Skip to main content
SpringerLink
Log in

Effects of Endogenous Glutamate on Extracellular Concentrations of GABA, Dopamine, and Dopamine Metabolites in the Prefrontal Cortex of the Freely Moving Rat: Involvement of NMDA and AMPA/KA Receptors

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Using microdialysis, interactions between endogenous glutamate, dopamine, and GABA were investigated in the medial prefrontal cortex of the freely moving rat. Interactions between glutamate and other neurotransmitters in the prefrontal cortex had already been studied using pharmacological agonists or antagonists of glutamate receptors. This research investigated whether glutamate itself, through the increase of its endogenous extracellular concentration, is able to modulate the extracellular concentrations of GABA and dopamine in the prefrontal cortex. Intracortical infusions of the selective glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) were used to increase the endogenous extracellular glutamate. PDC (0.5, 2, 8, 16 and 32 mM) produced a dose-related increase in dialysate glutamate in a range of 1–36 μM. At the dose of 16 mM, PDC increased dialysate glutamate from 1.25 to 28 μM. PDC also increased extracellular GABA and taurine, but not dopamine; and decreased extracellular concentrations of the dopamine metabolites DOPAC and HVA. NMDA and AMPA/KA receptor antagonists were used to investigate whether the increases of extracellular glutamate were responsible for the changes in the release of GABA, and dopamine metabolites. The NMDA antagonist had no effect on the increase of extracellular GABA, but blocked the decreases of extracellular DOPAC and HVA, produced by PDC. In contrast, the AMPA/KA antagonist blocked the increases of extracellular GABA without affecting the decreases of extracellular DOPAC and HVA produced by PDC. These results suggest that endogenous glutamate acts preferentially through NMDA receptors to decrease dopamine metabolism, and through AMPA/KA receptors to increase GABAergic activity in the medial prefrontal cortex of the awake rat.

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

  1. Goldman-Rakic, P. S. and Selemon, L. D. 1997. Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophrenia Bulletin 23:437–458.

    Google Scholar 

  2. Porras, A., Sanz, B. and Mora, F. 1997. Dopamine-glutamate interactions in the prefrontal cortex of the conscious rat: studies on ageing. Mech. Ageing Dev. 99:9–17.

    Google Scholar 

  3. Ottersen, O. P. and Storm-Mathissen, J. 1984. Glutamate and GABA-containing neurons in the mouse and rat brain, as demonstrated with a new immunocytochemical technique. J. Comp. Neurol. 229:374–429.

    Google Scholar 

  4. Conti, F., Rustioni, A., Petrusz, P. and Towle, A. C. 1987. Glutamate-positive neurons in the somatic sensory cortex of rats and monkeys. J. Neurosci. 7:1887–1901.

    Google Scholar 

  5. DeFelipe, J. and Fariñas, I. 1992. The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog. Neurobiol. 39:563–607.

    Google Scholar 

  6. Van Eden, C. G., Hoorneman, E. M. D., Buijs, R. M., Matthijssen, M. A. H., Geffard, M. and Uylings, H. B. M. 1987. Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level. Neuroscience 22:849–862.

    Google Scholar 

  7. Verney, C., Alvarez, C., Geffard, M. and Berger, B. 1990. Ultrastructural double-labelling study of dopamine terminals and GABA-containing neurons in rat anteromedial cerebral cortex. Eur. J. Neurosci. 2:960–972.

    Google Scholar 

  8. Peinado, J. M. and Mora, F. 1986. Glutamic acid as a putative transmitter of the interhemispheric corticocortical connections in the rat. J. Neurochem. 47:1598–1603.

    Google Scholar 

  9. Esclapez, M., Campistron, G. and Trottier, S. 1987. Immunocytochemical localization and morphology of GABA-containing neurons in the prefrontal and frontoparietal cortex of the rat. Neurosci. Lett. 77:131–136.

    Google Scholar 

  10. Segovia, G., Del Arco, A. and Mora, F. 1997. Endogenous glutamate increases extracellular concentrations of dopamine, GABA, and taurine through NMDA and AMPA/Kainate receptors in striatum of the freely moving rat: a microdialysis study. J. Neurochem. 69:1476–1483.

    Google Scholar 

  11. Javitt, D. C. and Zukin, S. R. 1991. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 148:1301–1308.

    Google Scholar 

  12. Hondo, H., Yonezawa, Y., Nakahara, T., Nakamura, K., Hirano, M., Uchimura, H. and Tashiro, N. 1994. Effect of phencyclidine on dopamine release in the rat prefrontal cortex: an in vivo microdialysis study. Brain Res. 633:337–342.

