Home LiteratureArticle Details
PMID: 19150393 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Hippocampal dynorphin immunoreactivity increases in response to gonadal steroids and is positioned for direct modulation by ovarian steroid receptors.

Neuroscience ·Vol. 159 ·No. 1 ·2009-03-03 ·Pages 204-16

Torres-Reveron A, Khalid S, Williams TJ, Waters EM, Jacome L, Luine VN, Drake CT, McEwen BS, Milner TA

Abstract

The hippocampal formation (HF) is involved in modulating learning related to drug abuse. While HF-dependent learning is regulated by both endogenous opioids and estrogen, the interaction between these two systems is not well understood. The mossy fiber (MF) pathway formed by dentate gyrus (DG) granule cell axons is involved in some aspects of learning and contains abundant amounts of the endogenous opioid peptide dynorphin (DYN). To examine the influence of ovarian steroids on DYN expression, we used quantitative light microscopic immunocytochemistry to measure DYN levels in normal cycling rats as well as in two established models of hormone-treated ovariectomized (OVX) rats. Rats in estrus had increased levels of DYN-immunoreactivity (ir) in the DG and certain CA3 lamina compared with rats in proestrus or diestrus. OVX rats exposed to estradiol for 24 h showed increased DYN-ir in the DG and CA3, while those with 72 h estradiol exposure showed increases only in the DG. Six hours of estradiol exposure produced no change in DYN-ir. OVX rats chronically implanted with medroxyprogesterone also showed increased DYN-ir in the DG and CA3. Next, dual-labeling electron microscopy (EM) was used to evaluate the subcellular relationships of estrogen receptor (ER) alpha-, ERbeta and progestin receptor (PR) with DYN-labeled MFs. ERbeta-ir was in some DYN-labeled MF terminals and smaller terminals, and had a subcellular association with the plasmalemma and small synaptic vesicles. In contrast, ERalpha-ir was not in DYN-labeled terminals, although some DYN-labeled small terminals synapsed on ERalpha-labeled dendritic spines. PR labeling was mostly in CA3 axons, some of which were continuous with DYN-labeled terminals. These studies indicate that ovarian hormones can modulate DYN in the MF pathway in a time-dependent manner, and suggest that hormonal effects on the DYN-containing MF pathway may be directly mediated by ERbeta and/or PR activation.

MeSH Terms
Animals Dynorphins/drug effects,metabolism Estradiol/pharmacology Estrous Cycle/physiology Female Gene Expression Regulation/drug effects,physiology Gonadal Steroid Hormones/classification,pharmacology Hippocampus/drug effects,metabolism Microscopy, Immunoelectron Mossy Fibers, Hippocampal/drug effects,physiology Ovariectomy Rats Rats, Sprague-Dawley Receptors, Estrogen/classification,metabolism,ultrastructure Time Factors
Chemicals
Gonadal Steroid Hormones Receptors, Estrogen Estradiol Dynorphins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Torres-Reveron A
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, 411 East 69th Street, New York, NY 10021, USA.
Khalid S
Williams T J
Waters E M
Jacome L
Luine V N
Drake C T
McEwen B S
Milner T A
References (97)
97 references, click to expand
  1. Focal stimulation of the mossy fibers releases endogenous dynorphins that bind kappa 1-opioid receptors in guinea pig hippocampus.
    J Neurochem. 1991 Jul;57(1):333-43 PMID: 1675664
  2. The opioid peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fibre synapses and modulates long-term potentiation.
    Nature. 1993 Apr 1;362(6419):423-7 PMID: 8096624
  3. Spinal cord dynorphin precursor intermediates decline during late gestation.
    J Neurochem. 1995 Sep;65(3):1374-80 PMID: 7643115
  4. Neurosteroids: endogenous regulators of the GABA(A) receptor.
    Nat Rev Neurosci. 2005 Jul;6(7):565-75 PMID: 15959466
  5. Ultrastructural localization of neuropeptide Y-like immunoreactivity in the rat hippocampal formation.
    Hippocampus. 1992 Apr;2(2):107-25 PMID: 1308177
  6. The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female.
    Epilepsia. 2006 Sep;47(9):1423-40 PMID: 16981857
  7. Addiction, dopamine, and the molecular mechanisms of memory.
    Neuron. 2000 Mar;25(3):515-32 PMID: 10774721
  8. Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors.
