, Volume 192, Issue 3, pp 303–316 | Cite as

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats

  • Tomohiro AbekawaEmail author
  • Koki Ito
  • Shin Nakagawa
  • Tsukasa Koyama
Original Investigation



Neurodevelopmental deficits of parvalbumin-immunoreactive γ-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-d-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH).


GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor.


Prenatal exposure (E15–E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH.


These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.


Prenatal MK-801 NMDA receptor Parvalbumin PCP METH 



This study was supported in part by Grant-in-Aid No 14370287 and No 15591207 for Scientific Research from the Ministry of Education, Science and Culture, Japan. The authors thank Ms Akiko Kato for her technical assistance.


  1. Abekawa T, Honda M, Ito K, Koyama T (2003) Effects of NRA0045, a novel potent antagonist at dopamine D4, 5-HT2A, and α1 adrenaline receptors, and NRA0160, a selective D4 receptor antagonist, on phencyclidine-induced behavior and glutamate release in rats. Psychopharmacology 169:247–256CrossRefPubMedGoogle Scholar
  2. Al-Amin HA, Weickert CS, Weinberger DR, Lipska BK (2001) Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus. Biol Psychiatry 49:528–539CrossRefPubMedGoogle Scholar
  3. Alcantara S, Ferrer I, Soriano E (1993) Postnatal development of parvalbumin and calbindin D28K immunoreactivities in the cerebral cortex of the rat. Anat Embryol Berl 188:63–73CrossRefPubMedGoogle Scholar
  4. Allen HL, Iversen LL (1990) Phencyclidine, dizocilpine and cerebrocortical neurons. Science 247:221CrossRefPubMedGoogle Scholar
  5. Bailey CDC, Brien JF, Reynolds JN (2001) Chronic prenatal ethanol exposure Increases GABAA receptor subunit protein expression in the adult guinea pig cerebral cortex. J Neurosci 21:4381–4389PubMedGoogle Scholar
  6. