Skip to main content
SpringerLink
Log in

Overview of the Brain Polyamine-Stress-Response: Regulation, Development, and Modulation by Lithium and Role in Cell Survival

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

An early transient increase in brain polyamine (PA) metabolism, termed the PA-stress-response (PSR), is a common reaction to stressful stimuli, including physical, emotional, and hormonal stressors, with a magnitude related to the stress intensity. In the extreme, traumatic injury can result in an incomplete PSR, with persistent accumulation of putrescine and eventual reduction in the concentrations of the higher polyamines (PAs), spermidine and spermine. Chronic intermittent application of stressors causes a recurrence of the brain PSR, but, in contrast, it leads to habituation of the response in the periphery (liver). Severe continuous stress, however, may lead to accumulation of brain PAs. Long-term inhibition of PA synthesis depletes brain PAs and can result in altered emotional reactivity to stressors. Furthermore, the brain PSR, in contrast to the periphery, can be blocked by a long-term, but not by short-term, treatment with lithium, the most efficacious treatment of manic–depressive illness. The brain PSR is developmentally regulated, and the switch to the mature pattern coincides with the cessation of the “stress hyporesponsive period” in the hypothalamic–pituitary–adrenocortical (HPA) system. In contrast to the brain and liver, the PSR in the adrenal and thymus is down-regulated by acute stressors. Transient up-regulation of the PSR, as in the brain and liver, is implicated in cell survival while its down-regulation is implicated in cell death. Taken together, the findings indicate that the PSR is a dynamic process that varies with the type, intensity, and duration of stressors, and implicate this response as an adaptive mechanism in the reaction to stressful events. Under persistent stressful conditions, however, the PSR may be maladaptive as may be reflected by PA accumulation. This raises the hypothesis that proper regulation of brain PSR may be critical for neuronal function and for an appropriate behavioral response to stressors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Abraham, I., Veenema, A. H., Nyakas, C., Harkany, T., Bohus, B. G. J., and Luiten, P. G. M. (1997). Effect of corticosterone and adrenalectomy on NMDA-induced cholinergic cell death in rat magnocellular nucleus basalis. J. Neuroendocrinol. 9:713–720.

    PubMed  Google Scholar 

  • Adibhatla, R. M., Hatcher, J. F., Sailor, K., and Dempsey, R. J. (2002). Polyamines and central nervous system injury: Spermine and spermidine decrease following transient focal cerebral ischemia in spontaneously hypertensive rats. Brain Res. 938:81–86.

    PubMed  Google Scholar 

  • Anderson, T. R., and Schanberg, S. M. (1975). Effect of thyroxine and cortisol on brain ornithine decarboxylase activity and swimming behavior in developing rat. Biochem. Pharmacol. 24:495–501.

    PubMed  Google Scholar 

  • Anisman, H., Zaharia, M. D., Meaney, M. J., and Merali, Z. (1998). Do early life events permanently alter behavioral and hormonal responses to stressors? Int. J. Dev. Neurosci. 16:149–164.

    PubMed  Google Scholar 

  • Armario, A., Hidalgo, J., and Giralt, M. (1988). Evidence that the pituitary-adrenal axis does not cross-adapt to stressors: Comparison to other physiological variables. Neuroendocrinology 47:263–267.

    PubMed  Google Scholar 

  • Avissar, S., Schreiber, G., Danon, A., and Belmaker, R. H. (1988). Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature 331:440–442.

    PubMed  Google Scholar 

  • Berridge, M. J. (1987). Inositol triphosphate and diacylglycerol: Two interacting second messengers. Annu. Rev. Biochem. 56:159–193.

    PubMed  Google Scholar 

  • Berridge, M. J., Downes, C. P., and Hanley, M. R. (1989). Neural and developmental action of lithium: A unifying hypothesis. Cell 59:411–419.

