Vortioxetine Reduces Marble Burying but only Transiently Enhances Social Interaction Preference in Adult Male BTBR T⁺Itpr3^tf/J Mice

Vortioxetine is a multimodal antidepressant with agonist activity at serotonin (5-HT)_1A and 5-HT_1B receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR T⁺Itpr3^tf/J (BTBR) mice, the 5-HT_1A partial agonist buspirone and SERT blocker fluoxetine enhanced social interaction but did not reduce marble burying. We hypothesized that vortioxetine through its actions at SERT and 5-HT_1A could improve BTBR sociability and via 5-HT_1B could reduce burying better than sertraline, a selective SERT blocker. Vortioxetine (5-10 mg/kg) or sertraline (2 mg/kg) was administered 30 min presociability and 75 min prior to marble burying tests. Vortioxetine (10 mg/kg) occupancy (%) was 84 ± 1 for SERT, 31 ± 12 for 5-HT_1A, and 80 ± 5 for 5-HT_1B in brain at 110 min postinjection, and serum oxytocin was 24% lower (p < 0.01) in vortioxetine-treated mice. Vortioxetine reduced novel object investigation, whereas sertraline enhanced overall sociability. However, the vortioxetine-induced increase in social sniffing was transient, as it was lost with 60-120 min presociability test delays in subsequent experiments. Vortioxetine and sertraline both reduced BTBR marble burying. Based on vortioxetine occupancy, actions at SERT and/or 5-HT_1B are more likely to underlie its behavioral effects than 5-HT_1A. Overall, vortioxetine has great potential for suppressing restrictive-repetitive behaviors, but it appears less promising as a sociability enhancer.