CHRONIC DRUG ACTIONS ON G PROTEIN COUPLED RECEPTOR MECHANISMS

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Many neurotransmitters in brain, as well as several drugs of abuse, act by binding to receptors belonging to the superfamily of G-protein-coupled receptors. These drugs include the opioids, which act directly at their own G-protein receptors, and cocaine, which increases extra-synaptic dopamine that binds to its own receptor. The goal of this project is to utilize animal models provided by the Center to examine how chronic treatment with opioids and psychostimulants affect coupling of different receptors to G-proteins in brain, and how these changes at the level of the receptor amd transducer then translate into downstream changes in opioid-mediated second messenger systems. In the first case, the coupling of receptor to G-proteins will be explored by [35/S]GTPgammaS autoradiography, which provides a neuroanatomical localization of the activation of G-protein receptors. Because this technique allows for a number of different receptors to be assayed simultaneously in brain sections from the same animals, this provides an ideal method to efficiently analyze brain tissue from Center-derived animals. This project will follow up on previous studies which showed that chronic morphine treatment produced selective attenuation of mu opioid-activated G-proteins in specific brainstem nuclei. These studies will determine the time course of the chronic morphine effect, and compare chronic treatment of rats with morphine to chronic treatment with other opioid agonists of different potencies and efficacies. The effects on non-contingent chronic administration morphine. To determine how these changes in receptor-G- protein coupling affect opioid second messenger systems, rats treated in the same way will be analyzed for opioid inhibition of forskolin- stimulated pro-enkephalin signal transduction systems in vivo. A second aim will examine the effect of chronic administration of cocaine and other psychostimulants on receptor-coupled G-proteins, with a particular focus on D2 dopamine receptors, 5-HT/1A receptors, and opioid receptors. To determine the effects of transporter selectivity and pharmacokinetics on modulation of receptor coupling to G-proteins, novel tropanes synthesized by the Center with well-defined specificities and durations of action will be administered chronically. This project will use information obtained from other Center projects in the planning of its studies, and provide information about receptor changes during chronic drug treatment that will be important for studies in other projects.