    PubMed  Google Scholar 

  • Bohn, M. C. (1984). Glucocorticoid induced teratologies of the nervous system. In Yanai, J. (ed.), Neurobehavioral Teratology, Elsevier, Amsterdam, pp. 365–387.

    Google Scholar 

  • Brune, B., Hartzell, P., Nicotera, P., and Orrenius, S. (1991). Spermine prevents endonuclease activation and apoptosis in thymocytes. Exp. Cell Res. 195:323–329.

    PubMed  Google Scholar 

  • Bueb, J.-L., Da Silva, A., Mousli, M., and Landry, Y. (1992). Natural polyamines stimulate G-proteins. Biochem. J. 282:545–550.

    PubMed  Google Scholar 

  • Caldecott-Hazard, S., Guze, B. H., Kling, M. A., Kling, A., and Baxter, L. R. (1991). Clinical and biochemical aspects of depressive disorders: I. Introduction, classification, and research techniques. Synapse 8:185–211.

    PubMed  Google Scholar 

  • Cotterrell, M., Balazs, R., and Johnson, A. L. (1972). Effects of corticosteroids on the biochemical maturation of rat brain: Postnatal cell formation. J. Neurochem. 19:2151–2167.

    PubMed  Google Scholar 

  • Cousin, M. A., Lando, D., and Moguilewsky, M. (1982). Ornithine decarboxylase induction by glucocorticoids in brain and liver of adrenalectomized rats. J. Neurochem. 38:1296–1304.

    PubMed  Google Scholar 

  • Cox, R. H., Hubbard, J. W., Lawler, J. E., Sanders, B. J., and Mitchell, V. P. (1985). Cardiovascular and sympathoadrenal responses to stress in swim-trained rats. J. Appl. Physiol. 58:1207–1214.

    PubMed  Google Scholar 

  • Danzin, C., Jang, M. J., Grove, J., and Bey, P. (1979). Effect of Alpha-difluoromethylornithine, enzyme activated irreversible inhibitor of ornithine decarboxylase, on polyamine levels in rat tissue. Life Sci. 24:519–524.

    PubMed  Google Scholar 

  • Ebstein, R. P., Hermoni, M., and Belmaker, R. H. (1980). The effect of lithium on noradrenaline-induced cyclic AMP accumulation in rat brain: Inhibition after chronic treatment and absence of supersensitivity. J. Pharmacol. Exp. Ther. 213:161–166.

    PubMed  Google Scholar 

  • Ferchmin, P. A., Rivera, E., and Eterovic, V. A. (1993). Alpha-difluoromethylornithine does not antagonize the behavioral effects of putrescine. Pharmacol. Biochem. Behav. 45:967–971.

    PubMed  Google Scholar 

  • Flamigni, F. F., Stefanelli, C., and Caldarera, C. M. (1986). Polyamine metabolism and function in the heart. J. Mol. Cell. Cardiol. 18:3–11.

    PubMed  Google Scholar 

  • Gilad, G. M., and Gilad, V. H. (1991). Polyamines can protect against ischemia-induced nerve cell death in gerbil forebrain. Exp. Neurol. 111:349–355.

    PubMed  Google Scholar 

  • Gilad, G. M., and Gilad, V. H. (1992). Polyamines in neurotrauma: Ubiquitous Molecules in Search of a Function. Biochem. Pharmacol. 44:401–407.

    PubMed  Google Scholar 

  • Gilad, G. M., and Gilad, V. H. (1995). Strain, stress, neurodegeneration and longevity. Review article. Mech. Age Dev. 78:75–83.

    Google Scholar 

  • Gilad, G. M., and Gilad, V. H. (1996). The brain polyamine-stress-response: Recurrence after repetitive stressor and inhibition by lithium. J. Neurochem. 67:1992–1996.

    PubMed  Google Scholar 

  • Gilad, G. M., and Gilad, V. H. (2002). Stress-induced dynamic changes in mouse brain polyamines. Role in behavioral reactivity. Brain Res. 943:23–29.

