G-protein coupled receptors are well known for converting an extracellular signal into an intracellular response. Emerging data, however, suggest that some receptors are primarily localized on intracellular membranes where they may play a unique role in the cell's physiology. Recently we have shown that activation of mGlu5 metabotropic glutamate receptors expressed on striatal nuclear membranes leads to rapid, sustained nuclear calcium responses that can be blocked by receptor specific antagonists. Current results demonstrate that both sodium-dependent and independent transporters are involved in moving agonist across both plasma and nuclear membranes as inhibition of either transport system blocks agonist-induced nuclear calcium changes. Remarkably, non-transported agonists induce rapid, transient calcium responses in striatal neurons whereas transported ligands induce long, sustained calcium plateaus. Finally, ligand stimulation of nuclear receptors initiates at least one signaling cascade that is known to alter gene transcription and regulate many paradigms of synaptic plasticity. Because these findings represent a radical departure from traditional models emphasizing cell surface receptors and their ligands, they have important cellular ramifications both in terms of the concept, i.e. that nuclear receptors can regulate nuclear calcium, as well as for mGlu5-specific functions throughout development and in association with synaptic plasticity. The goal of the current application is to utilize our established striatal system together with our newly characterized pharmacological tools to determine the long term consequences of intracellular receptor activation. Using both a candidate gene and an unbiased genomic approach, we will test the primary hypothesis that activation of cell surface versus intracellular mGlu 5 receptors leads to differential changes in gene expression. Inasmuch as mGlu5 receptors are also involved in the pathophysiology of various neurodegenerative and neuropsychiatric disorders such as Parkinson's disease, drug addiction, anxiety and schizophrenia they represent attractive targets for drug discovery. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for these disorders. Thus these studies are highly applicable to the purpose of the R21 mechanism. The metabotropic glutamate receptors play fundamental roles in modulating neuronal excitability, synaptic transmission, and various metabolic functions in both health and disease. Given that many of these receptors are largely intracellular, this application seeks to determine the functional consequences of intracellular metabotropic glutamate receptors. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for various neurodegenerative and neuropsychiatric disorders such as Parkinson's disease, drug addiction, anxiety and schizophrenia. [unreadable] [unreadable]