Acquiring the Excitatory and the Inhibitory Action of Dopamine in the Prefrontal Cortex During Postnatal Development

  • Kuei-Yuan Tseng

In this chapter I will first review recent electrophysiological findings on how DA D1 and D2 receptors influence excitatory and inhibitory neurotransmission in the PFC during the peripubertal transition to adulthood, the cellular mechanism underlying this DA modulation as well as its functional significance. Secondly, I will discuss how a developmental disruption of PFC DA modulation may underlie some of the cortical pathophysiological changes observed in schizophrenia and related psychiatry disorders.


Prefrontal Cortex Pyramidal Neuron GABAergic Interneuron Postnatal Development Neonatal Ventral Hippocampal Lesion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arnsten, A.F., Cai, J.X., Steere, J.C. and Goldman-Rakic, P.S. (1995) Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on mem-ory and motor performance in monkeys. J. Neurosci. 15, 3429-3439.PubMedGoogle Scholar
  2. Baldwin, A.E., Sadeghian, K. and Kelley, A.E. (2002) Appetitive instrumental learning re-quires coincident activation of NMDA and dopamine D1 receptors within the medial pre-frontal cortex. J. Neurosci. 22, 1063-1071.PubMedGoogle Scholar
  3. Becker, A., Grecksch, G., Bernstein, H.G., Hollt, V. and Bogerts, B. (1999) Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analy-sis. Psychopharmacology (Berl). 144, 333-338.CrossRefGoogle Scholar
  4. Benes, F.M., Vincent, S.L. and Molloy, R. (1993) Dopamine-immunoreactive axon varicosi-ties form nonrandom contacts with GABA-immunoreactive neurons of rat medial prefron-tal cortex. Synapse. 15, 285-295.CrossRefPubMedGoogle Scholar
  5. Benes, F.M., Taylor, J.B. and Cunningham, M.C. (2000) Convergence and plasticity of mono-aminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cereb. Cortex. 10, 1014-1027.CrossRefPubMedGoogle Scholar
  6. Casey, B.J., Giedd, J.N. and Thomas, K.M. (2000) Structural and functional brain develop-ment and its relation to cognitive development. Biol. Psychol. 54, 241-257.CrossRefPubMedGoogle Scholar
  7. Chambers, R.A., Moore, J., McEvoy, J.P. and Levin, E.D. (1996) Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia. Neuropsychopharmacology. 15, 587-594.CrossRefPubMedGoogle Scholar
  8. Chrapusta, S.J., Egan, M.F., Wyatt, R.J., Weinberger, D.R. and Lipska, B.K. (2003) Neonatal ventral hippocampal damage modifies serum corticosterone and dopamine release re-sponses to acute footshock in adult Sprague-Dawley rats. Synapse. 47, 270-277.CrossRefPubMedGoogle Scholar
  9. Cohen, J.D., Braver, T.S. and Brown, J.W. (2002) Computational perspectives on dopamine function in prefrontal cortex. Curr. Opin. Neurobiol. 12, 223-229.CrossRefPubMedGoogle Scholar
  10. Druzin, M.Y., Kurzina, N.P., Malinina, E.P. and Kozlov, A.P. (2000) The effects of local application of D2 selective dopaminergic drugs into the medial prefrontal cortex of rats in a delayed spatial choice task. Behav. Brain. Res. 109, 99-111.CrossRefPubMedGoogle Scholar
  11. Fellous, J.M., Houweling, A.R., Modi, R.H., Rao, R.P., Tiesinga, P.H. and Sejnowski, T.J. (2001) Frequency dependence of spike timing reliability in cortical pyramidal cells and in-terneurons. J. Neurophysiol. 85, 1782-1787.PubMedGoogle Scholar
  12. Floresco, S.B. and Phillips, A.G. (2001) Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex. Behav. Neurosci. 115, 934-939.CrossRefPubMedGoogle Scholar
