Opioids regulate the flow of neuronal activity in the hippocampal formation (HF) by modulating hippocampal interneurons and affecting afferent systems. Alterations in hippocampal opioid systems are associated with aging and seizure deficits. Our ultrastructural studies examining the subcellular distribution of opioids [enkephalins (ENKs) and dynorphins (DYNs)] in rat hippocampal pathways have provided anatomical evidence for pathway-specific modulatory roles on interneurons containing y-aminobutyric acid (GABA) and helped elucidate the mechanisms subserving seizure induced changes of opioids. They also suggest that the delta- and mu-opioid receptors (DOR and MOR), which mediate the actions of ENKs, are localized to different subpopulations of GABAergic interneurons and show that kappa-opioid receptors (KOR), which mediate the action of DYNs, are located on hypothalamic afferent terminals in the guinea pig HF. This continuing proposal takes advantage of the recent cloning and generation of antisera to opioid receptors and proposes 3 studies which aim to directly examine in the rat (and guinea pig, where relevant): (a) the structural basis for the receptor-mediated actions of opioids on hippocampal neurons; and (b) the selectivity of opioid receptors for either subclasses of GABAergic interneurons or afferent input. The studies will employ quantitative light and electron microscopic dual labeling immunocytochemistry. Study I will test the hypothesis that many of the profiles bearing opioid receptors are located within a functionally relevant distance from potential release sites on ENK- or DYN-containing profiles. Study II will test the hypothesis that: (1) DORs are primarily located on the terminals, post-synaptic sites and/or non-synaptic plasmalemma of subsets of GABAergic interneurons containing NPY and SOM; (2) MORs are present mostly on multiple subsets of GABAergic basket and chandelier cells; and (3) KORs may be positioned strategically so as to modulate input to GABAergic interneurons as well as granule cells. Study II also will test the premise that experimentally induced seizures differentially alter the number and/or subcellular distribution of MORs and DORs with respect to surviving GABAergic interneurons. Study III will examine the relationships of MORs and DORs to extrinsic hippocampal afferents. The hypothesis will be tested that: (1) MORs and DORs are on axon terminals near post-synaptic or non-synaptic plasmalemma sites on dendrites containing N-methyl-D-aspartate receptors in the dentate lateral perforant path zone; and (2) MORs and DORs are located on different pre- and post-synaptic sites relative to septal (especially cholinergic) and catecholaminergic terminals. These studies will provide insight on the contribution of hippocampal opioid neurons to mnemonic processes and the pathologies associated with disorders such as seizures in humans.
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