    PubMed  Google Scholar 

  • Gilad, G. M., Gilad, V. H., Eliyayev, Y., and Rabey, J. M. (1998). Developmental regulation of the brain polyamine-stress-response. Int. J. Dev. Neurosci. 16: 271–278.

    PubMed  Google Scholar 

  • Gilad, G. M., Gilad, V. H., Wyatt, R. J., and Casero, R. A., Jr. (1992). Chronic lithium treatment prevents the dexamethasone-induced increase of brain polyamine metabolizing enzymes. Life Sci. 50:p. L149-PL154.

    Google Scholar 

  • Gilad, V. H., Rabey, J. M., Eliyayev, Y., and Gilad, G. M. (2000). Different effects of acute postnatal stressors and long-term postnatal handling on stress-induced changes in behavior and in ornithine decarboxylase activity of adult rats. Dev. Brain Res. 120:255–259.

    Google Scholar 

  • Gilad, V. H., Rabey, J. M., Kimiagar, Y., and Gilad, G. M. (2001). The polyamine-stress-response: Tissue-, endocrine-and developmental-dependent regulation. Biochem. Pharmacol. 61:207–213.

    PubMed  Google Scholar 

  • Gold, P. W., Goodwin, F. K., and Chrousos, G. P. (1988). Clinical and biochemical manifestations of depression: Relation to the neurobiology of stress. New Engl. J. Med. 319:348–353.

    PubMed  Google Scholar 

  • Goodwin, F. K., and Jamison, C. R., (Eds.) (1990). Manic–Depressive Illness. Oxford University Press, New York.

    Google Scholar 

  • Hall, C. S. (1934). Emotional behavior in the rat: 1. Defecation and urination as measures of individual differences in emotionality. J. Comp. Physiol. Psychol. 81:385–403.

    Google Scholar 

  • Heim, C., Owens, M. J., Plotsky, P. M., and Nemeroff, M. D. (1997). Persistent changes in corticotropin-releasing factor systems due to early life stress: Relationship to the pathophysiology of major depression and post-traumatic stress disorder. Psychopharmacol. Bull.33:185–192.

    PubMed  Google Scholar 

  • Hietala, O. A., Laitinen, S. I., Laitnen, P. H., Lapinjoki, S. P., and Pajunen, A. E. I. (1983). The inverse changes of mouse brain ornithine and S-adenosylmethionine decarboxylase activities by chlorpromazine and imipramine. Dependence of ornithine decarboxylase induction on ß-adrenoceptors. Biochem. Pharmacol. 32:1581–1585.

    PubMed  Google Scholar 

  • Hightower, I. E. (1991). Heat shock, stress proteins, chaperons, and proteotoxicity. Cell 66:191–197.

    PubMed  Google Scholar 

  • Hirvonen, A., Immonen, T., Leinonen, P., Alhonen-Hongisto, L., Janne, A. O., and Janne, J. (1988). Effect of dexamethasone on the activity and expression of ornithine decarboxylase in rat liver and thymus. Biochim. Biophys. Acta 950:229–233.

    PubMed  Google Scholar 

  • Janne, J., Alhonen, L., and Leinonen, P. (1991). Polyamines: From molecular biology to clinical applications. Ann. Med. 23:241–259.

    PubMed  Google Scholar 

  • Jope, R. S., and Williams, M. B. (1994). Lithium and brain signal transduction systems. Biochem. Pharmacol. 47:429–441.

    PubMed  Google Scholar 

  • Kanba, S., Yagi, G., Nakaki, T., Kato, R., and Richelson, E. (1991). Potentiation by a sodium channel activator of effects of lithium ion on cyclic AMP, cyclic GMP and inositol phosphates. Neuropharmacology 30:497–500.

    PubMed  Google Scholar 

  • Kuhn, C. M., and Schanberg, S. M. (1998). Responses to maternal separation: Mechanisms and mediators. Int. J. Dev. NeuroSci. 16: 261–270.

