Background: The striatum is an important brain structure for the learning and memory as well as motor and cognitive skills. Abnormalities in subcellular localization and synaptic cell surface proteins occur within the striatum in Parkinson's disease (PD). In this study; we tested the effects of neurosteroid allopregnanolone (Allo) in the restoration of the nigrostriatal pathway output in 6-OHDA-lesioned rats. Methods: To simulate PD, 6-hydroxydopamine (6-OHDA) was injected into the rat's substantia nigra. Allo (5 and 20 mg/kg, orally) was administered on the day after the 6-OHDA injection and continued every other day for 8 weeks. Motor-skill learning and motor behaviors were assessed by the apomorphineinduced rotation, accelerating rotarod, beam-balance (BB) and beam-walk (BW), and bar tests. The levels of striatal postsynaptic density protein 95 (PSD-95) and neurexin 1 as well as cyclooxygenase-2 (COX-2) and caspase-3 proteins were determined by immunoblotting. Results: The data indicated that Allo significantly improved the 6-OHDA-induced motor impairment which revealed by the increase in the ability to remain on a rotating rod and the increase in balancing and crossing on beam and also with decrease in the degree of catalepsy in bar test. Furthermore, PSD-95 and neurexin 1 levels were significantly decreased, while COX-2 and activated caspase-3 were increased in the striatum of 6-OHDA-treated animals. The mentioned molecular changes were attenuated by Allo treatment. Conclusions: The data demonstrated that Allo has protective effect in 6-OHDA-treated rats and inhibits striatal inflammation and apoptosis and preserves pre-and post-synaptic proteins and maybe the synaptic integrity in nigrostriatal pathway. (C) 2017 Elsevier Masson SAS. All rights reserved.