Antipsychotic Drug Impact on Dopaminergic Neurons

Biological Sciences: 2nd Place (The Ohio State University Denman Undergraduate Research Forum)Antipsychotics are used to treat people diagnosed with schizophrenia by blocking dopamine receptors, specifically the D2 subtype. These drugs all increase dopamine in the extracellular to a similar extent by increasing firing rate and synthesis of new dopamine. However, the drugs vary on the rate of synthesis and the amount of dopamine’s metabolite, DOPAC. Previous research has shown this might be due to the difference of antipsychotic drugs’ affinity to the D2 autoreceptor. The purpose of this study is to explain the variability of antipsychotic drugs on the differences in DOPAC levels and dopamine synthesis rates. The way chosen to study this is through a computational model that records the amount of dopamine and DOPAC molecules in certain compartments of a neuron over a certain time. This model includes all known mechanisms and pathways in which dopamine and DOPAC can be created, transported, and metabolized. By studying the changes in levels of dopamine and DOPAC and the pathways involved, one can make conclusions about the area(s) that a drug acting on a dopaminergic neuron effects. When using antipsychotic drugs, the model showed that there was a difference between the leak of dopamine molecules out the vesicles into the cytosol depending on the drug used. The greater the ability the drug had to penetrate the membrane of the neuron and eventually vesicular membrane, the greater the amount of dopamine leaked out of the vesicle. The higher leak value directly correlated to higher cytosolic DOPAC levels and dopamine synthesis rates of the cytosolic pathway. These results explain another possible mechanism of the drug that controls synthesis rates besides D2 receptor activity.Academic Major: Pharmaceutical Science

Antipsychotic Drugs Influence Dopamine Neuron Terminals via Action on D2-receptors and Vesicles

Undergraduate Denman Research Forum - 2nd PlaceDopamine D2 antagonist antipsychotic drugs share the effects of increasing dopamine synthesis, dopamine neuron firing rate, and dopamine and DOPAC levels. These antagonists all raise extracellular dopamine to approximately 163% of control and DOPAC levels to approximately 200% of control without changing tissue level of dopamine. Variability in striatal tissue DOPAC level (190 – 350% of control) and rates of dopamine synthesis (190‐378% of control) reported after administration of various antipsychotic drugs gives evidence that these parameters are influenced by factors besides the antagonism of the D2 receptor. We used a computational model of dopaminergic terminals in the striatum to determine what parameters other than D2 receptors might be targets for the drugs. Simulation model results suggest that D2 receptor antagonism results in a slight increase in rate of dopamine exocytosis accompanied by a small increase in rate of dopamine synthesis needed to maintain the increase in rate of exocytosis and a small increase in rate of dopamine synthesis specifically dedicated to DOPAC secretion. Simulation model results also suggest that variable increases in levels of tissue DOPAC result from increases in passive diffusion of dopamine out from vesicles coupled with an increase in rate of dopamine synthesis required to maintain tissue levels of dopamine. Biochemical data reported in the literature suggests changes in passive diffusion depend on the ability of the antipsychotic drug to diffuse into and alkalinize vesicles. This variable increase in tissue DOPAC, but invariable increase in extracellular dopamine across all antipsychotic drugs, provides evidence that DOPAC levels are not a precise indicator of dopamine turnover. These findings also suggest there is a sensor that monitors dopamine vesicular levels and provides feedback to tyrosine hydroxlase activity.No embargoAcademic Major: Pharmaceutical Science