Neurochemical Research

, 31:201 | Cite as

Non-NMDA Glutamate Receptor Antagonist Injected into the Hypothalamic Paraventricular Nucleus Inhibits the Prolactin Response to Formalin Stress of Male Rats



The aim of the present investigations was to test the involvement of the glutamatergic innervation of the hypothalamic paraventricular nucleus in the prolactin response to stress. A non-NMDA (6-cyano-7-nitroquinoxaline-2,3-dione disodium, CNQX) or an NMDA glutamate receptor antagonist (dizocilpine hydrogen malate, MK-801) was injected bilaterally into the paraventricular nucleus of freely moving male rats and 15 min later the animals were exposed to formalin stress. Blood samples for prolactin and corticosterone were taken at different time points before and after administration of formalin. CNQX, when injected into the paraventricular nucleus, inhibited the formalin-induced rise in plasma prolactin and not significantly the increase in corticosterone. A similar effect was not observed if MK-801 was administered into the paraventricular nuclei or CNQX was injected outside the cell group. The findings indicate that the glutamatergic innervation of the paraventricular nucleus is involved in the mediation of the formalin-induced prolactin release.


Paraventricular nucleus Glutamatergic innervation Glutamate receptor Stress Prolactin Corticosterone 



The authors are grateful to Mrs. I. Salamon for excellent histochemical work, to Mrs. M. Mészáros and Mrs. M. Balázs for their excellent technical assistance and Mrs. E. Pirity for typing the manuscript. This work was supported by the Ministry of Health (ETT 054/2003 to B.H.), National Scientific Research Fund (OTKA T-042516 to B.H.) and the Hungarian Academy of Sciences.


