Abstract
Glutamate is an excitatory neurotransmitter involved in neuronal plasticity and neurotoxicity. Chronic stress produces several physiological changes on the spinal cord, many of them presenting sex-specific differences, which probably involve glutamatergic system alterations. The aim of the present study was to verify possible effects of exposure to chronic restraint stress and 17β-estradiol replacement on [3H]-glutamate release and uptake in spinal cord synaptosomes of ovariectomized (OVX) rats. Female rats were subjected to OVX, and half of the animals received estradiol replacement. Animals were subdivided in controls and chronically stressed. Restraint stress or estradiol had no effect on [3H]-glutamate release. The chronic restraint stress promoted a decrease and 17β-estradiol induced an increase on [3H]-glutamate uptake, but the uptake observed in the restraint stress +17β-estradiol group was similar to control. Furthermore, 17β-estradiol treatment caused a significant increase in the immunocontent of the three glutamate transporters present in spinal cord. Restraint stress had no effect on the expression of these transporters, but prevented the 17β-estradiol effect. We suggest that changes in the glutamatergic system are likely to take part in the mechanisms involved in spinal cord plasticity following repeated stress exposure, and that 17β-estradiol levels may affect chronic stress effects in this structure.
Similar content being viewed by others
References
Viau V (2002) Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes. J Neuroendocrinol 14:506–513. doi:10.1046/j.1365-2826.2002.00798.x
Bowmann RE (2005) Stress-induced changes in spatial memory are sexually differentiated and vary across the lifespan. J Neuroendocrinol 17:526–535. doi:10.1111/j.1365-2826.2005.01335.x
Gamaro GD, Xavier MH, Denardin JD et al (1998) The effects of acute and repeated restraint stress on the nociceptive response in rats. Physiol Behav 63:693–697. doi:10.1016/S0031-9384(97)00520-9
Fontella FU, Bruno AN, Balk RS et al (2005) Repeated stress effects on nociception and on ectonucleotidase activities in spinal cord synaptosomes of female rats. Physiol Behav 85:213–219. doi:10.1016/j.physbeh.2005.04.010
Tabajara AS, Fontella FU, Torres IL et al (2003) Gender differences in oxidative stress in spinal cord of rats submitted to repeated restraint stress. Neurochem Res 28:1315–1322. doi:10.1023/A:1024932028999
Yoshimura M, Jessell T (1990) Amino acid-mediated EPSPs at primary afferent synapses with substantia gelatinosa neurones in the rat spinal cord. J Physiol 430:315–335
Malmberg AB, Yaksh TL (1995) Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats. J Neurosci 15:2768–2776
Dickenson AH, Chapman V, Green GM (1997) The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol 28:633–638. doi:10.1016/S0306-3623(96)00359-X
Sluka KA, Willis WD (1998) Increased spinal release of excitatory amino acids following intradermal injection of capsaicin is reduced by a protein kinase G inhibitor. Brain Res 798:281–286. doi:10.1016/S0006-8993(98)00428-4
Vetter G, Geisslinger G, Tegeder I (2001) Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 92:213–218. doi:10.1016/S0304-3959(01)00258-5
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105. doi:10.1016/S0301-0082(00)00067-8
Liu D, Xu GY, Pan E et al (1999) Neurotoxicity of glutamate at the concentration released upon spinal cord injury. Neuroscience 93:1383–1389. doi:10.1016/S0306-4522(99)00278-X
Tao F, Liaw WJ, Zhang B et al (2004) Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals. Neuroscience 123:1045–1051. doi:10.1016/j.neuroscience.2003.11.026