    Google Scholar 

  13. Wedzony, K., Klimek, V. and Golembiowska, K. 1993. MK-801 elevates the extracellular concentration of dopamine in the rat prefrontal cortex and increases the density of striatal dopamine D1 receptors. Brain Res. 622:325–329.

    Google Scholar 

  14. Kashiwa, A., Nishikawa, T., Nishijima, K., Umino, A. and Takahashi, K. 1995. Dizocilpine (MK-801) elicits a tetrodotoxinsensitive increase in extracellular release of dopamine in rat medial frontal cortex. Neurochem. Int. 26:269–279.

    Google Scholar 

  15. Nishijima, K., Kashiwa, A. and Nishikawa, T. 1994. Preferential stimulation of extracellular release of dopamine in rat frontal cortex to striatum following competitive inhibition of the N-methyl-D-aspartate receptor. J. Neurochem. 63:375–378.

    Google Scholar 

  16. Yonezawa, Y., Kuroki, T., Kawahara, T., Tashiro, N. and Uchimura, H. 1998. Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur. J. Pharmacol. 341:45–56.

    Google Scholar 

  17. Hata, N., Nishikawa, T., Umino, A. and Takahashi, K. 1990. Evidence for involvement of N-methyl-D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex. Neurosci. Lett. 120:101–104.

    Google Scholar 

  18. Moghaddam, B., Adams, B., Verma, A. and Daly, D. 1997. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17:2921–2927.

    Google Scholar 

  19. Jones, C. A., Zempléni, E., Davis, B. and Reynolds, G. P. 1993. Glutamate stimulates dopamine release from cortical and limbic rat brain in vitro. Eur. J. Pharmacol. 242:183–187.

    Google Scholar 

  20. Feenstra, M. G. P., Van der Weij, W. and Botterblom, M. H. A. 1995. Concentration-dependent dual action of locally applied N-methyl-d-aspartate on extracellular dopamine in the rat prefrontal cortex in vivo. Neurosci. Lett. 201:175–178.

    Google Scholar 

  21. Jedema, H. P. and Moghaddam, B. 1996. Characterization of excitatory amino acid modulation of dopamine release in the prefrontal cortex of conscious rats. J. Neurochem. 66:1448–1453.

    Google Scholar 

  22. Pirot, S., Godbout, R., Mantz, J., Tassin, J.-P., Glowinski, J. and Thierry, A.-M. 1992. Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminegic and gabaergic components. Neuroscience 49:857–865.

    Google Scholar 

  23. Drejer, J., Honoré, T. and Schousboe, A. 1987. Excitatory amino acid-induced release of [3H]-GABA from cultured mouse cerebral cortex interneurons. J. Neurosci. 7:2910–2916.

    Google Scholar 

  24. Bridges, R. J., Stanley, M. S., Anderson, M. W., Cotman, C. W. and Camberlin, A. R. 1991. Conformationally defined neurotransmitter analogues. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer. J. Med. Chem. 34:717–725.

    Google Scholar 

  25. Thomsen, C., Hansen, L. and Suzdak, P. D. 1994. L-glutamate uptake inhibitors may stimulate phosphoinositide hydrolysis in baby hamster kidney cells expressing mGluR1a via heteroexchange with L-glutamate without direct activation of mGluR1a. J. Neurochem. 63:2038–2047.

    Google Scholar 

  26. Massieu, L., Morales-Villagrán, A. and Tapia, R. 1995. Accumulation of extracellular glutamate by inhibition of its uptake is not sufficient for inducing neuronal damage: an in vivo microdialysis study. J. Neurochem. 64:2262–2272.

    Google Scholar 

  27. Obrenovitch, T. P., Urenjak, J. and Zilkha, E. 1996. Evidence disputing the link between seizure activity and high extracellular glutamate. J. Neurochem. 66:2446–2454.

    Google Scholar 

  28. Matarredona, E. R., Santiago, M., Machado, A. and Cano, J. 1997. Lack of involvement of glutamate-induced excitotoxicity in MPP + toxicity in striatal dopaminergic terminals: possible involvement of ascorbate. Br. J. Pharmacol. 121:1038–1044.

    Google Scholar 

  29. Obrenovitch, T. P. and Urenjak, J. 1997. Altered glutamatergic transmission in neurological disorders: from high extracellular glutamate to excessive synaptic efficacy. Prog. Neurobiol. 51:39–87.

    Google Scholar 

  30. Segovia, G., Porras, A. and Mora, F. 1997. Effects of 4-amino-pyridine on extracellular concentrations of glutamate in striatum of the freely moving rat. Neurochem. Res. 22:1491–1497.

