Is the brain hormonally imprintable?


      Hormonal imprinting develops at the first encounter between the target hormone and its developing receptor in the perinatal critical period. This determines the binding and response capacity of the receptor-signal transduction system and hormone production of cells for life. Molecules similar to the hormone and excess or absence of the target hormone cause faulty imprinting with lifelong consequences. Prenatal or neonatal imprinting with opiates, other drugs and prenatal stress have harmful consequences on the adult brain. Perinatal imprinting with endorphin or serotonin decreases the serotonin level of the brain while increasing sexual activity and (as in the case of endorphin) aggression. Endorphin or serotonin antagonist treatment at weaning (late imprinting) also significantly reduces the serotonin content of the brain. Backed by literary data, these observations are discussed, and the possible consequences of medical treatments are shown. The paper concludes that an excess of molecules produced by the brain itself can provoke perinatal imprinting, and it points to the possibility of late imprinting of the brain by receptor level acting agents, including a brain product (endorphin).


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        • Csaba G.
        • Lantos T.
        Effect of hormones on Protozoa. Studies on the phagocytotic effect of histamine, 5-hydoxytryptamine and indoleacetic acid in Tetrahymena pyriformis.
        Cytobiologie. 1973; 7: 361-365
        • Csaba G.
        • Lantos T.
        Effect of insulin on glucose uptake of Protozoa.
        Experientia. 1975; 31: 1097-1098
        • Csaba G.
        • Németh G.
        Effect of hormones and their precursors on Protozoa—the selective responsiveness of Tetrahymena.
        Comp Biochem Physiol. 1980; 65B: 387-390
        • Christensen S.T.
        • Leick V.
        • Rasmussen L.
        • Wheatley D.N.
        Signaling in unicellular eukaryotes.
        Int Rev Cytol. 1998; 177: 181-253
        • Christopher G.K.
        • Sundermann C.H.
        Conventional and confocal microscopic studies of insulin receptor induction in Tetrahymena pyriformis.
        Exp Cell Res. 1992; 201: 477-484
        • Christopher G.K.
        • Sundermann C.H.
        Effect of long-term insulin exposure on insulin binding in Tetrahymena pyriformis.
        Tissue Cell. 1995; 27: 585-589
        • Csaba G.
        Phylogeny and ontogeny of hormone receptors: the selection theory of receptor formation and hormonal imprinting.
        Biol Rev. 1980; 55: 47-63
        • Csaba G.
        The unicellular Tetrahymena as a model cell for receptor research.
        Int Rev Cytol. 1985; 95: 327-377
        • LeRoith D.
        • Schiloach J.
        • Roth J.
        • Lesniak M.A.
        Evolutionary origins of vertebrate hormones: substances similar to mammalian insulin are native to unicellular eukaryotes.
        Proc Natl Acad Sci USA. 1980; 77: 6184-6186
        • LeRoith D.
        • Schiloach J.
        • Berelowitz M.
        • Frohman L.A.
        • Krieger B.T.
        • Roth J.
        Are messenger molecules in microbes the ancestors of the vertebrate hormones and tissue factors?.
        Fed Proc. 1983; 42: 2602-2607
        • Csaba G.
        • Kovács P.
        Insulin treatment (hormonal imprinting) increases the insulin production of the unicellular Tetrahymena long term. Is there a simultaneous formation of hormone receptor and hormone?.
        Cell Biol Int. 1995; 19: 1011-1014
        • Csaba G.
        • Kovács P.
        Localization of β-endorphin in Tetrahymena by confocal microscopy. Induction of the prolonged production of the hormone by hormonal imprinting.
        Cell Biol Int. 1999; 23: 695-702
        • Csaba G.
        • Kadar M.
        Durable sensitization of hormone receptors during differentiation in regenerating planarians by treatment with homologous or analogous hormone molecules.
        Exp Cell Biol. 1980; 48: 240-244
        • Csaba G.
        Interactions between the genetic programme and environmental influences in the perinatal critical period.
        Zool Sci. 1991; 8: 813-825
        • Csaba G.