Liaw WJ, Stephens RL Jr, Binns BC et al (2005) Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 115:60–70. doi:10.1016/j.pain.2005.02.006
Attwell D (2000) Brain uptake of glutamate: food for thought. J Nutr 130:1023–1025
Rothstein JD, Martin L, Levey AI et al (1994) Localization of neuronal and glial glutamate transporters. Neuron 13:713–725. doi:10.1016/0896-6273(94)90038-8
Niederberger E, Schmidtko A, Rothstein JD et al (2003) Modulation of spinal nociceptive processing through the glutamate transporter GLT-1. Neuroscience 116:81–87. doi:10.1016/S0306-4522(02)00547-X
Niederberger E, Schmidtko A, Coste O et al (2006) The glutamate transporter GLAST is involved in spinal nociceptive processing. Biochem Biophys Res Commun 346:393–399. doi:10.1016/j.bbrc.2006.05.163
Vera-Portocarrero LP, Mills CD, Ye Z et al (2002) Rapid changes in expression of glutamate transporters after spinal cord injury. Brain Res 927:104–110. doi:10.1016/S0006-8993(01)03329-7
Lortet S, Samuel D, Had-Aissouni L et al (1999) Effects of PKA and PKC modulators on high affinity glutamate uptake in primary neuronal cell cultures from rat cerebral cortex. Neuropharmacology 38:395–402. doi:10.1016/S0028-3908(98)00193-2
Volterra A, Trotti D, Tromba C et al (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14:2924–2932
Trotti D, Rizzini BL, Rossi D et al (1997) Neuronal and glial glutamate transporters possess an SH-based redox regulatory mechanism. Eur J NeuroSci 9:1236–1243. doi:10.1111/j.1460-9568.1997.tb01478.x
Trotti D, Danbolt NC, Volterra A et al (1998) Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci 19:328–334. doi:10.1016/S0165-6147(98)01230-9
Lee TS, McEwen BS (2001) Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu Rev Pharmacol Toxicol 41:569–591. doi:10.1146/annurev.pharmtox.41.1.569
McEwen BS (2001) Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 91:2785–2801
Blanchet PJ, Fang J, Hyland K (1999) Short-term effects of high-dose 17beta-estradiol in postmenopausal PD patients: a crossover study. Neurology 53:91–95
Cimarosti H, O’Shea RD, Jones NM et al (2006) The effects of estradiol on estrogen receptor and glutamate transporter expression in organotypic hippocampal cultures exposed to oxygen–glucose deprivation. Neurochem Res 31:483–490. doi:10.1007/s11064-006-9043-9
Prediger ME, Gamaro GD, Crema LM et al (2004) Estradiol protects against oxidative stress induced by chronic variate stress. Neurochem Res 29:1923–1930. doi:10.1023/B:NERE.0000042219.98446.e7
Dunkley PR, Heath JW, Harrison SM et al (1988) A rapid Percoll gradient procedure for isolation of synaptosomes directly from an S1 fraction: homogeneity and morphology of subcellular fractions. Brain Res 441:59–71. doi:10.1016/0006-8993(88)91383-2
Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the folin-phenol reagent. J Biol Chem 193:265–275
Leal MB, Emanuelli T, Porciuncula LD et al (2001) Ibogaine alters synaptosomal and glial glutamate release and uptake. NeuroReport 12:263–267. doi:10.1097/00001756-200102120-00017
Migues PV, Leal RB, Mantovani M et al (1999) Synaptosomal glutamate release induced by the fraction Bc2 from the venom of the sea anemone Bunodosoma caissarum. NeuroReport 10:67–70. doi:10.1097/00001756-199901180-00013
Fontella FU, Vendite DA, Tabajara AS et al (2004) Repeated restraint stress alters hippocampal glutamate uptake and release in the rat. Neurochem Res 29:1703–1709. doi:10.1023/B:NERE.0000035805.46592.6c
Queen SA, Kesslak JP, Bridges RJ (2006) Regional distribution of sodium-dependent excitatory amino acid transporters in rat spinal cord. J Spinal Cord Med 30:263–271