  1. 1.
    Brann DW, Mahesh VB (1997) Excitatory amino acids: evidence for a role in the control of reproduction and anterior pituitary hormone secretion. Endocrine Rev 18:678–700CrossRefGoogle Scholar
  2. 2.
    Monaghan DT, Bridges RJ, Cotman CW (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29:365–402PubMedCrossRefGoogle Scholar
  3. 3.
    Pohl CR, Lee LR, Smith MS (1989) Qualitative changes in luteinizing hormone and prolactin responses to N-methyl-aspartic acid during lactation in the rat. Endocrinology 124:1905–1911PubMedGoogle Scholar
  4. 4.
    Gay VL, Plant TM (1987) N-Methyl-d,l-aspartate elicits hypothalamic gonadotropin-releasing hormone release in prepubertal male rhesus monkeys. Endocrinology 120:2289–2296PubMedGoogle Scholar
  5. 5.
    Wilson R, Knobil E (1983) Acute effects of N-methyl-dl-aspartate on the release of pituitary gonadotropins and prolactin in female rhesus monkey. Brain Res 248:177–179CrossRefGoogle Scholar
  6. 6.
    Luderer U, Strobl FJ, Levine JE, Schwartz NB (1993) Differential gonadotropin responses to N-methyl-d-aspartate (NMDA) in metestrous, proestrous, and ovariectomized rats. Biol Reprod 48:857–866PubMedCrossRefGoogle Scholar
  7. 7.
    Abbud R, Smith MS (1991) Differences in the luteinizing hormone and prolactin responses to multiple injections of kainate as compared to N-methyl-d,l-aspartate, in cycling rats. Endocrinology 129:3254–3258PubMedCrossRefGoogle Scholar
  8. 8.
    Abbud R, Smith MS (1993) Altered luteinizing hormone and prolactin responses to excitatory amino acids during lactation. Neuroendocrinology 58:454–464PubMedCrossRefGoogle Scholar
  9. 9.
    Strobl FJ, Luderer U, Besecke L, Wolfe A, Schwartz NB, Levine JE (1993) Differential gonadotropin responses to N-methyl-d,l-aspartate in intact and castrated male rats. Biol Reprod 48:867–873PubMedCrossRefGoogle Scholar
  10. 10.
    D’Aniello G, Tolino A, D’Aniello A, Errico F, Fisher GH, Di Fiore MM (2000) The role of d-aspartic acid and N-methyl-d-aspartic acid in the regulation of prolactin release. Endocrinology 141:3862–3870PubMedCrossRefGoogle Scholar
  11. 11.
    Brann DW, Mahesh VB (1991) Endogenous excitatory amino acid involvement in the preovulatory and steroid-induced surge of gonadotropins in the female rat. Endocrinology 128:1541–1547PubMedGoogle Scholar
  12. 12.
    Brann DW, Ping L, Mahesh VB (1993) Possible role of non-NMDA receptor-mediated neurotranmission in steroid-induced and preovulatory gonadotropin surges in the rat. Mol Cell Neurosci 4:292–297CrossRefGoogle Scholar
  13. 13.
    Parker SL, Crowley WR (1993) Stimulation of oxytocin release in the lactating rat by central excitatory amino acid mechanisms: evidence for specific involvement of R,S-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-sensitive glutamate receptors. Endocrinology 133:2847–2854PubMedCrossRefGoogle Scholar
  14. 14.
    Zelena D, Makara GB, Nagy MG (2003) Effect of glutamate receptor antagonists on suckling-induced prolactin release in rats. Endocrine 21:147–152PubMedCrossRefGoogle Scholar
  15. 15.
    Zelena D, Makara GB, Jezova D (1999) Simultaneous blockade of two glutamate receptor subtypes (NMDA and AMPA) results in stressor-specific inhibition of prolactin and corticotropin release. Neuroendocrinology 69:316–323PubMedCrossRefGoogle Scholar
  16. 16.
    Bregonzio C, Navarro CE, Donoso AO (1998) NMDA receptor antagonists block stress-induced prolactin release in female rats at estrus. Eur J Pharmacol 350:259–265PubMedCrossRefGoogle Scholar
  17. 17.
    Al-Ghoul WM, Meeker RB, Greenwood RS (1997) Differential expression of five N-methyl-d-aspartate receptor subunit mRNAs in vasopressin and oxytocin neuroendocrine cells. Brain Res Mol Brain Res 44:262–272PubMedCrossRefGoogle Scholar
  18. 18.
    Aubry JM, Bartanusz V, Pagliusi S, Schulz P, Kiss JZ (1996) Expression of ionotropic glutamate receptor subunit mRNAs by paraventricular corticotropin-releasing factor (CRF) neurons. Neurosci Lett 205:95–98PubMedCrossRefGoogle Scholar
  19. 19.
    Eyigor Ö, Centers A, Jennes L (2001) Distribution of ionotropic glutamate receptor subunit mRNAs in the rat hypothalamus. J Comp Neurol 434:101–124PubMedCrossRefGoogle Scholar
  20. 20.
    Herman JP, Eyigor Ö, Ziegler DR, Jennes L (2000) Expression of ionotropic glutamate receptor subunit mRNAs in the hypothalamic paraventricular nucleus of the rat. J Comp Neurol 422:352–362PubMedCrossRefGoogle Scholar
