Dopamine Synthesis by Non-Dopaminergic Neurons in the Stratium of Mice with and without Degeneration of the Nigrostriatal Dopaminergic System

Abstract

Abstract—In the past 15 years, it has been shown that dopamine (DA) is synthesized in the brain not only by dopaminergic neurons but also by non-dopaminergic neurons expressing one of the complementary enzymes tyrosine hydroxylase or aromatic L-amino acid decarboxylase (hereinafter, decarboxylase). Moreover, L-DOPA, an intermediate product of DA synthesis, is transported from neurons containing tyrosine hydroxylase to neurons containing decarboxylase. The aim of this work was to test our hypothesis about the presence of DA synthesis by non-dopaminergic neurons in the murine striatum, a key link in the central regulation of motor function. For this, we used a methodological approach we developed that allows us to determine the intensity of cooperative synthesis as the difference between the total DA content in brain slices and in the incubation medium after incubation of the slices in Krebs–Ringer solution and Krebs–Ringer solution with the addition of a competitive L-DOPA membrane carrier inhibitor. Synthetic non-metabolizable 2-amino-2-norbornanecarboxylic acid, which, unlike the previously used inhibitors (L-tyrosine, L-leucine, etc.), does not directly or indirectly affect the functional activity of DA-ergic neurons, was used as an inhibitor for the first time. The use of this inhibitor made it possible to obtain evidence that the DA contained in the striatum of mice is normally synthesized not only by DAergic neurons (in axons), but also by non-dopaminergic neurons that express either tyrosine hydroxylase or decarboxylase. It was also shown that DA synthesis by non-dopaminergic neurons is performed in the striatum of mice with partial DAergic denervation caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a specific neurotoxin. We believe that the synthesis of DA by non-dopaminergic neuronsis an important neuroplasticity mechanism which contributes to the compensation of DA deficiency after the degeneration of nigrostriatal DA-ergic neurons. Thus, for the first time, evidence was obtained for the synthesis of DA by non-dopaminergic neurons in the striatum of healthy mice and mice with DA-ergic denervation of the striatum.