  13. Funahashi, S. and Inoue, M. (2000) Neuronal interactions related to working memory processes in the primate prefrontal cortex revealed by cross-correlation analysis. Cereb. Cortex. 10, 535-551.CrossRefPubMedGoogle Scholar
  14. Gaspar, P., Bloch, B. and Le Moine, C. (1995) D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Eur. J. Neuro-sci. 7, 1050-1063.CrossRefGoogle Scholar
  15. Giedd, J.N., Blumenthal, J., Jeffries, N.O., Rajapakse, J.C., Vaituzis, A.C., Liu, H., Berry, Y.C., Tobin, M., Nelson, J. and Castellanos, F.X. (1999) Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study. Prog Neyropsychopharmacol Biol. Psychiatry. 23, 571-588.Google Scholar
  16. Gogtay, N., Giedd, J.N., Lusk, L., Hayashi, K.M., Greenstein, D., Vaituzis, A.C., Nugent, T.F., 3rd, Herman, D.H., Clasen, L.S., Toga, A.W., Rapoport, J.L. and Thompson, P.M. (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc. Natl. Acad. Sci. U S A. 101, 8174-8179.CrossRefPubMedGoogle Scholar
  17. Goldman-Rakic, P.S., Muly, E.C. 3rd. and Williams, G.V. (2000) D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 31, 295-301.CrossRefPubMedGoogle Scholar
  18. Gorelova, N., Seamans, J.K. and Yang, C.R. (2002) Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J. Neurophysiol. 88, 3150-3166.CrossRefPubMedGoogle Scholar
  19. Goto, Y. and O’Donnell, P. (2002) Delayed mesolimbic system alteration in a developmental animal model of schizophrenia. J. Neurosci. 22, 9070-9077.PubMedGoogle Scholar
  20. Grobin, A.C. and Deutch, A.Y. (1998) Dopaminergic regulation of extracellular gamma-aminobutyric acid levels in the prefrontal cortex of the rat. J. Pharmacol. Exp. Ther. 285, 350-357.PubMedGoogle Scholar
  21. Gulledge, A.T. and Jaffe, D.B. (1998) Dopamine decreases the excitability of layer V pyrami-dal cells in the rat prefrontal cortex. J. Neurosci. 18, 9139-9151.PubMedGoogle Scholar
  22. Gurden, H., Takita, M. and Jay, T.M. (2000) Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex syn-apses in vivo. J. Neurosci. 20, RC106.PubMedGoogle Scholar
  23. Gurden, H., Tassin, J.P. and Jay, T.M. (1999) Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation. Neuroscience. 94, 1019-1027.CrossRefPubMedGoogle Scholar
  24. Harrison, P.J. and Weinberger, D.R. (2005) Schizophrenia genes, gene expression, and neuro-pathology: on the matter of their convergence. Mol. Psychiatry. 10, 40-68; image 45.CrossRefPubMedGoogle Scholar
  25. Horvitz, J.C. (2000) Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience. 96, 651-656.CrossRefPubMedGoogle Scholar
  26. Jay, T.M. (2003) Dopamine: a potential substrate for synaptic plasticity and memory mecha-nisms. Prog. Neurobiol. 69, 375-390.CrossRefPubMedGoogle Scholar
  27. Kondo, S. and Kawaguchi, Y. (2001) Slow synchronized bursts of inhibitory postsynaptic currents (0.1-0.3 Hz) by cholinergic stimulation in the rat frontal cortex in vitro. Neurosci-ence. 107, 551-560.CrossRefGoogle Scholar
  28. Le Pen, G., Grottick, A.J., Higgins, G.A., Martin, J.R., Jenck, F. and Moreau, J.L. (2000) Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophrenia. Behav. Pharma-col. 11, 257-268.Google Scholar
  29. Le Pen, G. and Moreau, J.L. (2002) Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: reversal by clozapine, olanzapine and risper-idone but not by haloperidol. Neuropsychopharmacology. 27, 1-11.CrossRefPubMedGoogle Scholar