    Brain Res Brain Res Rev. 2001 Nov;37(1-3):153-61 PMID: 11744083
  9. Region-specific changes in prodynorphin mRNA and ir-dynorphin A levels after kindled seizures.
    J Mol Neurosci. 1999 Aug-Oct;13(1-2):69-75 PMID: 10691294
  10. Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation.
    Neuroscience. 2005;130(1):151-63 PMID: 15561432
  11. Seizures, neuropeptide regulation, and mRNA expression in the hippocampus.
    Prog Brain Res. 1990;83:371-90 PMID: 2203104
  12. Morphometry of a peptidergic transmitter system: dynorphin B-like immunoreactivity in the rat hippocampal mossy fiber pathway before and after seizures.
    Hippocampus. 1999;9(3):255-76 PMID: 10401641
  13. Ultrastructural localization of extranuclear progestin receptors in the rat hippocampal formation.
    J Comp Neurol. 2008 Nov 1;511(1):34-46 PMID: 18720413
  14. Hippocampal dynorphin B injections impair spatial learning in rats: a kappa-opioid receptor-mediated effect.
    Neuroscience. 1998 Jul;85(2):375-82 PMID: 9622237
  15. Prodynorphin storage and processing in axon terminals and dendrites.
    FASEB J. 2006 Oct;20(12):2124-6 PMID: 16966485
  16. Exocytosis from neuronal large dense-cored vesicles.
    Int Rev Cytol. 1990;121:67-126 PMID: 1972143
  17. Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus.
    Endocrinology. 2002 Nov;143(11):4366-74 PMID: 12399433
  18. Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus.
    J Comp Neurol. 1981 May 10;198(2):335-50 PMID: 6263955
  19. Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster.
    J Comp Neurol. 1987 Jan 22;255(4):497-510 PMID: 2880880
  20. Hormonal effects on the brain.
    Epilepsia. 1998;39 Suppl 8:S2-8 PMID: 9915614
  21. Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha.
    Endocrinology. 2003 May;144(5):2055-67 PMID: 12697714
  22. Co-expression of steroid hormone receptors in opioid peptide-containing neurons correlates with patterns of gene expression during the estrous cycle.
    Brain Res Mol Brain Res. 1996 Sep 1;40(2):275-84 PMID: 8872312
  23. Localization of estrogen receptor alpha (ER alpha) in pyramidal neurons of the developing rat hippocampus.
    Brain Res Dev Brain Res. 2001 Jun 29;128(2):165-75 PMID: 11412902
  24. Cellular sites for dynorphin activation of kappa-opioid receptors in the rat nucleus accumbens shell.
    J Neurosci. 1999 Mar 1;19(5):1804-13 PMID: 10024364
  25. Gonadal hormone modulation of dendrites in the mammalian CNS.
    J Neurobiol. 2005 Jul;64(1):34-46 PMID: 15884004
  26. Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors.
    Brain. 2007 Apr;130(Pt 4):1017-28 PMID: 17347252
  27. Gestational and ovarian sex steroid antinociception: synergy between spinal kappa and delta opioid systems.
    Brain Res. 1998 May 25;794(1):61-7 PMID: 9630517
  28. Dynorphin is contained within hippocampal mossy fibers: immunochemical alterations after kainic acid administration and colchicine-induced neurotoxicity.
    Proc Natl Acad Sci U S A. 1983 Jan;80(2):589-93 PMID: 6132379
  29. Seizure related changes in the regulation of opioid genes and transcription factors in the dentate gyrus of rat hippocampus.
    Neuroscience. 1995 Sep;68(1):73-81 PMID: 7477937
  30. Opioid modulation of recurrent excitation in the hippocampal dentate gyrus.
    J Neurosci. 2000 Jun 15;20(12):4379-88 PMID: 10844006
  31. Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles.
