Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 10, Pages 4319-4327Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00386
Keywords
Autism; Lu AA21004; multimodal antidepressant; repetitive burying; social; serotonin
Funding
- Max and Minnie Tomerlin Voelcker Fund
- Summer Physiology Research Program
- National Institutes of Health [MH086708]
- Lindow, Stephens & Treat Research Award, Congressionally Directed Medical Research Program [AR110109]
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Vortioxetine is a multimodal antidepressant with agonist activity at serotonin (5-HT)(1A) and 5-HT1B receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR T(+)Itpr3(tf)/J (BTBR) mice, the 5-HT1A 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-HT1A could improve BTBR sociability and via 5-HT1B 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-HT1A, and 80 5 for 5-HT1B 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-HT1B are more likely to underlie its behavioral effects than 5-HT1A. Overall, vortioxetine has great potential for suppressing restrictive-repetitive behaviors, but it appears less promising as a sociability enhancer.
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