Related Experiment Video
Updated: Mar 10, 2026
Stress-Enhanced Fear Learning, a Robust Rodent Model of Post-Traumatic Stress Disorder
Published on: October 13, 2018
Chronic Vortioxetine Treatment Reduces Exaggerated Expression of Conditioned Fear Memory and Restores Active Coping
Lauren Hatherall1, Connie Sánchez1, David A Morilak1
1Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark.
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.
