Objective: Neurosteroids are known to exert diverse functions in the brain. 5α-reductase (5α-R), a rate-limiting enzyme involved in the biosynthesis of neurosteroids is inhibited by finasteride. Clinical studies suggest that administration of finasteride causes the emergence of affective symptoms and cognitive dysfunction. Modeling this in rats would provide an opportunity to understand the mechanisms. Accordingly, in the present study, we evaluated the effects of repeated finasteride administration on spatial learning and memory in the partially baited radial arm maze task (RAM) and social cognitive behavior in the social interaction test. Further, to initiate the quest to understand the mechanisms underlying the effects of finasteride, in a separate group of animals, acetylcholinesterase (AChE) activity in the frontal cortex, hippocampus, septum and striatum was estimated.
Methods: 2 months old male Wistar rats were trained to learn a partially baited radial arm maze task (four trials per day till they reach a choice accuracy of 80 %). Following this, rats were administered with either vehicle (HPβCD) or finasteride (30 or 100 mg/Kg, s.c.) for 7 days and then subjected to retention test on the eighth day. To evaluate the social cognition, finasteride was administered for 7 days, followed by social interaction test on the eighth day. All the sessions were video-recorded and analyzed using Noldus Ethovision XT™ software. Following finasteride administration, on the eighth day, rats were euthanized, and AChE activity was estimated by modified Ellman's method.
Results: Finasteride (100 mg/Kg, s.c.) administration decreased the percent correct choice during the retention trial of the RAM task. This was paralleled by an increase in the number of total number of errors and reference memory errors. In the social interaction test, finasteride (100 mg/Kg, s.c.) administration decreased the time spent with the rat compared to the object, implying decreased sociability and diminished social preference evidenced by similar time spent with the novel and familiar rat. Reduced AChE activity was observed in the frontal cortex, hippocampus and septum.
Conclusion: Our study provides evidence that repeated administration of finasteride decreases social interaction and results in cognitive deficits, potentially through a cholinergic mechanism. Further studies are required to understand the exact link between the cognitive effects and the cholinergic system. A deeper probe of the current findings holds promise for the development of novel neurosteroid-based therapeutics to treat affective and cognitive disorders.
Keywords: 5α-reductase; Allopregnanolone; Cognition; Depression; Finasteride; Memory deficits; Neurosteroids; Spatial learning.
Copyright © 2020 Elsevier Ltd. All rights reserved.