    PubMed  Google Scholar 

  • Kvetnanky, R., McCarty, R., Thoa, N. B., Lake, C. R., and Kopin, I. J. (1979). Sympatho-adrenal responses of spontaneously hypertensive rats to immobilization stress. Am. J. Physiol. 246:H457-H462.

    Google Scholar 

  • Lachman, H. M., and Papolos, D. F. (1989). Abnormal signal transduction: A hypothetical model for bipolar affective disorder. Life Sci. 45:1413–1426.

    PubMed  Google Scholar 

  • Li, P. P., Sibony, D., Green, M. A., and Warsh, J. J. (1993). Lithium modulation of phosphoinositide signaling system in rat cortex—Selective effect on phorbol ester binding. J. Neurochem. 61:1722–1730.

    PubMed  Google Scholar 

  • Lukkarainen, J., Kauppinen, R. A., Koistinaho, J., Halmekyto, M., Alhonen, L., and Janne, J. (1996). Cerebral energy metabolism and immediate early gene induction following severe incomplete ischaemia in transgenic mice overexpressing the human ornithine decarboxylase gene: Evidence that putrescine is not neurotoxic in vivo. Eur. J. Neurosci. 7:1840–1849.

    Google Scholar 

  • Manji, H. K., Etcheberrigaray, R., Chen, G., and Olds, J. L. (1993). Lithium decreases membrane-associated protein kinase-C in hippocampus—Selectivity for the alpha-isozyme. J. Neurochem. 61:2303–2310.

    PubMed  Google Scholar 

  • Manji, H. K., Moore, G. J., Rajkowska, G., and Chen, G. (2000). Neuroplasticity and cellular resilience in mood disorders. Mol. Psychol. 5:578–593.

    Google Scholar 

  • Marti, O., Gavalda, A., Gomez, F., and Armario, A. (1994). Direct evidence for chronic stress-induced facilitation of the adrenocorticotropin response to a novel acute stressor. Neuroendocrinology 60:1–7.

    Google Scholar 

  • Marton, J. L., and Feurstein, B. G. (1986). Polyamine–DNA interactions: Possible site of new cancer chemotherapeutic intervention. Pharmacol. Res. 3:311–317.

    Google Scholar 

  • Masana, M. I., Bitran, J. A., Hsiao, J. K., and Potter, W. Z. (1992). In vivo evidence that lithium inactivates GI modulation of adenylate cyclase in brain. J. Neurochem. 59:200–205.

    PubMed  Google Scholar 

  • Matsui, I., and Pegg, A. E. (1980). Effect of thioacetamide, growth hormone or partial hepatectomy on spermidine acetylase activity of rat liver cytosol. Biochim. Biophys. Acta 633:87–94.

    PubMed  Google Scholar 

  • Morgan, J. I., and Curran, T. (1991). Stimulus-transcription coupling in the nervous system: Involvement of the inducible proto-oncogenes fos and jun. Annu. Rev. Neurosci. 14:421–451.

    PubMed  Google Scholar 

  • Moruzzi, M. S., Marverti, G., Piccinini, G., Frassineti, C., and Monti, G. (1993). Effect of spermine on membrane associated and membrane-inserted forms of protein kinase C. Mol. Cell. Biochem. 124:1–9.

    PubMed  Google Scholar 

  • Nichols, C. G., Makhina, E. N., Pearson, W. L., Sha, O., and Lopatin, A. N. (1966). Inward rectification and implications for cardiac excitability. Citc. Res. 78:1–7.

    Google Scholar 

  • Nisenbaum, L. K., Zigmond, M. J., Sved, A. F., and Abercrombie, E. D. (1991). Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J. Neurosci. 11:1478–1484.

    PubMed  Google Scholar 

  • Nonaka, S., and Chuang, D. M. (1998). Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport 9:2081–2084.

