Opioid peptides are present in presynaptic terminals in several areas of the limbic system, but their role in synaptic transmission remains obscure. In the dentate gyrus, the gateway into the hippocampus, opioid peptides appear to be crucial for long term potentiation (LTP) of the synapse between the lateral perforant path (LPP) and the principal neurons of the dentate, the dentate granule cells. Understanding the cellular and molecular mechanisms of opioid induced LTP in the dentate would give insights into the role of opioids and opioid receptors in learning, memory and, perhaps, also into the conditioning that sustains opiate addiction. The model will be the dentate gyrus in the rat hippocampal slice. In the rat dentate, enkephalin is present in the terminals of the LPP and the opioid antagonist, naloxone, blocks LTP of the LPP to granule cell synapse. The goal is to determine how enkephalin release from the LPP acts to produce LTP in the dentate. The hypothesis is that release of enkephalin from the LPP terminals facilities LTP by suppressing GABAergic inhibition of the dentate neurons. This hypothesis will be tested using both extracellular and intracellular recording techniques in the hippocampal slice.
The specific aims are: 1) Determine if a more specific opioid antagonist than naloxone can be used to block dentate LTP. The effects of more specific opioid antagonists will be tested; 2) Determine if blockade of GABAergic inhibition eliminates the opioid dependent component of LTP. This would be expected if opioids are acting by disinhibiting the granule cells; 3) Test whether release of enkephalin from the LPP increases depolarization of granule cells during a stimulus train; and 4) Determine if release of enkephalin from the LPP suppresses inhibitory postsynaptic potentials in dentate granule cells.