        Phylogeny and ontogeny of chemical signaling: origin and development of hormone receptors.
        Int Rev Cytol. 1994; 155: 1-48
        • Csaba G.
        Hormonal imprinting: its role during the evolution and development of hormones and receptors.
        Cell Biol Int. 2000; 24: 407-424
        • Csaba G.
        • Nagy S.U.
        Influence of the neonatal suppression of TSH production (neonatal hyperthyroidism) on response to TSH in adulthood.
        J Endocrinol Invest. 1987; 8: 557-561
        • Bern H.A.
        • Jones L.A.
        • Mori T.
        • Young P.N.
        Exposure of neonatal mice to steroids: longterm effects on the mammary gland and other reproductive structures.
        J Steroid Biochem. 1975; 6: 673-676
        • Bern H.A.
        • Edery M.
        • Mills K.T.
        • Kohrman A.F.
        • Mori T.
        • Larson L.
        Long term alterations in histology and steroid receptor level of the genital tract and mammary gland following neonatal exposure of female BALB/cCrgl mice to various doses of diethylstilbestrol.
        Cancer Res. 1987; 47: 4165-4172
        • Eriksson P.
        • Archer T.
        • Frederiksson A.
        Altered behaviour in adult mice exposed to a single low dose of DDT and its fatty acid conjugate as neonates.
        Brain Res. 1990; 514: 141-142
        • Gibson D.F.C.
        • Roberts S.A.
        • Evans G.S.
        Changes in the hormone dependency of epithelial cell proliferation in the genital tract of mice following neonatal oestrogen treatment.
        Eur J Cancer. 1991; 27: 1295-1301
        • Iguchi T.
        Cellular effects of early exposure to sex hormones and antihormones.
        Int Rev Cytol. 1992; 139: 1-57
        • Mirzahosseini S.
        • Karabélyos C.s.
        • Dobozy O.
        • Csaba G.
        Changes in sexual behavior of adult male and female rats neonatally treated with vitamin D3.
        Hum Exp Toxicol. 1996; 15: 573-576
        • Tchernitchin A.
        • Thernitchin N.N.
        Imprinting of path of heterodifferentiation by prenatal or neonatal exposure to hormones, pharmaceuticals, pollutants and other agents and conditions.
        Med Sci Res. 1992; 20: 391-397
        • Tchernitchin A.
        • Tchernitchin N.N.
        • Mena M.A.
        • Unda C.
        • Soto J.
        Imprinting: perinatal exposures cause the development of diseases during the adult age.
        Acta Biol Hung. 1999; 50: 425-440
        • Nelson K.G.
        • Sakai Y.
        • Eitzman B.
        • Steel T.
        • McLachlan J.A.
        Exposure to diethylstilbestrol during a critical developmental period of the mouse reproductive tract leads to persistent induction of two estrogen-regulated genes.
        Cell Growth Differ. 1994; 5: 595-606
        • Csaba G.
        • Kovács P.
        Impact of 5-azacytidine on insulin binding and insulin induced receptor formation in Tetrahymena.
        Biochem Biophys Res Commun. 1990; 168: 709-713
        • McLachlan J.A.
        • Burow M.
        • Chiang T-C.
        • Li S.F.
        Gene imprinting in developmental toxicology: a possible interface between physiology and pathology.
        Toxicol Lett. 2001; 120: 161-164
        • Csaba G.
        • Kovács P.
        • Pállinger É.
        Single treatment (hormonal imprinting) of newborn rats with serotonin increases the serotonin content of cells in adults.
        Cell Biol Int. 2002; 26: 663-668
        • Csaba G.
        • Kovács P.
        • Pállinger É.
        Effect of a single neonatal endorphin treatment on the hormone (endorphin, serotonin, hCG) content of adult rat mast cells.
        Cell Biol Int. 2003; 27: 423-427
        • Barraclough C.A.
        Modification in the CNS regulation of reproduction after exposure of prepubertal rats to steroid hormones.
        Rec Prog Horm Res. 1966; 22: 503-516
        • Gorski R.A.
        Hypothalamic imprinting by gonadal steroid hormones.
