5α-reductase converts testosterone to dihydrotestosterone (DHT), which is more potent than the testosterone. Increased DHT levels are observed in benign prostatic hyperplasia (BPH) and alopecia. Therefore finasteride, a selective 5α-reductase inhibitor, is used to treat patients with BPH and alopecia. However, patients on finasteride treatment reported adverse neuropsychiatric effects after initiating therapy that continued even after stopping the medication (Irwig 2012). These included anxiety, depression, cognitive impairments, and emotional sensitivity (Altomare and Capella 2002; Ganzer et al., 2015; Rahimi-Ardabili et al., 2006). In our preliminary study, short-term finasteride administration for six days induced depression-like phenotype in the forced swim test (FST) and splash test (Sasibhushana et al., 2019). However, whether short-term finasteride administration induces anxiety and cognitive dysfunction is not known. Accordingly, in the current study, we aimed to expand the previous findings, by examining if finasteride induces depression-like behavior in the sucrose preference test (SPT) and anxiety-like behavior in the elevated plus maze (EPM), open field test (OFT), light-dark test (L-D test) and novelty suppressed feeding test (NSFT). Further, we evaluated the effect of finasteride administration on learning and memory in the novel object recognition and location tests (NORT & NOLT).

Although there is substantial clinical data on finasteride-induced behavioral effects (Giatti et al., 2023; Leliefeld et al., 2023), there is very little understanding on the underlying mechanisms. Neuronal plasticity, particularly, synaptic plasticity, has been demonstrated to be one of the pathophysiological processes which might be affected in depression and in the effects of antidepressants (Duman et al., 2016; Liu et al., 2017). Previous studies from our laboratory showed that impaired hippocampal synaptic plasticity in depressed rats and was restored by the antidepressant treatment (Bhagya et al., 2011, 2015). Neurosteroids such as DHT and ALLO have been shown to be involved in long term potentiation (LTP) and metaplasticity (Brandt et al., 2020; Izumi et al., 2013). Izumi et al. showed that inhibition of 5α-R by finasteride resulted in the inhibition of low frequency stimulation induced long term depression and metaplastic LTP indicating the role of 5α-reduced neurosteroids like allopregnanolone. Further, finasteride administration inhibited the conversion of testosterone to DHT which resulted in impaired LTP and decreased synaptic density in the hippocampus (Brandt et al., 2020). Accordingly, we examined changes in the presynaptic and postsynaptic plasticity in the Schaffer collateral-CA1 synapses in the hippocampus.

One of the potential pathways by which finasteride might be inducing anxiety and depression is by increasing the production of corticosterone. Inhibition of 5α-R by finasteride may not only increase the production of 11-deoxycorticosterone through the availability of progesterone but also decrease the degradation of corticosterone, resulting in the net increase in corticosterone levels. Evidence for the role of corticosterone comes from a study where they show that transfection of 5α-R decreases cortisol levels in hepatocytes and finasteride/dutasteride augments the actions of cortisol (Nasiri et al., 2015). Another line of evidence towards this comes from a clinical study, which shows that the metabolism of cortisol is inhibited for as long as 4 weeks, in patients treated with dutasteride (Maeda et al., 2018). To verify if this mechanism is involved in the CNS effects of finasteride, we examined the corticosterone levels following short-term finasteride administration. Thus, the aim of the current study was to comprehensively understand the short-term finasteride administration-induced behavioral changes, and its cellular and molecular underpinnings.