    Endocr Rev. 2007 Feb;28(1):1-19 PMID: 17018839
  32. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport.
    J Neurosci. 1997 Apr 1;17(7):2295-313 PMID: 9065491
  33. Estrogen regulation of prodynorphin gene expression in the rat adenohypophysis: effect of the antiestrogen tamoxifen.
    Endocrinology. 1995 Apr;136(4):1589-94 PMID: 7895668
  34. Chronic opiate agonists down-regulate prodynorphin gene expression in rat brain.
    Brain Res. 1991 Nov 1;563(1-2):132-6 PMID: 1786525
  35. The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system.
    J Neurosci. 2008 Jan 9;28(2):407-14 PMID: 18184783
  36. Ultrastructure of the dynorphin-immunoreactivity in rat brain hippocampal mossy fiber system.
    Acta Histochem Suppl. 1990;38:161-71 PMID: 1981940
  37. Sex and estrogen influence drug abuse.
    Trends Pharmacol Sci. 2004 May;25(5):273-9 PMID: 15120494
  38. Ovarian steroids modulate leu-enkephalin levels and target leu-enkephalinergic profiles in the female hippocampal mossy fiber pathway.
    Brain Res. 2008 Sep 26;1232:70-84 PMID: 18691558
  39. Progestin receptors mediate progesterone suppression of epileptiform activity in tetanized hippocampal slices in vitro.
    Neuroscience. 2000;101(4):895-906 PMID: 11113338
  40. Memory retention is modulated by acute estradiol and progesterone replacement.
    Behav Neurosci. 2001 Apr;115(2):384-93 PMID: 11345963
  41. Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner.
    J Comp Neurol. 2005 Jan 17;481(3):252-65 PMID: 15593136
  42. Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis.
    Endocrinology. 1998 Nov;139(11):4708-13 PMID: 9794483
  43. Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling.
    Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13162-7 PMID: 16938840
  44. Effects of cocaine on c-fos and preprodynorphin mRNA levels in intact and ovariectomized Fischer rats.
    Brain Res Bull. 2002 Jul;58(3):295-9 PMID: 12128156
  45. Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue?
    Trends Neurosci. 2005 Feb;28(2):79-85 PMID: 15667930
  46. Estrogen-BDNF interactions: implications for neurodegenerative diseases.
    Front Neuroendocrinol. 2006 Dec;27(4):404-14 PMID: 17069877
  47. Characterization of the prodynorphin and proenkephalin neuropeptide systems in rat hippocampus.
    J Neurosci. 1985 Mar;5(3):808-16 PMID: 3838345
  48. Ultrastructural heterogeneity of enkephalin-containing terminals in the rat hippocampal formation.
    J Comp Neurol. 1995 Jul 31;358(3):324-42 PMID: 7560290
  49. Seizures induce dramatic and distinctly different changes in enkephalin, dynorphin, and CCK immunoreactivities in mouse hippocampal mossy fibers.
    J Neurosci. 1988 Jun;8(6):1852-62 PMID: 2898512
  50. LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats.
    Brain Res. 1995 Dec 12;703(1-2):26-30 PMID: 8719612
  51. Elevation of guinea pig brain preprodynorphin mRNA expression and hypothalamic-pituitary-adrenal axis activity by "binge" pattern cocaine administration.
    Brain Res Bull. 2001 May 1;55(1):65-70 PMID: 11427339
  52. Dynorphin and the kappa 1 ligand [3H]U69,593 binding in the human epileptogenic hippocampus.
    Epilepsy Res. 1997 Oct;28(3):189-205 PMID: 9332884
  53. Sex differences in progesterone receptor expression: a potential mechanism for estradiol-mediated sexual differentiation.
    Endocrinology. 2002 Oct;143(10):3727-39 PMID: 12239082
  54. Modulation by the dorsal, but not the ventral, hippocampus of the expression of behavioural sensitization to amphetamine.