  21. 21.
    Petralia RS, Wenthold RJ (1996) Types of excitatory amino acid receptors and their localization in the nervous system and hypothalamus. In Brann DW, Mahesh VB (eds) Excitatory amino acid receptors: their role in neuroendocrine function. CRC Press, New York, pp55–101Google Scholar
  22. 22.
    Decavel C, van den Pol AN (1992) Converging GABA- and glutamate-immunoreactive axons make synaptic contact with identified hypothalamic neurosecretory neurons. J Comp Neurol 316:104–116PubMedCrossRefGoogle Scholar
  23. 23.
    van den Pol AN (1991) Glutamate and aspartate immunoreactivity in hypothalamic presynaptic axons. J Neurosci 11:2087–2101PubMedGoogle Scholar
  24. 24.
    van den Pol AN, Wuarin JP, Dudek FE (1990) Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science 250:1276–1278PubMedCrossRefGoogle Scholar
  25. 25.
    Csáki Á, Kocsis K, Halász B, Kiss J (2000) Localization of glutamatergic/aspartatergic neurons projecting to the hypothalamic paraventricular nucleus studied by retrograde transport of (3H)d-aspartate autoradiography. Neuroscience 101:637–655PubMedCrossRefGoogle Scholar
  26. 26.
    Lin W, McKinney K, Liu L, Lakhlni S, Jennes L (2003) Distribution of vesicular glutamate transporter 2 messenger ribonucleic acid and protein in the septum-hypothalamus of the rat. Endocrinology 144:662–670PubMedCrossRefGoogle Scholar
  27. 27.
    Wuarin JP, Dudek FE (1991) Excitatory amino acid antagonists inhibit synaptic responses in the guinea pig hypothalamic paraventricular nucleus. J Neurophysiol 65:946–951PubMedGoogle Scholar
  28. 28.
    Bodnár I, Bánky Z, Nagy MG, Halász B (2005) Non-NMDA glutamate receptor antagonist injected into the hypothalamic paraventricular nucleus blocks the suckling stimulus-induced release of prolactin. Brain Res Bull 65:163–168PubMedCrossRefGoogle Scholar
  29. 29.
    Paxinos G, Watson C (eds) (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic Press, San DiegoGoogle Scholar
  30. 30.
    Kacsóh B, Veress Z, Tóth BE, Avery LM, Grosvenor CE (1993) Bioactive and immunoreactive variants of prolactin in milk and serum of lactating rats and their pups. J Endocrinol 138:243–257PubMedGoogle Scholar
  31. 31.
    Zelena D, Mergl Z, Földes A, Kovács KJ, Tóth Z, Makara GB (2003) Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint. Am J Physiol Endocrinol Metab 285:E1110–E1117PubMedGoogle Scholar
  32. 32.
    Jezová D, Tokarev D, Rusnák M (1995) Endogenous excitatory amino acids are involved in stress-induced adrenocorticotropin and catecholamine release. Neuroendocrinology 62:326–332PubMedCrossRefGoogle Scholar
  33. 33.
    Kim D-H, Moon Y-S, Jung J-S, Suh H-W, Song D-K (2003) Route-dependent effects of the non-NMDA receptor antagonist CNQX on plasma corticosterone levels in mice. Prog Neuro-Psychopharmacol Biol Psych 27:1055–1058CrossRefGoogle Scholar
  34. 34.
    Ziegler DR, Herman JP (2000) Local integration of glutamate signaling in the hypothalamic paraventricular region: regulation of glucocorticoid stress responses. Endocrinology 141:4801–4804PubMedCrossRefGoogle Scholar
  35. 35.
    Feldman S, Weidenfeld J (2004) Involvement of endogeneous glutamate in the stimulatory effect of norepinephrine and serotonin on the hypothalamo-pituitary-adrenocortical axis. Neuroendocrinology 79:43–53PubMedCrossRefGoogle Scholar
  36. 36.
    Daftary SS, Boudaba C, Szabó K, Tasker JG (1998) Noradrenergic excitation of magnocellular neurons in the rat hypothalamic paraventricular nucleus via intranuclear glutamatergic circuits. J Neurosci 18:10619–10628PubMedGoogle Scholar
  37. 37.
    Freeman ME, Kanyicska B, Lerant A, Nagy MG (2000) Prolactin: structure, function and regulation of secretion. Physiol Rev 80:1523–1631PubMedGoogle Scholar
  38. 38.
    Tóth BE, Homicskó K, Radnai B, Maruyama W, DeMaria JE, Vecsernyés M, Fekete MIK, Fülöp F, Naoi M, Freeman ME, Nagy MG (2001) Salsolinol is a putative endogenous neuro-intermediate lobe prolactin-releasing factor. J Neuroendocrinol 13:1042–1050PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Ibolya Bodnár
    • 1
  • Zsuzsanna Bánky
    • 1
  • Béla Halász
    • 1
    • 2
  1. 1.Neuroendocrine Research LaboratoryHungarian Academy of Sciences and Semmelweis UniversityBudapestHungary
  2. 2.Department of Human Morphology and Developmental BiologySemmelweis UniversityBudapestHungary

Personalised recommendations