  30. Leslie, C.A., Robertson, M.W., Cutler, A.J. and Bennett, J.P., Jr. (1991) Postnatal develop-ment of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative auto-radiographic analysis. Brain. Res. Dev. Brain. Res. 62, 109-114.CrossRefPubMedGoogle Scholar
  31. Lewis, D.A., Volk, D.W. and Hashimoto, T. (2004) Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology (Berl). 174, 143-150.CrossRefGoogle Scholar
  32. Lewis, B.L. and O’Donnell, P. (2000) Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential ‘up’ states in pyramidal neurons via D(1) dopamine recep-tors. Cereb. Cortex. 10, 1168-1175.CrossRefPubMedGoogle Scholar
  33. Lipska, B.K., Jaskiw, G.E. and Weinberger, D.R. (1993) Postpubertal emergence of hyperre-sponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal dam-age: a potential animal model of schizophrenia. Neuropsychopharmacology. 9, 67-75.PubMedGoogle Scholar
  34. Lipska, B.K. and Weinberger, D.R. (1994) Subchronic treatment with haloperidol and clozap-ine in rats with neonatal excitotoxic hippocampal damage. Neuropsychopharmacology. 10, 199-205.PubMedGoogle Scholar
  35. Lipska, B.K., Chrapusta, S.J., Egan, M.F. and Weinberger, D.R. (1995) Neonatal excitotoxic ventral hippocampal damage alters dopamine response to mild repeated stress and to chronic haloperidol. Synapse. 20, 125-130.CrossRefPubMedGoogle Scholar
  36. Lipska, B.K. and Weinberger, D.R. (1998) Prefrontal cortical and hippocampal modulation of dopamine-mediated effects. Adv. Pharmacol. 42, 806-809.CrossRefPubMedGoogle Scholar
  37. Lipska, B.K. and Weinberger, D.R. (2000) To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 23, 223-239.CrossRefPubMedGoogle Scholar
  38. Lipska, B.K., Aultman, J.M., Verma, A., Weinberger, D.R. and Moghaddam, B. (2002) Neo-natal damage of the ventral hippocampus impairs working memory in the rat. Neuropsy-chopharmacology. 27, 47-54.CrossRefGoogle Scholar
  39. Lipska, B.K., Lerman, D.N., Khaing, Z.Z. and Weinberger, D.R. (2003a) The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain. Eur. J. Neurosci. 18, 3097-3104.CrossRefPubMedGoogle Scholar
  40. Lipska, B.K., Lerman, D.N., Khaing, Z.Z., Weickert, C.S. and Weinberger, D.R. (2003c) Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur. J. Neurosci. 18, 391-402.CrossRefPubMedGoogle Scholar
  41. Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G. and Wu, C. (2004) Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793-807.CrossRefPubMedGoogle Scholar
  42. Monyer, H., Burnashev, N., Laurie, D.J., Sakmann, B. and Seeburg, P.H. (1994) Developmen-tal and regional expression in the rat brain and functional properties of four NMDA recep-tors. Neuron. 12, 529-540.CrossRefPubMedGoogle Scholar
  43. Mrzljak, L., Bergson, C., Pappy, M., Huff, R., Levenson, R. and Goldman-Rakic, P.S. (1996) Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature. 381, 245-248.CrossRefPubMedGoogle Scholar
  44. Muly, E.C., 3rd, Szigeti, K. and Goldman-Rakic, P.S. (1998) D1 receptor in interneurons of macaque prefrontal cortex: distribution and subcellular localization. J. Neurosci. 18, 10553-10565.PubMedGoogle Scholar
  45. O’Donnell, P., Lewis, B.L., Weinberger, D.R. and Lipska, B.K. (2002) Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats. Cereb Cortex. 12, 975-982.CrossRefPubMedGoogle Scholar
