Efficacy of a Multimodal Versus a Selective Serotonin Reuptake Inhibitor to Enhance Sociability and Reduce Marble Burying in BTBR Mice

Background:  Impaired social behavior is the most drug treatment-resistant core autism symptom. Selective serotonin reuptake inhibitors (SSRIs, such as fluoxetine or Prozac) block serotonin (5-HT) clearance from brain extracellular fluid by the serotonin transporter (SERT). SSRIs enhance social behavior for some autism patients and in socially deficient BTBRT+Itpr3tf/J (BTBR) mice, but generally they fail to aid the majority of patients with autism. The 5-HT_1A receptor partial agonist, buspirone (2 mg/kg) enhanced BTBR sociability just as well as Prozac (10 mg/kg) did. This finding led us to hypothesize that a multimodal SSRI such as vortioxetine might better enhance social and reduce restrictive repetitive behaviors via combined pharmacological targeting of SERT and 5-HT_1A receptors.

Objectives: Vortioxetine inhibits SERT, and is a 5-HT_1A agonist, among other actions. We sought to compare the efficacy of vortioxetine versus an SSRI to enhance sociability and reduce marble burying in mice. Occupancy of 5-HT_1A receptors by vortioxetine in behavior-tested mice was subsequently measured. Since the hormones oxytocin and corticosterone can shape behaviors and 5-HT_1A governs their release, their levels in vortioxetine and vehicle treated groups were compared.

Methods: Adult male BTBR mice were used to examine the effects of blocking SERT with the highly specific SSRI citalopram versus vortioxetine, a multimodal antidepressant, at a range of doses on social preferences and on repetitive burying. Vortioxetine (5 or 10 mg/kg) or citalopram (0.5, 5, or 50 mg/kg) were administered by i.p. injection 30, 60 or 120 min before sociability tests, and 75, 105 or 165 min before marble burying tests. [³H] escitalopram was used to assess SERT occupancy, while [³H] WAY-100635 was used for 5-HT_1A receptor occupancy by ex vivo autoradiography. Serum hormone levels were measured using enzyme-linked immunoassay kits and a microplate reader.

Results: In social interaction preference tests, vortioxetine (10 mg/kg) administered 30 min before testing enhanced social sniffing (p<0.05) relative to vehicle controls, in contrast to citalopram, which lacked efficacy to do so at all doses. However, the sociability enhancing effect of vortioxetine was lost if administered 60 -120 min before testing. Vortioxetine (10 mg/kg) and citalopram (50 mg/kg) significantly reduced marble burying (p<0.02) at all post-administration times measured. At 110 min after administration, 10 mg/kg vortioxetine achieved occupancies (%) of 84 ± 1, 31± 12 and 80 ± 5 of SERT, 5-HT_1A and also 5-HT_1Breceptors in various brain regions with relatively high ligand binding densities. Oxytocin levels were slightly elevated (p <0.05) in vortioxetine and citalopram treated mice. Corticosterone levels did not significantly differ among treatment groups following the behavior tests.

Conclusions:  Overall, these findings indicate that both vortioxetine and citalopram have greater potential to suppress restrictive-repetitive behaviors than to enhance sociability, at least in BTBR mice. Only vortioxetine enhanced social sniffing, albeit transiently. Further investigation of vortioxetine as a potential treatment for core autism symptoms in other mouse models would help to establish its potential as a therapeutic to ameliorate core autism symptoms. Vortioxetine’s properties at other 5-HT receptor subtype targets might have also contributed to these effects.