        Adv Exp Med Biol. 2002; 511: 57-70
        • Tena-Sempere M.
        • Gonzalez L.C.
        • Pinilla L.
        • Huhtaniemi I.
        • Aguilar E.
        Neonatal imprinting and regulation of estrogen receptor alpha and beta mRNA expression by estrogen in the pituitary and hypothalamus of the male rat.
        Neuroendocrinology. 2001; 73: 12-25
        • Dorner G.
        • Schenk R.
        • Schmiedel B.
        • Ahrens L.
        Stressful events in prenatal life of bi- and homosexual men.
        Exp Clin Endocrinol. 1983; 81: 83-87
        • Insel T.R.
        • Kinsley C.H.
        • Mann P.E.
        • Bridges R.S.
        Prenatal stress has long-term effects on brain opiate receptors.
        Brain Res. 1990; 511: 93-97
        • Kinsley C.H.
        • Mann P.E.
        • Bridges R.S.
        Prenatal stress alters morphine- and stress-induced analgesia in male and female rats.
        Pharmacol Biochem Behav. 1988; 30: 123-128
        • Sternberg W.F.
        • Ridgway C.G.
        Effects of gestational stress and neonatal handling on pain, analgesia and stress behavior of adult mice.
        Physiol Behav. 2003; 78: 375-383
        • Reznikov A.G.
        • Nosenko N.D.
        • Tarasenko L.V.
        • Sinitsyn P.V.
        • Polyakova L.I.
        Early and long-term neuroendocrine effects of prenatal stress in male and female rats.
        Neurosci Behav Physiol. 2001; 31: 1-5
        • Rothe T.
        • Langer M.
        Prenatal diazepam exposure affects beta-adrenergic receptors in brain regions of adult rat offspring.
        Neurochem. 1988; 51: 1361-1366
        • Deutch A.Y.
        • Gruen R.J.
        • Roth R.H.
        The effects of perinatal diazepam exposure on stress-induced activation of the mesotelencephalic dopamine system.
        Neuropsychopharmacology. 1989; 2: 105-114
        • Gruen R.J.
        • Elsworth J.D.
        • Roth R.H.
        Regionally specific alterations in the low-affinity GABAA receptor following perinatal exposure to diazepam.
        Brain Res. 1990; 514: 151-154
        • Rimanoczy A.
        • Vathy I.
        Prenatal exposure to morphine alters brain mu opioid receptor characteristics in rat.
        Brain Res. 1995; 690: 245-248
        • Vathy I.
        • Rimanoczy A.
        • Eaton R.C.
        • Katay L.
        Modulation of catecholamine turnover rate in brain regions of rats exposed prenatally to morphine.
        Brain Res. 1994; 662: 209-215
        • Vathy I.
        • Rimanoczy A.
        • Eaton R.C.
        • Katay L.
        Sex dimorphic alterations in postnatal brain catecholamines after gestational morphine.
        Brain Res Bull. 1995; 36: 185-193
        • Yanai J.
        • Huleihel R.
        • Izrael M.
        • Metsuyanim S.
        • Shahak H.
        • Vatury O.
        • et al.
        Functional changes after prenatal opiate exposure related to opiate receptors' regulated alterations in cholinergic innervation.
        Int. J Neuropsychopharmacol. 2003; 6: 253-265
        • Vathy I.
        Effects of prenatal morphine and cocaine on postnatal behaviors and brain neurotransmitters.
        NIDA Res Monogr. 1995; 158: 88-114
        • Wang H.Y.
        • Yeung J.M.
        • Friedman E.
        Prenatal cocaine exposure selectively reduces mesocortical dopamine release.
        Pharmacol Exp Ther. 1995; 273: 121-125
        • Heyser C.J.
        • McKenzie D.L.
        • Athalie F.
        • Spear N.E.
        • Spear L.P.
        Effects of prenatal exposure to cocaine on heart rate and nonassociative learning and retention in infant rats.
        Teratology. 1994; 49: 470-478
        • Rubio P.
        • de Fonseca F.R.
        • Munoz R.M.
        • Ariznavarreta C.