    Google Scholar 

  31. Konig, J. R. F. and Klippel, R. A. 1967. The rat brain. R. E. Krieger Publishing Co., New York.

    Google Scholar 

  32. Del Arco, A., Castañeda, T. R. and Mora, F. 1998. Amphetamine releases GABA in striatum of the freely moving rat: involvement of calcium and high affinity transporter mechanisms. Neuropharmacology 37:199–205.

    Google Scholar 

  33. Clements, J, Lester, R. A. J., Tong, G. T, Jahr, C. E. and Westbrook, G. L. 1992. The time course of glutamate in the synaptic cleft. Science 258:1498–1501.

    Google Scholar 

  34. Barbour, B. and Häusser, M. 1997. Intersynaptic diffusion of neurotransmitter. Trends Neurosci. 20:377–384.

    Google Scholar 

  35. Kullmann, D., Erdemli, G. and Asztely, F. 1996. LTP of AMPA and NMDA receptor-mediated signals: evidence for presynaptic expression and extrasynaptic glutamate spill-over. Neuron 17:461–474.

    Google Scholar 

  36. Asztely, F., Erdemli, G. and Kullmann, D. 1997. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18:281–293.

    Google Scholar 

  37. Huntley, G. W., Vickers, J. C. and Morrison, J. H. 1994. Cellular and synaptic localization of NMDA and non-NMDA receptors subunits in neocortex: organizational features related to cortical circuitry, function and disease. Trends Neurosci. 17:536–543.

    Google Scholar 

  38. Bianchi, L., Galeffi, F., Bartolini, S., Bolam, J. P. and Della Corte, L. 1996. The evoked release of endogenous amino acids in the direct and indirect pathways of the basal ganglia. A dual microdialysis study in the freely moving rat. Pages 176–177, in González-Mora, J. L., Borges, R. and Mas, M. (eds.), Monitoring molecules in neurosciences, University of La Laguna

  39. Kendrick, K. M., Guevara-Guzman, R., De la Riva, C., Christensen, J., Ostergaard, K. and Emson, P. C. 1996. NMDA and kainate-evoked release of nitric oxide and classical transmitters in the rat striatum: in vivo evidence that nitric oxide may play a neuroprotective role. Eur. J. Neurosci. 8:2619–2634.

    Google Scholar 

  40. Attwell, D., Barbour, B. and Szatkowski, M. 1993. Nonvesicular release of neurotransmitter. Neuron 11:401–407.

    Google Scholar 

  41. Grobin, A. C. and Deutch, A. Y. 1998. Dopaminergic regulation of extracellular γ-aminobutyric acid levels in the prefrontal cortex of the rat. J. Pharmacol. Exp. Ther. 285:350–357.

    Google Scholar 

  42. Santiago, M., Machado, A. and Cano, J. 1993. Regulation of the prefrontal cortical dopamine release by GABAA and GABAB receptor agonists and antagonists. Brain Res. 630:28–31.

    Google Scholar 

  43. Del Arco, A., Martínez, R. and Mora, F. 1998. Amphetamine increases extracellular concentrations of glutamate in the prefrontal cortex of the awake rat: a microdialysis study. Neurochem. Res. 23:1153–1158.

    Google Scholar 

  44. Huxtable, R. J. 1989. Taurine in the central nervous system and mammalian actions of taurine. Prog. Neurobiol. 32:471–533.

    Google Scholar 

  45. Menéndez, N., Solís, J. M., Herreras, O., Herranz, A. S. and Del Río, R. M. 1990. Role of endogenous taurine in the glutamate analogue-induced neurotoxicity in the rat hippocampus in vivo. J. Neurochem. 55:714–717.

    Google Scholar 

  46. Kamisaki, Y., Maeda, K., Ishimura, M., Omura, H. and Itoh, T. 1993. Effects of taurine on depolarization-evoked release of amino acids from rat cortical synaptosomes. Brain Res. 627:181–185.

    Google Scholar 

  47. Murphy, B. L., Arnsten, A. F. T., Goldman-Rakic, P. S. and Roth, R. H. 1996. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc. Natl. Acad. Sci. USA 93:1325–1329.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology. Faculty of Medicine, University Complutense, Madrid (, Spain)

    Alberto Del Arco & Francisco Mora

  2. Department of Physiology, Faculty of Medicine, Universidad Complutense, Ciudad Universitaria, Madrid, SPAIN

    Francisco Mora

Authors
  1. Alberto Del Arco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco Mora
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Del Arco, A., Mora, F. Effects of Endogenous Glutamate on Extracellular Concentrations of GABA, Dopamine, and Dopamine Metabolites in the Prefrontal Cortex of the Freely Moving Rat: Involvement of NMDA and AMPA/KA Receptors. Neurochem Res 24, 1027–1035 (1999). https://doi.org/10.1023/A:1021056826829

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021056826829

Search

Navigation