This is a resubmission of a revised application that extends work completed as part of our previously funded FIRST Award. The research outlined in this proposal centers on an investigation of the ionic mechanisms involved in generation of the complex activity patterns exhibited by mesencephalic dopamine neurons. The rational for these studies derives from an extensive literature indicating that alterations in dopamine cell firing pattern represent a mechanism through which these cells alter their influence on target neurons in the forebrain. The principal objectives of the experiments proposed in this application are organized into three specific aims. In the first, intra- and extracellular recording techniques will be used to identify and characterize the ionic mechanisms responsible for generating bursting activity in dopamine neurons. These experiments will make us of an in vitro model of patterned activity developed in our laboratory and will focus on delineating the role of voltage-gated Ca 2, channels and excitatory amino acid receptors in generating the plateaulike oscillations in membrane potential that appear to drive bursting activity in these neurons. In the second specific aim, current and voltage clamp techniques will be used to test the hypothesis that an apamin-insensitive Ca2+-dependent conductance: (1) contributes to the hyperpolarization that terminates the plateau phase of the bursting oscillation and (2) regulates the temporal organization of spikes within bursts by contributing to the mechanism underlying spike frequency adaptation. In the third and final aim, a multidisciplinary approach, involving both molecular and electrophysiological approaches will be used to test the hypothesis that an increase in the functional expression of apamin-sensitive Ca2""""""""-activated K+ channels is responsible for the loss Of normal activity patterns in vitro. By more clearly understanding these basic physiological mechanisms, we hope to gain additional insights regarding the etiopathological basis of DA related disorders and the relevant pharmacological actions of the drugs used to treat them.
