Involvement of 5-HT7 receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents

Dec 3, 2014Neuropharmacology

Role of 5-HT7 receptors in how vortioxetine affects daily rhythms and short-term memory in rodents

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Abstract

Incubation of tissue explants from PER2::LUC mice with 0.1 μM vortioxetine increased the period length of PER2 bioluminescence.

Vortioxetine affects circadian behavior and episodic memory by targeting serotonin receptors involved in these processes.
Significant delays in wheel-running behavior were observed in Sprague-Dawley rats treated with 10 mg/kg vortioxetine before activity onset.
The increase in circadian period length caused by vortioxetine was reversed when a 5-HT7 receptor partial agonist (AS19) was present.
In the object recognition test, vortioxetine treatment led to increased exploration of a novel object, an effect blocked by AS19.

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Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 μM vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents.

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Involvement of 5-HT7 receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents

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