        • Martin-Calderon J.L.
        • Navarro M.
        Long-term behavioral effects of perinatal exposure to delta-9-tetrahydrocannabinol in rats: possible role of pituitary–adrenal axis.
        Life Sci. 1995; 56: 2169-2176
        • Bonnin A.
        • de Miguel R.
        • Hernadez M.I.
        • Ramos J.A.
        • Fernandez-Ruiz J.J.
        The prenatal exposure to delta-9-tetrahydrocannabinol affects the gene expression and the activity of tyrosine hydroxylase during early brain development.
        Life Sci. 1995; 56: 2177-2184
        • Thadani P.V.
        The intersection of stress, abuse and development.
        Psychoneuroendocrinology. 2002; 27: 221-230
        • Campbell J.H.
        • Perkins P.
        Transgenerational effects of drug and hormonal treatments in mammals: a review of observations and ideas.
        Prog Brain Res. 1988; 73: 535-553
        • Csaba G.
        • Knippel B.
        • Karabélyos C.
        • Inczefi-Gonda Á.
        • Hantos M.
        • Tóthfalusi L.
        • et al.
        Effect of neonatal β-endorphin imprinting on sexual behavior and brain serotonin level in adult rats.
        Life Sci. 2003; 73: 103-114
        • Csaba G.
        • Knippel B.
        • Karabélyos C.s.
        • Inczefi-Gonda Á.
        • Hantos M.
        • Tekes K.
        Impact of a single neonatal serotonin treatment (hormonal imprinting) on the brain serotonin content and sexual behavior of adult rats.
        Life Sci. 2003; 73: 2703-2711
        • Csaba G.
        • Pállinger É.
        Prolonged impact of pubertal serotonin treatment (hormonal imprinting) on the later serotonin content of white blood cells.
        Life Sci. 2002; 71: 879-885
        • Csaba G.
        • Knippel B.
        • Karabélyos C.s.
        • Inczefi-Gonda Á.
        • Hantos M.
        • Tekes K.
        Endorphin excess at weaning durably influences sexual activity, uterine estrogen receptors binding capacity and brain serotonin level of female rats.
        Horm Metab Res. 2004; 36: 39-43
        • Csaba G.
        • Inczefi-Gonda Á.
        • Kovács P.
        • Pállinger É.
        H1-receptor blocker antihistamine, terfenadine durably influences the glucocorticoid receptor, and lymphocyte histamine content of weanling rats.
        Pharmacol Res. 2003; 48: 241-244
        • Csaba G.
        • Kovács P.
        • Pállinger É.
        Prolonged effect of the tricyclic antidepressant mianserine on the serotonin and histamine content of young rats' white blood cells and mast cells. A case of late imprinting.
        Pharmacol Res. 2003; 48: 457-460
        • Csaba G.
        • Knippel B.
        • Karabélyos C.s.
        • Inczefi-Gonda Á.
        • Hantos M.
        • Tóthfalusi L.
        • et al.
        Effect of mianserin treatment at weaning with the serotonion antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.
        Life Sci. 2004; 75: 939-946
        • Mollereau C.
        • Parmentier M.
        • Mailleux P.
        • Butour J.L.
        • Moisand C.
        • Chalon P.
        • et al.
        ORL1, a novel member of the opioid receptor family:cloning, functional expression and localization.
        FEBS Lett. 1994; 341: 33-38
        • Neal Jr, C.R.
        • Mansour A.
        • Reinscheid R.
        • Nothacker H.P.
        • Civelli O.
        • Akil H.
        Opioid receptor-like (ORL1) receptor distribution in the rat central nervous system: comparison of ORL1 receptor mRNA expression with (125)I-[(14)Tyr]-orphanin FQ binding.
        J Comp Neurol. 1999; 412: 563-605
        • Bridge K.E.
        • Wainwright A.
        • Reilly K.
        • Oliver K.R.
        Autoradiographic localization of (125)i[Tyr(14)] nociceptin/orphanin FQ binding sites in macaque primate CNS.
        Neuroscience. 2003; 118: 513-523
        • Peluso J.