    PubMed  Google Scholar 

  • Obayashi, M., Matsui-Yuasa, I., Kitano, A., Kobayashi, K., and Otani, S. (1992). Posttranscriptional regulation of spermidine/spermine N1-acetyltransferase with stress. Biochim. Biophys. Acta 1131:41–46.

    PubMed  Google Scholar 

  • Paschen, W., Schmidt-Kastner, R., Hallmayer, J., and Djuricic, B. (1988). Polyamines in cerebral ischemia. Neurochem. Pathol. 9:1–20.

    PubMed  Google Scholar 

  • Pegg, A. E., and McCann, P. P. (1982). Polyamine metabolism and function. Am. J. Physiol. 243:C212-C221.

    PubMed  Google Scholar 

  • Periyasami, S., Kothapalli, M. R., and Hoss, W. (1994). Regulation of the phosphoinositide cascade by polyamines in brain. J. Neurochem. 63:1319–1327.

    PubMed  Google Scholar 

  • Pol, O., Campmany, L., Gil, M., and Armario, A. (1992). Behavioral and neurochemical changes in response to acute stressors: Influence of previous chronic exposure to immobilization. Pharmacol. Biochem. Behav. 42:407–412.

    PubMed  Google Scholar 

  • Prince, C. R., and Anisman, H. (1984). Acute and chronic stress effects on performance in a forced-swim task. Behav. Neural Biol. 4:99–119.

    Google Scholar 

  • Richards, S. F., Fox, K., Peng, T., Hsiao, J., and Gout, P. W. (1990). Inhibition of hormone-stimulated ornithine decarboxylase activity by lithium chloride. Life Sci. 47:233–240.

    PubMed  Google Scholar 

  • Rosellini, R. A., and Seligman, M. E. P. (1977). Failure to escape shock following repeated exposure to inescapable shock. Bull. Psychon. Soc. 7:251–253.

    Google Scholar 

  • Russell, D. H., and Gfeller, E. (1974). Distribution of putrescine spermidine and spermine in rhesus monkey brain. Decrease in spermidine and spermine concentration in motor cortex after electrical stimulation. J. Neurobiol. 5:349–354.

    PubMed  Google Scholar 

  • Sapolsky, R. M. (1996). Stress, glucocorticoids and damage to the nervous system: The current state of confusion. Stress 1:1–19.

    PubMed  Google Scholar 

  • Sapolsky, R. M., and Meaney, M. J. (1986). Maturation of the adrenocortical stress response: Neuroendocrine control mechanisms and the stress hyporesponsive periods. Brain Res. Rev. 11:65–76.

    Google Scholar 

  • Schlesinger, M. J. (1994). How the cell copes with stress and the function of heat shock proteins. Ped. Res. 36:1–6.

    Google Scholar 

  • Schuber, F. (1989). Influence of polyamines on membrane functions. Biochem. J. 260:1–10.

    PubMed  Google Scholar 

  • Schubert, T., Stoll, L., and Muller, W. E. (1991). Therapeutic concentrations of lithium and carbamazepine inhibit cGMP accumulation in human lymphocytes. A clinical model for a possible common mechanism of action? Psychopharmacology 104:45–50.

    PubMed  Google Scholar 

  • Seiler, N. (1991). Pharmacological properties of natural polyamines and their depletion by biosynthesis inhibitors as a therapeutic approach. Prog. Drug. Res. 37:107–159.

    PubMed  Google Scholar 

  • Seiler, N., and Bolkenius, F. N. (1985). Polyamine reutilization and turnover in brain. Neurochem. Res. 10:529–544.

    PubMed  Google Scholar 

  • Selye, H. (1936). A syndrome produced by diverse nocuous agents. Nature 138:32–37.

    Google Scholar 

  • Sheng, M., and Greenberg, M. E. (1990). The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 4:477–485.

