Whereas more research is needed

Whereas more research is needed to identify the precise mechanism by which FIN exerts its antidyskinetic effect, the LED209 receptor that it can negatively modulate dopaminergic transmission is also supported by our previous findings. Indeed, we have previously shown that FIN completely reversed the behavioral alterations induced by exaggerated dopaminergic activation in rodents. Specifically, in Sprague-Dawley rats, systemic FIN injections countered the prepulse inhibition (PPI) deficits and stereotyped behaviors exerted by dopaminergic agonists, but not by the N-methyl-d-aspartate receptor antagonist dizocilpine (Bortolato et al., 2008). Notably, in a subsequent study we demonstrated that these behavioral effects occurred through a negative modulation of dopaminergic receptors in the striatum (Devoto et al., 2012). Furthermore, in both C57BL/6 mice and Long-Evans rats FIN was able to rescue the PPI loss mediated by selective D1 receptor activation (Frau et al., 2013, Frau et al., 2016, Mosher et al., 2016). Importantly, unlike the most used anti-dopaminergic drugs, the behavioral effects of FIN were not accompanied by catalepsy, catatonia or other motor impairments. 5AR is the critical enzyme involved in neurosteroidogenesis as well as in androgens synthesis. Accordingly, the use of FIN and other 5AR inhibitor analogs in the clinical settings is based on the blockade of the conversion of testosterone into dihydrotestosterone (DHT), which has been shown to exert a key role in the pathogenesis of both prostatic hyperplasia and androgenic alopecia (Paba et al., 2011). We recently found that the acute administration of FIN resulted in a significant reduction of the 5AR metabolite allopregnanolone, and increase in its substrates pregnenolone and dehydroepiandrosterone in the rat striatum (Frau et al., 2015). This is of particular importance, as a wide literature suggested that these steroids might modulate dopaminergic function (Di Paolo, 1994, Sánchez et al., 2010). For instance, pregnenolone was recently shown to rescue the altered behavioral outcomes of dopamine transporter knockout mice, which mirror dopamine receptor hyperactivation in the striatum (Wong et al., 2012). Although the neurobiological underpinnings of pregnenolone are not completely understood, it acts as potent agonists of σ1 receptors (Maurice et al., 2006), which have been shown to modulate D1 receptor signaling (Navarro et al., 2010). Similarly, allopregnanolone and dehydroepiandrosterone sulfate modulate the behavioral effects of D1 receptor activation (Frye et al., 2006, Dong et al., 2007), and allopregnanolone has been shown to affect the phosphorylation of DARPP-32 (Mani et al., 2000, Frye and Walf, 2010), a key molecule in D1 receptor signaling cascade and dyskinesia (Svenningsson et al., 2004, Picconi et al., 2003, Santini et al., 2007). Thus, the anti-dopaminergic effect of 5AR inhibitors may derive from a complex modification of the levels of several neurosteroids, which would affect striatal dopamine receptor function. FIN has been on the market for over twenty years for the treatment of male pattern hair loss and benign prostatic hyperplasia, showing limited side effects in patients. Thus, if this drug will be demonstrated to exert beneficial effects for dyskinesia in Parkinson's patients, it may be rapidly introduced in the clinical practice, at least in male subjects. The feasibility of a clinical application is also supported by other clinical findings showing the ability of FIN to produce therapeutic effects in adult male patients affected by Tourette Syndrome (Bortolato et al., 2007, Muroni et al., 2011), a psychiatric disorder characterized by motor fluctuations and phonic tics, which pathophysiology has also been ascribed to striatal dopaminergic dysregulation (Felling and Singer, 2011, Jeffries et al., 2002, Denys et al., 2013). More importantly, FIN was also able to attenuate motor and non-motor side-effects elicited by dopamine replacement therapies in PD patients, such as blepharospasm and pathological gambling (Bortolato et al., 2010, Bortolato et al., 2012).