The neurodegenerative process in Parkinson’s disease involves exacerbated inflammation with the participation of astrocytes. The P2Y1 receptor (P2Y1R) is a purinergic receptor predominantly expressed in astrocytes, regulating their activity, proliferation, and glutamate release. Therefore, our investigation explores whether the P2Y1R contributes to dopaminergic neuron degeneration, potentially via astrocytic involvement. To study dopaminergic degeneration, we injected 9 µg 6-hydroxydopamine into the right striatum (STR) of male Sprague-Dawley rats aged 6-8 weeks (ethical approval: 167/2019). Dopamine-depleted rats exhibited intense astrogliosis within 7 days, along with increased P2Y1R expression in the substantia nigra pars compacta (SNpc), mainly detected in astrocytes rather than dopaminergic neurons. Intranasal administration of the P2Y1R-specific agonist, MRS2365, for 7 days exacerbated the forelimb use asymmetry in dopamine-depleted rats at the dose of 90nmol/kg, indicating motor impairment. Similarly, dopaminergic neuron death was exacerbated in the STR and SNpc at 90 nmol/kg, while the 10 nmol/kg dose exhibited the same effect in SNpc. To further explore the P2Y1R’s role in the basal ganglia, we recorded striatal medium spiny neurons (MSNs) using the whole-cell patch clamp technique. Preliminary findings indicate that MRS2365 increased the intrinsic excitability of MSNs. Furthermore, the agonist also induced long-term depression (LTD) in MSNs, without affecting glutamate release probability in the corticostriatal pathway. Our results suggest the potential involvement of the P2Y1R in dopaminergic degeneration, possibly acting through astrocytes and the modulation of GABAergic MSN activity. Financial support: São Paulo Research Foundation (doctorate scholarship 2019/24553-5 and thematic project 2018/07366-4).