    PubMed  Google Scholar 

  • Singh, S. S., Chauhan, A., Brockerhoff, H., and Chauhan, V. P. S. (1995). Differential effects of spermine on phosphatidylinositol 3-kinase and phosphatidylinositol 5-kinase. Life Sci. 57:685–694.

    PubMed  Google Scholar 

  • Soliman, K. F. A., Reams, R. R., Udoye, M. O., and Nonavinakere, V. K. (1997). Inhibition of the adrenal ornithine decarboxylase activity by immobilization stress and/or dexamethasone. Life Sci. 60: 2383–2387.

    PubMed  Google Scholar 

  • Sparapani, M., Virgili, M., Ortali, F., and Contestabile, A. (1997). Effects of chronic lithium treatment on ornithine decarboxylase induction and excitotoxic neuropathology in the rat. Brain Res. 765:164–168.

    PubMed  Google Scholar 

  • Starkman, M. N., Giordani, B., Gebarski, S. S., Berent, S., Schork, A., and Schteingart, D. E. (1999). Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Biol. Psychol. 45:1595–1602.

    Google Scholar 

  • Tabor, C. W., and Tabor, H. (1984). Polyamines. Annu. Rev. Biochem. 53:749–790.

    PubMed  Google Scholar 

  • Tizabi, Y., Gilad, V. H., and Gilad, G. M. (1989). Effects of chronic stressors or corticosterone treatment on the septo-hippocampal cholinergic system of the rat. Neurosci. Lett. 105:177–182.

    PubMed  Google Scholar 

  • Umemoto, S., Noguchi, K., Kawai, Y., and Senba, E. (1994). Repeated stress reduces the subsequent stress-induced expression of Fos in rat brain. Neurosci. Lett. 167:101–104.

    PubMed  Google Scholar 

  • Wang, S., Bartolome, J. V., and Schanberg, S. M. (1996). Neonatal deprivation of maternal touch may suppress ornithine decarboxylase via downregulation of proto-oncogenes c-myc and max. J. Neurosci. 16: 836–842.

    PubMed  Google Scholar 

  • Weiss, J. M., Glazer, H. I., Pohorecky, L. A., Brick, J., and Miller, N. E. (1975). Effects of chronic exposure to stressors on avoidance-escape behavior and on brain norepinephrine. Psychosom. Med. 37:522–534.

    PubMed  Google Scholar 

  • Weiss, J. M., Goodman, P. A., Losito, B. G., Corrigan, S., Charry, J. M., and Bailey, W. H. (1981). Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine, and serotonin levels in various regions of rat brain. Brain Res. Rev. 3:167–201.

    Google Scholar 

  • Willner, P. (1990). Animal models of depression: An overview. Pharmacol. Ther. 45:425–455.

    PubMed  Google Scholar 

  • Young, L. T., Li, P. P., Kish, S. J., Siu, K. P., and Warsh, J. J. (1991). Postmortem cerebral cortex Gs α-subunit levels are elevated in bipolar affective disorder. Brain Res. 553:323–326.

    PubMed  Google Scholar 

  • Zoli, M., Ferraguti, F., Biagini, G., Cintra, A., Fuxe, K., and Agnati, L. F. (1991). Corticosterone treatment counteracts lesions induced by neonatal treatment with monosodium glutamate in the mediobasal hypothalamus of the male rat. Neurosci. Lett. 132: 225–228.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research and Development, Laboratory of Neuroscience, Assaf Harofeh Medical Center, Zrifin, Israel

    Gad M. Gilad & Varda H. Gilad

Authors
  1. Gad M. Gilad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Varda H. Gilad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gad M. Gilad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gilad, G.M., Gilad, V.H. Overview of the Brain Polyamine-Stress-Response: Regulation, Development, and Modulation by Lithium and Role in Cell Survival. Cell Mol Neurobiol 23, 637–649 (2003). https://doi.org/10.1023/A:1025036532672

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025036532672

Search

Navigation