In the mammalian brain, D-/L-serine regulates fundamental physiological processes including synaptic plasticity, energy homeostasis, lipid metabolism, and cell survival. Recent findings from our group (Di Maio et al., 2023) indicated notable variations in serine enantiomer concentrations in the caudate-putamen of Parkinson's disease (PD) patients and the CSF of de-novo PD patients. Nevertheless, the impact of the severity of dopaminergic loss on the central levels of serine enantiomers remains uncertain. To gain deeper insight into this matter, the current study examines the occurrence of central metabolic alterations in serine enantiomers within two well-established preclinical models of PD: the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey and the MPTP-plus-probenecid mouse models. Moreover, the effect of oral D-serine supplementation (⁓100 mg/kg/day) was assessed in MPTPp-treated mice. In monkeys, MPTP administration produced severe denervation of nigrostriatal dopaminergic fibres (⁓75%), leading to significantly increased levels of serine enantiomers in the rostral putamen, but not in the subthalamic nucleus, and the lateral/medial globus pallidus. Moreover, this neurotoxin reduced striatal expression of the astrocytic serine transporter ASCT1, and of the glycolytic enzyme GAPDH. Conversely, the metabolism of serine enantiomers and the protein expression of ASCT1 and GAPDH remained unaffected in the brain of MPTPp-treated mice, which exhibited only mild dopaminergic degeneration (⁓30%). Interestingly, D-serine supplementation did not produce harmful effects on the dopaminergic nigrostriatal system under both physiological and MPTP conditions. Our findings provide insights into a neuroadaptive mechanism linking the severity of dopaminergic nigrostriatal degeneration to striatal serine enantiomer upregulation and highlight the safety of D-serine supplementation.