This is a proposal to study and relate three aspects of the modulatory actions of dopamine in the neostriatum. 1. Modulation of excitatory amino acid-induced ligand-gated conductances. 2. Modulation of intrinsic, voltage-gated conductances. 3. Contribution of signal transduction pathways to dopamine modulation. An understanding of the function interactions between dopamine and excitatory amino acids in the neostriatum is of both clinical and scientific relevance because abnormalities in the actions of these substances have been implicated in neurological and psychiatric disturbances such as Parkinson's Disease, affective disorders and Huntington's Disease. This proposal is one of the first forays into examining dopaminergic modulation of excitatory amino acid function from an electrophysiological perspective. It brings together the diverse electrophysiological, pharmacological and morphological methodologies necessary to perform these experiments and examines a set of specific hypotheses. The major hypothesis that guides these studies is that the direction of modulation produced by dopamine is a function of both the subtype of excitatory amino acid receptor and the subtype of dopamine receptor activated. This proposal has three specific aims. The first will determine the factors that control dopamine's ability to modulate responses mediated by activation of excitatory amino acid receptors. Experiments will investigate the contribution of ligand-gated conductances, activation of pre-and/or postsynaptic elements and the potential ability of the same neostriatal neurons to respond to activation of different dopamine receptor subtypes.
The second aim will examine the contribution of intrinsic, voltage-gated membrane conductances to the differential modulatory action of dopamine. Dopamine may affect one or more intrinsic, voltage-dependent ion channels that alter membrane conductances. These conductances interact with ligand-gated conductances to sculpt the resulting membrane potential changes that control the output of the cell.
The third aim will examine the contribution of signal transduction pathways to the modulatory actions of dopamine. Experiments will assess contributions of G proteins, cyclic AMP-dependent protein kinase and protein kinase C-dependent mechanisms. Significant and important information will be derived from this proposal. I will elucidate the rules that guide dopamine's modulation of responses induced by excitatory amino acids in the neostriatum. It will identify the contribution of intrinsic membrane currents and second messenger systems tot he mechanisms responsible for this modulation. These outcomes will be instrumental in developing rational strategies to treat diseases caused by dysfunctions in dopamine and excitatory amino acid systems.
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