Considerable evidence suggests that the neurotransmitter dopamine is involved in behavioral motivation and reward, and abnormal regulation of dopamine release may contribute to symptoms of psychosis, mania, and depression. The major goals of this grant proposal are to identify the pharmacology of transmitter receptors and characterize the ionic conductances that are involved in the regulation of the excitability of dopamine neurons. Experiments will use microelectrodes or patch pipettes to record membrane potentials and currents from single neurons in the rat brain slice. Recordings will be made in the ventral tegmental area (VTA) because these dopamine cells innervate those mesolimbic structures that are associated with emotional behavior and mental illness. Proposed experiments will build on our previous electrophysiological studies which showed that dopamine neurons receive """"""""fast"""""""" excitatory synaptic inputs mediated by NMDA receptors, and """"""""slow"""""""" excitatory input (slow EPSC) mediated by metabotropic glutamate receptors (mGluRs). The receptor pharmacology of the slow EPSC will be investigated , as well as the ionic conductances that underlie its unusual """"""""U""""""""-shaped current-voltage relationship. Because the slow EPSC is only evoked by focal stimulation of the pontine region of the brain slice, we will test the hypothesis that this input originates from cells in the pedunculopontine nucleus. Experiments will also identify ionic conductances and neurotransmitters that regulate NMDA-induced burst firing. Modulation of burst firing may be clinically important because bursts of action potentials have been shown to greatly potentiate the amount of dopamine released from nerve terminals. Finally, studies will characterize neurotransmitter receptors that modulate the NMDA receptor-mediated component of synaptic transmission. By increasing our understanding of how excitatory inputs are regulated by ionic conductances and neurotransmitters, this may ultimately lead to better treatment if psychiatric illnesses.
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