A small dopamine permeability of storage vesicle membranes and end product inhibition of tyrosine hydroxylase are sufficient to explain changes occurring in dopamine synthesis and storage after inhibition of neuron firing

Abstract

Computer simulations of dopamine (DA) regulation at a striatal varicosity were developed to determine basic principles that explain the pattern of changes in level of neurotransmitter and its rate of synthesis and metabolism when DA neuron firing is inhibited. The models suggest that DA synthesis is normally at a slower rate because of end-product inhibition of tyrosine hydroxylase (TH) by cytosolic DA. The vast majority of DA in the cytosol arrives there via "recycling"--DA that was released during an exocytotic event is moved into the cytosol via the dopamine transporter (DAT). When neuronal firing is inhibited, the amount of cytosolic DA markedly decreases as there is no recycling. The rate of DA synthesis then increases because of the loss of end-product inhibition of TH. The newly synthesized DA is stored in vesicles, thus increasing the total amount of DA in the vesicles. A small amount of DA is continually leaking out of vesicles, and the amount leaking out increases proportionally to the amount of DA in vesicles. When the amount of DA leaking out balances the amount being stored by the vesicular monoamine transporter, DA accumulates in the cytosol. The accumulating DA inhibits TH activity, and the system enters a steady state condition characterized by approximately double the normal amount of DA in vesicles and approximately normal rate of DA synthesis and metabolism.