Vortioxetine reverses medial prefrontal cortex-mediated cognitive deficits in male rats induced by castration as a model of androgen deprivation therapy for prostate cancer
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Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors.
We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression.
Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro.
ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide.
These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer.
KeywordsCognitive flexibility Antidepressant Androgen Medial prefrontal cortex Ventral hippocampus Medial dorsal thalamus Prostate cancer
Androgen deprivation therapy
Attentional set-shifting test
Food and Drug Administration
Functional magnetic resonance imaging
Medial dorsal thalamus
Medial prefrontal cortex
Sulforhodamine B assay
The authors thank Dr. Sarah Bulin for assistance with the electrophysiological experiments.
This work was supported by research grant RP180055 from the Cancer Prevention and Research Institute of Texas; research grant R01 CA224672 from the National Cancer Institute, National Institutes of Health; the Quincy and Estine Lee Endowment Fund; and pilot funding provided by the Mays Cancer Center, UT Health San Antonio. Gene expression data were generated by the Mays Cancer Center Genomics Shared Resource Facility (P30 CA054174). In-kind support was provided by H. Lundbeck A/S, which generously provided the drug-containing chow and control chow.
Compliance with ethical standards
All research procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Texas Health, San Antonio, and are compliant with the ethical standards of the National Institutes of Health as specified in the Guide for the Care and Use of Laboratory Animals.
Conflict of interest
Vortioxetine was provided by H. Lundbeck A/S, which had no input into the conduct of the study, analysis or interpretation of the data, and no role in the decision to publish or in the writing of the manuscript. Dr. Morilak receives research funding from Alkermes that has no relation to the present work. All other authors declare that they have no conflicts of interest.
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