Effects of Acute Serotonin Reuptake Inhibitor Treatment and Serotonin Depletion On Sociability in Juvenile BALB/Cj and C57BL/6J Mice

Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized, in part, by deficits in social behaviors. Many studies have associated ASDs with hyperserotonemia and abnormal regulation of brain serotonin, and serotonergic neurotransmission has been implicated in a variety of social behaviors in humans and animals. The serotonergic system also mediates various forms of anxiety, and several of these are heightened in patients with ASDs. The role of serotonin in the development of sociability (tendency to seek social interaction) and anxiety during prepubescence is not well understood. Previous work has demonstrated that prepubescent BALB/cJ mice show reduced sociability relative to prepubescent C57BL/6J mice. Objectives: We systemically manipulated the serotonergic system with the selective serotonin reuptake inhibitor (SSRI) citalopram and the serotonin depletor p-chlorophenylalanine (PCPA) in prepubescent C57BL/6J and BALB/cJ mice. We assessed the acute effects of these pharmacological agents in a social choice test and the elevated zero maze test (EZM). We hypothesized that acute citalopram would decrease sociability in the social choice test and increase non-social anxiety-related behaviors (anxiogenesis) in the EZM. We further hypothesized that PCPA would increase sociability and decrease anxiety-related behaviors (anxiolysis). Methods: In the first experiment, 31-day-old male and female BALB/cJ and C57BL/6J mice received a single i.p. injection of citalopram (10 mg/kg) or saline, and a half-hour later were tested for sociability towards an unfamiliar, gonadectomized A/J ‘stimulus' mouse. In a second experiment, 29-to-33-day-old male BALB/cJ mice received a single i.p. injection of citalopram (1 or 10 mg/kg) or saline, and were then tested for sociability a half-hour later. The following day, they received another injection of citalopram at the same dose or of saline, and were then tested on the EZM a half-hour later. In a third experiment, male BALB/cJ and C57BL/6J mice received 3 days of twice-daily injections of PCPA (100 or 300 mg/kg/day) or saline. On the fourth day, the 29-to-33-day-old mice were tested for sociability, then received a final injection of PCPA at the same dose or of saline. On the fifth day, mice were tested on the EZM. Results: In the first experiment, the experimental groups did not differ in their locomotor activity or their exploratory behaviors prior to exposure to the stimulus mouse. Citalopram-treated mice showed lower sociability than saline-treated mice, and this effect was more pronounced in the BALB/cJ mice than the C57BL/6J mice (social investigation time, Wilcoxon-Mann-Whitney tests: C57BL/6J saline vs. citalopram, U = 59, p < 0.001; BALB/cJ saline vs. citalopram, U = 49, p < 0.01). No differences due to sex were detected. The results of the second and third experiments will be presented. Conclusions: The results of these experiments will clarify the relationship between sociability and non-social anxiety during the little-studied developmental period of prepubescence in mice. These experiments will also elucidate the role that serotonin plays in these processes during prepubescence, and this may provide insights into the neural mechanisms of reduced sociability and heightened anxiety-related behaviors, two behavioral endophenotypes highly relevant to ASDs.