    Int J Neuropsychopharmacol. 2008 Jun;11(4):497-508 PMID: 18047756
  55. Kappa opioid receptors in rat spinal cord vary across the estrous cycle.
    Brain Res. 2000 Apr 7;861(1):168-72 PMID: 10751578
  56. Methamphetamine alters prodynorphin gene expression and dynorphin A levels in rat hypothalamus.
    Eur J Pharmacol. 1999 Jan 22;365(2-3):183-6 PMID: 9988101
  57. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system.
    J Comp Neurol. 1997 Dec 1;388(4):507-25 PMID: 9388012
  58. Immunoreactive dynorphin is regulated by estrogen in the rat anterior pituitary.
    Neuroendocrinology. 1988 Jan;47(1):1-6 PMID: 2893308
  59. Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility.
    Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12021-6 PMID: 10518569
  60. Estrogen-induced increase in the magnitude of long-term potentiation occurs only when the ratio of NMDA transmission to AMPA transmission is increased.
    J Neurosci. 2005 Aug 24;25(34):7780-91 PMID: 16120779
  61. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus.
    J Comp Neurol. 2006 Oct 10;498(5):712-26 PMID: 16917850
  62. Opioid systems in the dentate gyrus.
    Prog Brain Res. 2007;163:245-63 PMID: 17765723
  63. Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep.
    Endocrinology. 2004 Jun;145(6):2959-67 PMID: 14988383
  64. Immunocytochemical localization of nuclear estrogen receptors and progestin receptors within the rat dorsal raphe nucleus.
    J Comp Neurol. 1998 Feb 16;391(3):322-34 PMID: 9492203
  65. Endogenous opioids released from perforant path modulate norepinephrine actions and inhibitory postsynaptic potentials in guinea pig CA3 pyramidal cells.
    J Pharmacol Exp Ther. 1991 Jul 1;258(1):18-26 PMID: 2072294
  66. A light and electron microscopic analysis of the mossy fibers of the rat dentate gyrus.
    J Comp Neurol. 1986 Apr 22;246(4):435-58 PMID: 3700723
  67. Localization and quantitation of proenkephalin-derived neuropeptides in the rat hippocampus.
    Neuropeptides. 1985 Feb;5(4-6):437-40 PMID: 2860602
  68. Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.
    FASEB J. 2008 Jul;22(7):2393-404 PMID: 18310464
  69. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat.
    J Comp Neurol. 1993 Oct 8;336(2):293-306 PMID: 8245220
  70. Neuropeptide co-expression in the magnocellular neurosecretory system of the female rat: evidence for differential modulation by estrogen.
    Neuroscience. 1993 Jun;54(4):1001-18 PMID: 8341419
  71. Estrogen-mediated structural and functional synaptic plasticity in the female rat hippocampus.
    Horm Behav. 1998 Oct;34(2):140-8 PMID: 9799624
  72. Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus.
    Nature. 1993 Jun 3;363(6428):451-4 PMID: 8099201
  73. Synergistic effects of progesterone and oestradiol on rat LH subunit mRNA.
    J Mol Endocrinol. 1990 Apr;4(2):119-25 PMID: 2344389
  74. The effects of morphine treatment and morphine withdrawal on the dynorphin and enkephalin systems in Sprague-Dawley rats.
    Psychopharmacology (Berl). 1995 Apr;118(4):391-400 PMID: 7568625
  75. Subcellular relationships between cholinergic terminals and estrogen receptor-alpha in the dorsal hippocampus.
    J Comp Neurol. 2003 Sep 1;463(4):390-401 PMID: 12836175
  76. Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor.
    Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11110-4 PMID: 7479947
  77. Cocaine, dopamine and the endogenous opioid system.
    J Addict Dis. 1996;15(4):73-96 PMID: 8943583
  78. Microinjection of dynorphin into the hippocampus impairs spatial learning in rats.
    Pharmacol Biochem Behav. 1990 Feb;35(2):429-35 PMID: 1969641
  79. Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats.
    Neurobiol Learn Mem. 2006 Jul;86(1):35-46 PMID: 16529958
  80. Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters.
