The basal ganglia play an important role in voluntary movement and substance dependence. Excitatory glutamatergic corticostriatal projections from the cerebral cortex innervate the basal ganglia at the striatal medium spiny neuron, which also receives modulatory dopamine projections from midbrain nuclei. Both dopamine and glutamate have been implicated in numerous neuropsychiatric disorders including Parkinson's disease and substance dependence. Using a newly developed imaging technique, we have recently shown that dopamine depresses the release of glutamate from a subset of cortical terminals providing filtering of cortical information to the striatum. We hypothesize that alterations in striatal dopamine release lead to long-term changes in striatal excitation mediated by dopamine receptor hypersensitivity and neuroplasticity. There are three major goals: 1) Using mouse models for dopamine depletion and dopamine excess, we will study the effect of altered dopamine availability on striatal synaptic plasticity, 2) we will define the mechanisms underlying these neuroplastic alterations, and 3) we will determine if drug-induced behaviors are determined by such adaptations. We will utilize a newly developed imaging technique that allows direct visualization of release from corticostriatal presynaptic terminals in murine striatal slice preparations. These optical studies will be integrated with whole-cell patch clamp recordings to delineate the characteristics of the corticostriatal pathway and the effects of dopamine transmission at the medium spiny neuron. In vivo manipulations of transgenic and wild-type mice will provide models with which to investigate synaptic plasticity that occurs with dopamine depletion and dopamine excess. The outcome of these investigations will demonstrate how alterations in dopamine release produce corticostriatal plasticity and show mechanistically how aberrant striatal excitation might lead to certain neuropsychiatric signs and symptoms. This project is expected to provide further insights into pharmacological alternatives for the treatment of movement disorders and addiction.
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