  46. O’Donnell, P. (2003) Dopamine gating of forebrain neural ensembles. Eur. J. Neurosci. 17, 429-435.CrossRefPubMedGoogle Scholar
  47. Petit, T.L., LeBoutillier, J.C., Gregorio, A. and Libstug, H. (1988) The pattern of dendritic development in the cerebral cortex of the rat. Brain. Res. 469, 209-219.PubMedGoogle Scholar
  48. Pirot, S., Godbout, R., Mantz, J., Tassin, J.P., Glowinski, J. and Thierry, A.M. (1992) Inhibi-tory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neu-rons: evidence for the involvement of both dopaminergic and GABAergic components. Neuroscience. 49, 857-865.CrossRefPubMedGoogle Scholar
  49. Rao, S.G., Williams, G.V. and Goldman-Rakic, P.S. (2000) Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory. J. Neurosci. 20, 485-494.PubMedGoogle Scholar
  50. Schultz, W. (2002) Getting formal with dopamine and reward. Neuron. 36, 241-263.CrossRefPubMedGoogle Scholar
  51. Seamans, J.K., Floresco, S.B. and Phillips, A.G. (1998) D1 receptor modulation of hippocam-pal-prefrontal cortical circuits integrating spatial memory with executive functions in the rat. J. Neurosci. 18, 1613-1621.PubMedGoogle Scholar
  52. Seamans, J.K., Gorelova, N., Durstewitz, D. and Yang, C.R. (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J. Neurosci. 21, 3628-3638.PubMedGoogle Scholar
  53. Segalowitz, S.J. and Davies, P.L. (2004) Charting the maturation of the frontal lobe: an elec-trophysiological strategy. Brain. Cogn. 55, 116-133.CrossRefPubMedGoogle Scholar
  54. Sesack, S.R., Hawrylak, V.A., Matus, C., Guido, M.A. and Levey, A.I. (1998a) Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse im-munoreactivity for the dopamine transporter. J. Neurosci. 18, 2697-2708.PubMedGoogle Scholar
  55. Sesack, S.R., Hawrylak, V.A., Melchitzky, D.S. and Lewis, D.A. (1998b) Dopamine innerva-tion of a subclass of local circuit neurons in monkey prefrontal cortex: ultrastructural analysis of tyrosine hydroxylase and parvalbumin immunoreactive structures. Cereb. Cortex. 8, 614-622.CrossRefPubMedGoogle Scholar
  56. Shu, Y., Hasenstaub, A., Badoual, M., Bal, T. and McCormick, D.A. (2003) Barrages of synaptic activity control the gain and sensitivity of cortical neurons. J. Neurosci. 23, 10388-10401.PubMedGoogle Scholar
  57. Smiley, J.F., Levey, A.I., Ciliax, B.J. and Goldman-Rakic, P.S. (1994) D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines. Proc. Natl. Acad. Sci. U S A. 91, 5720-5724.CrossRefPubMedGoogle Scholar
  58. Spear, L.P. (2000) The adolescent brain and age-related behavioral manifestations. Neurosci. Biobehav. Rev. 24, 417-463.CrossRefPubMedGoogle Scholar
  59. Szabadics, J., Lorincz, A. and Tamas, G. (2001) Beta and gamma frequency synchronization by dendritic GABAergic synapses and gap junctions in a network of cortical interneurons. J. Neurosci. 21, 5824-5831.PubMedGoogle Scholar
  60. Tarazi, F.I., Tomasini, E.C. and Baldessarini, R.J. (1999) Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: An autoradiographic study. Dev. Neurosci. 21, 43-49.CrossRefPubMedGoogle Scholar
  61. Tarazi, F.I. and Baldessarini, R.J. (2000) Comparative postnatal development of dopamine D(1), D(2) and D(4) receptors in rat forebrain. Int. J. Dev. Neurosci. 18, 29-37.CrossRefPubMedGoogle Scholar
  62. Trantham-Davidson, H., Neely, L.C., Lavin, A. and Seamans, J.K. (2004) Mechanisms under-lying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J. Neurosci. 24, 10652-10659.CrossRefPubMedGoogle Scholar