Nakamura Y, Kubo H, Kataoka K (1994) Uptake of transmitter amino acids by glial plasmalemmal vesicles from different regions of rat central nervous system. Neurochem Res 19:1145–1150. doi:10.1007/BF00965148
Phillis JW, Wu PH (1982) The effect of various centrally active drugs on adenosine uptake by the central nervous system. Comp Biochem Physiol 72:179–187
Lovick TA (2008) GABA in the female brain – Oestrous cycle-related changes in GABAergic function in the periaqueductal grey matter. Pharmacol Biochem Behav 90:43–50. doi:10.1016/j.pbb.2007.12.014
Nicholls DG (1989) Release of glutamate, aspartate, and gamma-aminobutyric acid from isolated nerve terminals. J Neurochem 52:331–341. doi:10.1111/j.1471-4159.1989.tb09126.x
Turner TJ, Dunlap K (1995) Prolonged time course of glutamate release from nerve terminals: relationship between stimulus duration and the secretory event. J Neurochem 64:2022–2033
Tavares RG, Tasca CI, Santos CE et al (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40:621–627. doi:10.1016/S0197-0186(01)00133-4
Raiteri L, Zappettini S, Milanese M et al (2007) Mechanisms of glutamate release elicited in rat cerebrocortical nerve endings by ‘pathologically’ elevated extraterminal K+ concentrations. J Neurochem 103:952–961. doi:10.1111/j.1471-4159.2007.04784.x
Suchak SK, Baloyianni NV, Perkinton MS et al (2003) The ‘glial’ glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. J Neurochem 84:522–532. doi:10.1046/j.1471-4159.2003.01553.x
Bridges RJ, Kavanaugh MP, Chamberlin AR (1999) A pharmacological review of competitive inhibitors and substrates of high-affinity, sodium-dependent glutamate transport in the central nervous system. Curr Pharm Des 5:363–379
Madrigal JL, Caso JR, de Cristobal J et al (2003) Effect of subacute and chronic immobilisation stress on the outcome of permanent focal cerebral ischaemia in rats. Brain Res 979:137–145. doi:10.1016/S0006-8993(03)02892-0
Weng HR, Chen JH, Cata JP (2006) Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 138:1351–1360. doi:10.1016/j.neuroscience.2005.11.061
Hirata A, Nakamura R, Kwak S et al (1997) AMPA receptor-mediated slow neuronal death in the rat spinal cord induced by long-term blockade of glutamate transporters with THA. Brain Res 771:37–44. doi:10.1016/S0006-8993(97)00709-9
Madrigal JL, Olivenza R, Moro MA et al (2001) Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 24:420–429. doi:10.1016/S0893-133X(00)00208-6
Claiborne J, Nag S, Mokha SS (2006) Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male. J Neurosci 26:13048–13053. doi:10.1523/JNEUROSCI.4783-06.2006
Craft RM, Mogil JS, Aloisi AM (2004) Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain 8:397–411. doi:10.1016/j.ejpain.2004.01.003
Keller JN, Germeyer A, Begley JG et al (1997) 17-beta-Estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron. J Neurosci Res 50:522–530. doi:10.1002/(SICI)1097-4547(19971115)50:4<522::AID-JNR3>3.0.CO;2-G
Pawlak J, Brito V, Küppers E et al (2005) Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen. Brain Res Mol Brain Res 29(138):1–7. doi:10.1016/j.molbrainres.2004.10.043
Sato K, Matsuki N, Ohno Y et al (2003) Estrogen inhibit l-glutamate uptake activity of astrocytes via membrane estrogen receptor alpha. J Neurochem 86:1498–1505. doi:10.1046/j.1471-4159.2003.01953.x
Reagan LP, Rosell DR, Wood GE et al (2004) Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc Natl Acad Sci USA 101:2179–2184. doi:10.1073/pnas.0307294101
Autry AE, Grillo CA, Piroli GG et al (2006) Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus. Neuroendocrinology 83:371–379. doi:10.1159/000096092