    J Neurosci. 1994 Jun;14(6):3736-50 PMID: 7911518
  81. Estradiol facilitates kainic acid-induced, but not flurothyl-induced, behavioral seizure activity in adult female rats.
    Epilepsia. 2000 May;41(5):510-5 PMID: 10802755
  82. Variations in opioid peptide levels during the estrous cycle in Sprague-Dawley rats.
    Neuropeptides. 2006 Jun;40(3):195-206 PMID: 16540166
  83. Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats.
    J Comp Neurol. 1997 Dec 1;388(4):603-12 PMID: 9388019
  84. Kappa 2 opioid receptors inhibit NMDA receptor-mediated synaptic currents in guinea pig CA3 pyramidal cells.
    J Neurosci. 1994 Sep;14(9):5580-9 PMID: 7916046
  85. Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms.
    J Appl Physiol (1985). 2001 Dec;91(6):2785-801 PMID: 11717247
  86. Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites.
    J Comp Neurol. 2001 Jan 15;429(3):355-71 PMID: 11116225
  87. Prodynorphin peptide distribution in the forebrain of the Syrian hamster and rat: a comparative study with antisera against dynorphin A, dynorphin B, and the C-terminus of the prodynorphin precursor molecule.
    J Comp Neurol. 1989 Oct 15;288(3):353-86 PMID: 2571622
  88. Hippocampal excitability increases during the estrous cycle in the rat: a potential role for brain-derived neurotrophic factor.
    J Neurosci. 2003 Dec 17;23(37):11641-52 PMID: 14684866
  89. Stimulation of endogenous opioid release displaces mu receptor binding in rat hippocampus.
    Neuroscience. 1990;37(1):45-53 PMID: 1978741
  90. Dynorphin and epilepsy.
    Prog Neurobiol. 1996 Dec;50(5-6):557-83 PMID: 9015827
  91. Alterations in prodynorphin gene expression and dynorphin levels in different brain regions after chronic administration of 14-methoxymetopon and oxycodone-6-oxime.
    Brain Res Bull. 2006 Jul 31;70(3):233-9 PMID: 16861108
  92. Gender differences in prodynorphin but not proenkephalin mRNA expression in the striatum of adolescent rats exposed to prenatal cocaine.
    Neurosci Lett. 2007 Jun 29;421(3):213-7 PMID: 17574751
  93. Estrogen modulates learning in female rats by acting directly at distinct memory systems.
    Neuroscience. 2007 Jan 5;144(1):26-37 PMID: 17052857
  94. A polyclonal antibody to the rat oestrogen receptor expressed in Escherichia coli: characterization and application to immunohistochemistry.
    J Endocrinol. 1992 Nov;135(2):333-41 PMID: 1474341
  95. Monoclonal and polyclonal antibodies to human progesterone receptor peptide-(533-547) recognize a specific site in unactivated (8S) and activated (4S) progesterone receptor and distinguish between intact and proteolyzed receptors.
    Endocrinology. 1990 Sep;127(3):1167-75 PMID: 2201532
  96. Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats.
    Endocrinology. 2002 Feb;143(2):436-44 PMID: 11796496
  97. Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation.
    J Comp Neurol. 2005 Oct 17;491(2):81-95 PMID: 16127691
Article Info
Journal
Neuroscience
Abbr.
Neuroscience
ISSN
0306-4522
DOI
10.1016/j.neuroscience.2008.12.023
Published
2009-03-03
Epub
2008-00-24
Pages
204-16
Language
English
Region
United States
NLM ID
7605074
PMCID
PMC2647575
Subset
IM
Grants
NINDS NIH HHS · NS07080 · United States
NIDA NIH HHS · DA08259 · United States
NINDS NIH HHS · R01 NS007080 · United States
NIDA NIH HHS · R01 DA008259 · United States
NINDS NIH HHS · R01 NS007080-42 · United States
NIDA NIH HHS · R01 DA008259-12S1 · United States
NIGMS NIH HHS · T32 GM007739 · United States
NIDA NIH HHS · R01 DA008259-15 · United States
External Links
PubMed source DOI: 10.1016/j.neuroscience.2008.12.023 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2