        • LaForge K.S.
        • Matthes H.W.
        • Kreek M.J.
        • Kieffer B.L.
        • Gaveriaux-Ruff C.
        Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells.
        J Neuroimmunol. 1998; 81: 184-192
        • Mollereau C.
        • Mouledous L.
        Tissue distribution of the opioid receptor-like(ORL1)receptor.
        Peptides. 2000; 21: 907-917
        • Clarke S.
        • Chen Z.P.
        • Hsu M.S.
        • Pintar J.
        • Hill R.
        • Kitchen I.
        Quantitative autoradiographic mapping of the ORL1, mu, delta and kappa-receptors in the brains of knockout mice lacking the ORL1 receptor gene.
        Brain Res. 2001; 906: 13-24
        • Moran T.D.
        • Abdulla F.A.
        • Smith P.A.
        Cellular neurophysiological actions of nociceptin/orphanin FQ.
        Peptides. 2000; 21: 969-976
        • Darland T.
        • Heinricher M.M.
        • Grandy D.K.
        Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more.
        Trends Neurosci. 1998; 21: 215-221
        • Houtani T.
        • Nishi M.
        • Takeshima H.
        • Nukada T.
        • Sugimoto T.
        Structure and regional distribution of nociceptin/orphanin FQ precursor.
        Biochem Biophys Res Commun. 1996; 219: 714-719
        • Calo G.
        • Guerrini R.
        • Rizzi A.
        • Salvadori S.
        • Regoli D.
        Pharmacology of nociceptin and its receptor: a novel therapeutic target.
        Br J Pharmacol. 2000; 129: 1261-1283
        • Mogil J.S.
        • Pasternak G.W.
        The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family.
        Pharmacol Rev. 2001; 53: 381-415
        • Okuda-Ashitaka E.
        • Minami T.
        • Tachibana S.
        • Yoshihara Y.
        • Nishiuchi Y.
        • Kimura T.
        • et al.
        Nocistatin, a peptide that blocks nociceptin action in pain transmission.
        Nature. 1998; 392: 286-289
        • Allen R.G.
        • Peng B.
        • Pellegrino M.J.
        • Miller E.D.
        • Grandy D.K.
        • Lundblad J.R.
        • et al.
        Altered processing of pro-orphaninFQ/nociceptin and pro-opiomelanocortin-derived peptides in the brains of mice expressing defective prohormone convertase 2.
        J Neurosci. 2001; 21: 5864-5870
        • Ahmadi S.
        • Kotalla C.
        • Guhring H.
        • Takeshima H.
        • Pahl A.
        • Zeilhofer H.U.
        Modulation of synaptic transmission by nociceptin/orphanin FQ and nocistatin in the spinal cord dorsal horn of mutant mice lacking the nociceptin/orphanin FQ receptor.
        Mol Pharmacol. 2001; 59: 612-618
        • Nakagawa T.
        • Kaneko M.
        • Inamura S.
        • Satoh M.
        Intracerebroventricular administration of nocistatin reduces inflammatory hyperalgesia in rats.
        Neurosci Lett. 1999; 265: 64-66
        • Kest B.
        • Sarton E.
        • Dahan A.
        Gender differences in opioid-mediated analgesia: animal and human studies.
        Anesthesiology. 2000; 93: 539-547
        • Terchner S.A.
        • Mitchell J.M.
        • Fields H.L.
        Brainstem pain modulating circuitry is sexually dimorphic with respect to mu and kappa opioid receptor function.
        Pain. 2000; 85: 153-159
        • Tekes K.
        • Hantos M.
        • Csaba G.
        Single neonatal treatment with β-endorphin (hormonal imprinting) extremely enhances nocistatin level of cerebrospinal fluid in adult rats.
        Life Sci. 2004; 74: 1993-1997
        • Bigsby R.
        • Chapin R.E.
        • Daston G.P.
        • Davis B.J.
        • Gorski J.
        • Gray L.E.
        • et al.
        Evaluating the effects of endocrine disruptors on endocrine function during development.
        Environ Health Perspect. 1999; 107: 613-618