  63. Traub, R.D., Whittington, M.A., Stanford, I.M. and Jefferys, J.G. (1996) A mechanism for generation of long-range synchronous fast oscillations in the cortex. Nature. 383, 621-624.CrossRefPubMedGoogle Scholar
  64. Tseng, K.Y. and O’Donnell, P. (2004) Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J. Neurosci. 24, 5131-5139.CrossRefPubMedGoogle Scholar
  65. Tseng, K.Y. and O’Donnell, P. (2005a) Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation. Cereb. Cortex. 15, 49-57.CrossRefPubMedGoogle Scholar
  66. Tseng, KY. and O’Donnell, P. (2005b) Dopaminergic modulation of cortical and striatal up states. In: J.P. Bolam, C.A. Ingham and P.J. Magill (Eds.), The Basal Ganglia VIII, SECTION: Physiological and Anatomical Studies of the Functional Organization of the Basal Ganglia. Springer Science and Business Media, New York, pp. 467-474.Google Scholar
  67. Tseng, K.Y., Mallet, N., Toreson, K.L., Le Moine, C., Gonon, F. and O’Donnell, P. (2006a) Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo. Synapse. 59, 412-417.CrossRefPubMedGoogle Scholar
  68. Tseng, K.Y., Amin, F., Lewis, B. L. and O’Donnell, P. (2006b) Altered prefrontal cortical metabolic response to mesocortical activation in adult animals with a neonatal ventral hip-pocampal lesion. Biol. Psychiatry. 60, 585-590.CrossRefPubMedGoogle Scholar
  69. Tseng, K.Y. and O’Donnell, P. (2007a) Dopamine modulation of prefrontal cortical interneu-rons changes during adolescence. Cereb. Cortex. 17, 1235-1240.CrossRefPubMedGoogle Scholar
  70. Tseng, K.Y. and O’Donnell, P. (2007b) Dopamine D2 receptors recruit a GABA component for their attenuation of excitatory synaptic transmission in the adult rat prefrontal cortex. Synapse. (In press).Google Scholar
  71. Tseng, K.Y., Lewis, B.L., Lipska, B.K. and O’Donnell, P. (2007) Post-pubertal disruption of medial prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia. Biol. Psychiatry. Jan 2; [Epub ahead of print]Google Scholar
  72. Vincent, S.L., Khan, Y. and Benes, F.M. (1993) Cellular distribution of dopamine D1 and D2 receptors in rat medial prefrontal cortex. J. Neurosci. 13, 2551-2564.PubMedGoogle Scholar
  73. Vincent, S.L., Pabreza, L. and Benes, F.M. (1995) Postnatal maturation of GABA- immunoreactive neurons of rat medial prefrontal cortex. J. Comp. Neurol. 355, 81-92.CrossRefPubMedGoogle Scholar
  74. Wang, J. and O’Donnell, P. (2001) D(1) dopamine receptors potentiate NMDA-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb. Cortex. 11, 452-462.CrossRefPubMedGoogle Scholar
  75. Williams, K., Russell, S.L., Shen, Y.M. and Molinoff, P.B. (1993) Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro. Neuron. 10, 267-278.CrossRefPubMedGoogle Scholar
  76. Zhu, J.J. (2000) Maturation of layer 5 neocortical pyramidal neurons: amplifying salient layer 1 and layer 4 inputs by Ca 2+ action potentials in adult rat tuft dendrites. J. Physiol. 526 Pt 3, 571-587.Google Scholar
  77. Zhu, Y., Stornetta, R.L. and Zhu, J.J. (2004) Chandelier cells control excessive cortical excita-tion: characteristics of whisker-evoked synaptic responses of layer 2/3 nonpyramidal and pyramidal neurons. J Neurosci. 24, 5101-5108.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kuei-Yuan Tseng
    • 1
  1. 1.Department of Cellular & Molecular PharmacologyRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA

Personalised recommendations