title: Involvement of 5-HT₇ receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents.
abstract: 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.
authors.affiliation: Lundbeck Research USA, 215 College Avenue, Paramus, NJ 07652, USA. westrich@fdu.edu
authors.forename: Ligia
authors.initials: L
authors.lastname: Westrich
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
authors.forename: Ouria
authors.initials: O
authors.lastname: Dkhissi-Benyahya
authors.forename: Connie
authors.initials: C
authors.lastname: Sánchez
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*; D000078784:Vortioxetine
chemical_list: D056950:Period Circadian Proteins; D010879:Piperazines; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine; C513312:Per2 protein, mouse; C104425:serotonin 7 receptor