Chronic Vortioxetine Treatment Reduces Exaggerated Expression of Conditioned Fear Memory and Restores Active Coping Behavior in Chronically Stressed Rats

Abstract

Background: Stress is a risk factor for depression and anxiety disorders, disrupting neuronal processes leading to exaggerated fear and compromised coping behaviors. Current antidepressants are only partially effective. Vortioxetine, a novel multimodal antidepressant, is a serotonin transporter inhibitor; 5-HT3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B partial agonist; and 5-HT1A agonist. We have shown that chronic dietary vortioxetine administration reversed stress-induced deficits in cognitive flexibility. In the present studies, we investigated the generality of vortioxetine's effects on other stress-related behavioral changes after different types of chronic stress.

Methods: In experiment 1, rats were fear-conditioned by pairing a tone with footshock, then exposed to chronic plus acute prolonged stress. In experiment 2, rats were exposed to chronic unpredictable stress. In both experiments, beginning on day 4 of chronic stress, vortioxetine was given in the diet (24 mg/kg/d). In experiment 1, effects of vortioxetine were tested on stress-induced changes in retention and extinction of cue-conditioned fear, and in experiment 2, on coping behavior on the shock probe defensive burying test after chronic stress.

Results: Chronic stress exaggerated the expression of conditioned fear memory. Vortioxetine restored fear memory to control levels and rendered extinction in stressed rats comparable with that in controls. In experiment 2, chronic unpredictable stress caused a shift from active to passive coping behavior, and vortioxetine restored active coping.

Conclusions: Vortioxetine reduced exaggerated expression of conditioned fear and restored adaptive coping behavior following 2 different types of chronic stress, adding to the evidence of its therapeutic potential in the management of depression and anxiety disorders.

Keywords: coping; depression; fear memory; stress; vortioxetine.

Figure 1.

Animals exposed to chronic plus acute prolonged stress treatment exhibited an exaggeration of fear memory, and chronic treatment with vortioxetine in the diet normalized fear memory in stressed rats to a level comparable with that in unstressed controls. (A) Timeline for experiment 1. Rats were habituated to the chambers, fear conditioned, and assigned to groups prior to beginning the 15-day Chronic plus Acute Prolonged Stress (CAPS) stress treatment. Vortioxetine or control diets were given beginning on day 4 of CAPS treatment. Rats were tested for fear memory and extinction on the third day after the end of CAPS treatment. (B) As expected, because rats were assigned to groups after fear conditioning, there were no differences in freezing behavior during fear conditioning. (C) Chronically stressed rats that received control diet showed an exaggerated fear memory, measured as a significant increase in freezing during tone 1 of the extinction session (**P < .01 compared with unstressed rats receiving control diet). Chronic dietary vortioxetine treatment restored freezing during tone 1 to a level comparable to that in unstressed control rats (++P < .01 compared with stressed rats receiving control diet). (D) Consistent with the enhanced fear memory seen during tone 1, CAPS stress increased freezing only in response to the first 4 tones presented during extinction (*P < .05, CAPS control diet compared with unstressed-control diet). There were no other significant effects of either stress or drug on extinction, and the final level of freezing achieved at the end of extinction training was comparable in all groups. All data presented as mean ± SEM; n = 12–14 rats/group.

Figure 2.

Animals exposed to chronic unpredictable (CUS) stress exhibited a shift from active to passive coping behavior on the shock probe defensive burying test, and chronic treatment with vortioxetine normalized coping behavior in stressed rats. (A) Time line for experiment 2. Rats were assigned to groups prior to beginning the 14-day CUS treatment. Vortioxetine or control diets were given beginning on day 4 of CUS treatment. Rats were tested in the shock probe defensive burying test on the 3rd day after the end of CAPS treatment. (B) CUS increased immobility in rats receiving control diet (*P<.05 compared with unstressed controls), and vortioxetine in the diet reduced immobility of CUS-treated rats to a level comparable with that in controls (+P<.05 compared with CUS-control diet). (C) CUS reduced burying behavior in rats receiving control diet (*P<.05 compared with unstressed controls), and vortioxetine in the diet restored burying behavior of CUS-treated rats to a level comparable with that in controls (+P<.05 compared with CUS-control diet). In this experiment, vortioxetine alone reduced burying in unstressed rats (#P<.05 compared with unstressed-control diet). (D) To assess active coping behavior as a proportion of total coping behavior (active + passive), the bury ratio was analyzed. CUS decreased the bury ratio in rats receiving control diet, indicating a shift from active to passive coping behavior (*P<.05 compared with unstressed controls), and vortioxetine in the diet restored the bury ratio of CUS-treated rats to be comparable with that in unstressed control rats (+P<.05 compared with CUS-control diet). All data presented as mean ± SEM; n = 6 rats/group.