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  • br Funding br Introduction l Dihydroxyphenylalanine


    Introduction l-3,4-Dihydroxyphenylalanine (l-DOPA) is the gold-standard treatment for the motor symptoms of Parkinson's disease (PD); however, its chronic use induces severe motor complications that eventually limit its long-term efficacy (Bastide et al., 2015). The most disabling side effect is represented by the onset of dyskinesias, involuntary choreo-dystonic movements that dramatically affect patients’ quality of life. l-DOPA-induced dyskinesias (LIDs) have been shown to reflect abnormal dopaminergic transmission (Berthet and Bezard, 2009, Bastide et al., 2015), and, in particular, dysfunctions in downstream signaling of D1 receptors (Fiorentini et al., 2016, Aubert et al., 2005, Feyder et al., 2011, Westin et al., 2007). Converging evidence shows that dopamine signaling is modulated by neuroactive steroids (NASs) (Di Paolo, 1994, Sánchez et al., 2010); in particular, we previously reported that the behavioral effects of dopaminergic agonists are influenced by inhibition of 5-alpha reductase (5AR), a key rate-limiting enzyme in NASs synthesis/metabolism (Paba et al., 2011). Specifically, we showed that, in rodent models, the 5AR inhibitors finasteride (FIN) and dutasteride attenuated the severity of a broad set of behavioral alterations induced by D1 receptor-selective and non-selective agonists, such as hyperactivity, stereotyped behaviors and prepulse inhibition deficits (Frau et al., 2016, Frau et al., 2013). Of note, these antidopaminergic effects were not accompanied by extrapyramidal symptoms, even at the higher tested doses (Bortolato et al., 2008). Furthermore, recent evidence has shown that 5AR inhibition may elicit neuroprotective effects in animal models of PD (Litim et al., 2015, Litim et al., 2016). Based on this evidence, we postulated that 5AR inhibition may exert therapeutic properties on LID, and tested this hypothesis investigating whether FIN may impact on the development and dopamine hydrochloride sale of dyskinesia induced by l-DOPA in male and female 6-hydroxydopamine (6-OHDA)-lesioned rats. In addition, we investigated whether FIN may interfere with the ability of l-DOPA to ameliorate rat forelimb use in the stepping test, and whether reduction of LID takes place via modulation of D1- or D2/D3-receptor function.
    Material and methods
    Discussion The results of the present study show for the first time that the prototypical 5AR inhibitor FIN significantly reduces development and expression of dyskinesia induced by l-DOPA in 6-OHDA-lesioned rats under different treatment regimens. Importantly, the lower dose of FIN, which produced significant dampening of AIMs (equal to the higher dose) when given as preventive treatment in male rats, did not affect the therapeutic efficacy of l-DOPA in the stepping test. Preservation of the therapeutic effect of l-DOPA is, in fact, a key point when exploring a potential antidyskinetic target. Acute experiments in l-DOPA-primed rats indicated that the antidyskinetic effect of FIN may be exerted via modulation of both the D1- and D2/D3 receptor pathways, which are both known to be involved in the expression of dyskinesia (Bastide et al., 2015, Cenci and Konradi, 2010, Solís et al., 2015, Sebastianutto et al., 2016). According to our previous results, the effect of FIN on ropinirole-induced dyskinesia might be ascribed to its ability to modulate DA D3 receptor pathway, rather than DA D2 receptors (Frau et al., 2016). At the same time, these latter results, along with the efficacy of FIN in counteracting dyskinesia induced by apomorphine, excluded a possible pre-synaptic effect of FIN (i.e. by a modulation of dopamine release from serotonin neurons). Importantly, FIN produced significant antidyskinetic effect also in female parkinsonian rats; however, when comparing the results in the two genders, it appears that the effect of FIN was more pronounced in males, as indicated by the most effective antidyskinetic properties elicited by the lower FIN dose in this gender. Previous studies have indicated that 5AR expression and activity are finely regulated upon the influence of sex hormones (Sánchez et al., 2006). In particular, the expression of 5AR isoform 2 is under the positive control of testosterone, opposite to the 5AR type 1 isoform (Torres and Ortega, 2003). In addition, rats subjected to orchiectomy, in which testosterone and dihydrotestosterone levels are very low, show higher 5AR 1 levels (Torres and Ortega, 2003). Although further investigations are warranted, it could be speculated that the higher FIN sensitivity observed in males may rely on a divergent expression and/or activity of the two isoforms due to different physiological levels of testosterone between genders. Moreover, we cannot exclude an influence of the estrogen levels during the estrous cycle in the lower response to the effect of FIN in females. On the other hand, male subjects would represent a more feasible target for an investigation of the effect of FIN on dyskinesia in humans, as this drug is currently used only in males (see below).