Women are more susceptible to several aspects of drug addiction than men, including relapse following stressful events. Addictive processes critically involve hippocampal circuitry that supports spatial and episodic memory acquisition processes. In contrast to the impaired cognition observed in males after chronic stress, females display enhanced spatial memory following chronic stress suggesting ovarian hormone involvement. Within the dorsal hippocampus, it is well established that ovarian steroids, in particular estrogens, can modulate CA1 pyramidal cell activity and long-term potentiation (LTP), the cellular model of learning. During the last grant period we found that ovarian hormones also regulate enkephalins and the mu- and delta-opioid receptors (MORs and DORs, respectively) in a manner that could promote learning processes under certain conditions. Specifically, at proestrus (high estrogen): 1) enkephalin levels are elevated in mossy fibers (MFs), which synapse on the dendrites of CA3 pyramidal cells;2) increased MORs are present on the plasma membrane of parvalbumin GABAergic interneurons, which inhibit CA3 pyramidal cells;3) fewer DORs are present on the plasma membrane of pyramidal cells;and 4) MF stimulation may induce an opioid-dependent potentiation of CA3 field excitatory post- synaptic potentials. Chronic stress, which can trigger the release of opioid peptides, has maladaptive morphological responses in males that are not seen in females, and may also elevate MOR expression in parvalbumin interneurons in females. This renewal application proposes to test the central hypothesis that chronic stress leads to adaptive changes in the opioid system of females to promote CA3 LTP and other plastic processes that support drug-related learning. Approaches using a combination of light and electron microscopic immunocytochemistry, RT-PCR, in situ hybridization, in vitro slice electrophysiology and immobilization stress will test this hypothesis.
Aim 1 will determine if chronic stress alters: 1) the levels and/or subcellular distribution of enkephalins within MFs and in lateral perforant path (LPP) afferents to CA3 and 2) opioid-mediated LTP and/or other forms of opioid-mediated plasticity at MF/LPP- CA3 synapses in a manner promoting learning processes in females.
Aim 2 will determine if following chronic stress MORs and DORs have altered: 1) expression and cellular distributions;2) trafficking within select cell types;and/or 3) phosphorylated levels or distributions in the CA3 region in a manner promoting excitation and learning processes in females.

Public Health Relevance

The results of these studies will elucidate potential mechanisms through which ovarian steroids, by targeting neurons that release, express or respond to opioids, may influence hippocampal-dependent learning relevant to drug abuse. These studies will improve our understanding of sex differences in the nature and etiology of drug abuse and have implications for tailoring treatment interventions to maximize positive outcomes for females and males.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-A (02))
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Pilotte, Nancy S
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Ryan, James D; Zhou, Yan; Contoreggi, Natalina H et al. (2018) Sex Differences in the Rat Hippocampal Opioid System After Oxycodone Conditioned Place Preference. Neuroscience 393:236-257
Randesi, Matthew; Zhou, Yan; Mazid, Sanoara et al. (2018) Sex differences after chronic stress in the expression of opioid-, stress- and neuroplasticity-related genes in the rat hippocampus. Neurobiol Stress 8:33-41
McAlinn, Helena R; Reich, Batsheva; Contoreggi, Natalina H et al. (2018) Sex Differences in the Subcellular Distribution of Corticotropin-Releasing Factor Receptor 1 in the Rat Hippocampus following Chronic Immobilization Stress. Neuroscience 383:98-113
Newell, Andrew J; Lalitsasivimol, Diana; Willing, Jari et al. (2018) Progesterone receptor expression in cajal-retzius cells of the developing rat dentate gyrus: Potential role in hippocampus-dependent memory. J Comp Neurol 526:2285-2300
Ma, Qian; Yang, Jianmin; Milner, Teresa A et al. (2017) SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington's disease. JCI Insight 2:
McEwen, Bruce S; Milner, Teresa A (2017) Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res 95:24-39
Johnson, Kenneth W; Herold, Karl F; Milner, Teresa A et al. (2017) Sodium channel subtypes are differentially localized to pre- and post-synaptic sites in rat hippocampus. J Comp Neurol 525:3563-3578
Burgdorf, Caitlin E; Schierberl, Kathryn C; Lee, Anni S et al. (2017) Extinction of Contextual Cocaine Memories Requires Cav1.2 within D1R-Expressing Cells and Recruits Hippocampal Cav1.2-Dependent Signaling Mechanisms. J Neurosci 37:11894-11911
Zille, Marietta; Karuppagounder, Saravanan S; Chen, Yingxin et al. (2017) Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke 48:1033-1043
Cole, Daniel C; Chung, Youngcheul; Gagnidze, Khatuna et al. (2017) Loss of APOBEC1 RNA-editing function in microglia exacerbates age-related CNS pathophysiology. Proc Natl Acad Sci U S A 114:13272-13277

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