargyline treatment enhanced brain 5‐HT concentrations to promote preference for social interaction much like a selective serotonin reuptake inhibitor, except these effects were only observed in C57BL/6 mice. Conversely we also demonstrated that PCPA induced‐decreases in available brain serotonin generally suppressed mouse sociability. In these experiments the social behavior of BTBR mice was less responsive to serotonergic manipulation via these two catabolic enzymes than C57BL/6 mice. Overall, these findings lend further support to the hypothesis that preference for sociability and social novelty is shaped by central 5‐HT availability.

Support or Funding Information

NIH‐R21HD081261, Autism Idea Award AR110109 and the South Texas Advanced Research Training‐Undergraduate Program (GM097632)