The study of dopamine dynamics in transgenic mouse models

Brain slice experiments are a robust and controlled platform for the study of neurotransmitter dynamics using electrochemistry. The isolation and study of brain slices from genetically altered animals is critical for the understanding of neurotransmitter dynamics. The dynamics of biogenic amine neurotransmitters are important for movement and addiction studies. This dissertation focuses on the use of five separate transgenic mouse models to increase the understanding of biogenic amine transmission in the brain. Fast scan cyclic voltammetry and amperometry at carbon fiber microelectrodes were used to directly monitor the dynamics of dopamine, serotonin, and norepinephrine. The amount of neurotransmitter available to act on neuronal targets is a balance of release and uptake. A transgenic mouse model lacking the presynaptic protein synapsin was used to show that dopamine has a unique presynaptic architecture making it susceptible to release facilitation by cocaine, a drug of abuse. Additionally, mice expressing different amounts of the dopamine transporter were studied to show that the dopamine transporter is a critical regulator of extracellular dopamine concentrations. The importance of mitochondrial energy output was studied in animals lacking uncoupling protein 2, a regulator of mitochondrial function and two disease state mouse models indicated a relationship between obesity and dopamine release that does not extend to mental retardation. High performance liquid chromatography was used to support the conclusions drawn from the electrochemical measurements in brain tissue. Finally, methodologies related to brain slice experimentation were evaluated to better understand how these measurements can be improved.