Zschocke J, Bayatti N, Clement AM et al (2005) Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. J Biol Chem 280:34924–34932. doi:10.1074/jbc.M502581200
Wen ZH, Wu GJ, Chang YC et al (2005) Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats. Neuroscience 133:807–817. doi:10.1016/j.neuroscience.2005.03.015
Wu GJ, Chen WF, Sung CS et al (2007) Preventive effects of intrathecal methylprednisolone administration on spinal cord ischemia in rats: the role of excitatory amino acid metabolizing systems. Neuroscience 147:294–303. doi:10.1016/j.neuroscience.2007.04.040
Burgess LH, Handa RJ (1992) Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology 131:1261–1269. doi:10.1210/en.131.3.1261
Carey MP, Deterd CH, de Koning J et al (1995) The influence of ovarian steroids on hypothalamic–pituitary–adrenal regulation in the female rat. J Endocrinol 144:311–321
Dayas CV, Xu Y, Buller KM et al (2000) Effects of chronic oestrogen replacement on stress-induced activation of hypothalamic–pituitary–adrenal axis control pathways. J Neuroendocrinol 12:784–794. doi:10.1046/j.1365-2826.2000.00527.x
McCormick CM, Linkroum W, Sallinen BJ et al (2002) Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats. Stress 5:235–247. doi:10.1080/1025389021000061165
Lunga P, Herbert J (2004) 17B-Oestradiol modulates glucocorticoid, neural and behavioural adaptations to repeated restraint stress in female rats. J Neuroendocrinol 16:776–785. doi:10.1111/j.1365-2826.2004.01234.x
Walf AA, Frye CA (2005) Antianxiety and antidepressive behavior produced by physiological estradiol regimen may be modulated by hypothalamic–pituitary–adrenal axis activity. Neuropsychopharmacology 30:1288–1301. doi:10.1038/sj.npp.1300713
Uht RM, Anderson CM, Webb P et al (1997) Transcriptional activities of estrogen and glucocorticoid receptors functionally integrated at the AP-1 response element. Endocrinology 138:2900–2908. doi:10.1210/en.138.7.2900
Kinyamu HK, Archer TK (2003) Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Mol Cell Biol 3:5867–5881. doi:10.1128/MCB.23.16.5867-5881.2003
Sheng Z, Yanai A, Fujinaga R et al (2003) Gonadal and adrenal effects on the glucocorticoid receptor in the rat hippocampus, with special reference to regulation by estrogen from an immunohistochemical view-point. Neurosci Res 46:205–218
Wang S, Lim G, Yang L (2006) Downregulation of spinal glutamate transporter EAAC1 following nerve injury is regulated by central glucocorticoid receptors in rats. Pain 120:78–85. doi:10.1016/j.pain.2005.10.015
Fillenz M (1995) Physiological release of excitatory amino acids. Behav Brain Res 71:51–67. doi:10.1016/0166-4328(95)00045-3
Voutsinos-Porche B, Bonvento G, Tanaka K et al (2003) Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37:275–286. doi:10.1016/S0896-6273(02)01170-4
Beart PM, O’Shea RD (2007) Transporters for l-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150:5–17. doi:10.1038/sj.bjp. 0706949
Acknowledgments
This work was supported by National Research Council of Brazil (CNPq), Fundação de Amparo à Pesquisa do Rio Grande do Sul (PRONEX/FAPERGS), and FINEP/Rede IBN 01.06.0842-00. Leonardo M. Crema was the recipient of a CAPES fellowship.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Crema, L.M., Vendite, D., Horn, A.P. et al. Effects of Chronic Restraint Stress and Estradiol Replacement on Glutamate Release and Uptake in the Spinal Cord from Ovariectomized Female Rats. Neurochem Res 34, 499–507 (2009). https://doi.org/10.1007/s11064-008-9810-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-008-9810-x