CAMP CASCADE--ROLE IN OPIATE MODULATION OF NMDA CURRENTS

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Tolerance and dependence are two major problems which interfere with the clinical utility & opiate drugs and promote their abuse. The cellular mechanisms underlying either process have not been well understood. Opiates reportedly induce dramatic changes in the activity of intracellular cAMP cascade in rat brain, but it remains unclear how these biochemical changes affect synaptic transmission in different brain regions and if they play an important role in the development of tolerance and dependence. In hippocampal dentate gyrus, our recent studies have shown that mu agonists inhibit NMDA receptor-mediated synaptic currents in granule cells through a G protein-mediated mechanism. The present project proposes to further examine the modulatory effect of acute and chronic opiate on NMDA currents in the dentate, and to determine the role of cAMP cascade in transducing opiate effects. The hypothesis to be evaluated is that acute opiates suppress NMDA currents by inhibiting cAMP-dependent phosphorylation in granule cells, while the upregulation of cAMP cascade by chronic opiates may profoundly enhance NMDA currents, which in turn facilitates the development of tolerance and dependence. To test this hypothesis, evoked and spontaneous NMDA currents will be recorded from dentate granule cells in the hippocampal slice using whole-cell recording techniques. Experiments will focus on following specific aims: 1) To determine the type(s) and location (presynaptic vs. postsynaptic) of opiate receptors that inhibit NMDA currents. 2) To examine how NMDA currents are modulated by manipulation of the cAMP cascade, and if acute opioid effects are mediated by inhibiting cAMP cascade. 3) and 4) To evaluate how chronic morphine alters NMDA currents and the activity of cAMP cascade in granule cells, and if these alterations contribute to the development of tolerance and dependence.