Effects of vortioxetine on cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment. Effects of vortioxetine on cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment

Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer, but more than half of patients treated with ADT experience debilitating cognitive impairments in domains known to be mediated by the hippocampus and prefrontal cortex. Unfortunately, there are few treatments to prevent or reverse these changes from occuring, thus severely decreasing quality of life in patients. To begin studying these deficits, surgically castrated rats were used to model cognitive impairments associated with the spatial learning and executive function, then chronically treated with the multimodal antidepressant, vortioxetine, as in intervention to reverse these impairments. Vortioxetine effectively rescued cognitive deficits in after surgical castration, and increased resposivity in in vivo evoked local field potentials within the Schaeffer Collateral-CA1 pathway and the ventral hippocampus-mPFC pathway. Surgical castration also induced significant changes in gene expression within the mPFC and the dorsal hippcampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that these two regions may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients that experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit level plasticity-related mechanisms compromised by ADT. Overall design: Whole genome microarray in tissue collected from the dorsal hippocampus (dHipp) or medial prefrontal cortex (mPFC) of surgically castrated rats after chronic dietary drug treatment with the antidepressant vortioxetine (40 mg/kg/day at free-feeding or 28 mg/kg/day at food restriction for 17 days), compared to sham controls and animals receiving control diet (n=2-6/group, 4 groups total x two brain regions)