Studies on the Formation of 6‐Hydroxydopamine in Mouse Brain After Administration of 2,4,5‐Trihydroxyphenylalanine (6‐HydroxyDOPA)

Abstract: 2,4,5‐Trihydroxyphenylalanine (6‐OH‐DOPA) destroys central and peripheral noradrenergic neurons, while sparing dopaminergic neurons. Previous studies indicate that 6‐OH‐DOPA toxicity is mediated by the formation of 6‐hydroxydopamine. However, levels of 6‐hydroxydopamine in brain following peripheral administration of 6‐OH‐DOPA have not been documented. In the current study, 6‐OH‐DOPA and 6‐hydroxydopamine were measured in brain by HPLC with electrochemical detection after intraperitoneal injection of 6‐OH‐DOPA. When mice were injected with 100 mg 6‐OH‐DOPA/kg, 6‐hydroxydopamine levels in the striatum were highest (1.9 μg/g) at 15 min and fell slowly to 24% of the peak value at 4 h. Experiments with reserpine indicated that the relative stability of 6‐hydroxydopamine was largely dependent upon storage in synaptic vesicles. Reserpine (10 mg/kg) lowered striatal 6‐hydroxydopamine levels to 21.6% of control (non‐reserpine‐treated) values at 1 h, and to 8.9% of control values at 4 h. Levels of 6‐hydroxydopamine in the striatum at 1 h were increased 113% by pargyline (100 mg/kg), 145% by α‐methyldopahydrazine (carbidopa; 25 mg/kg), and 261% by pargyline and carbidopa together. Levels of dopamine in the striatum were unchanged at 2.5 h after 200 mg 6‐OH‐DOPA/kg (with pargyline and 50 mg carbidopa/kg), whereas levels of norepinephrine in the frontal cortex fell by 77%. At the same time, 6‐hydroxydopamine levels were 8.8‐fold higher in the striatum (5.54 μ/g) than in the cortex (0.63 μg/g). The latter results show that the striatum is resistant to 6‐OH‐DOPA‐mediated depletion of catechol‐amines even though the concentrations of 6‐hydroxydopamine approach those of endogenous dopamine.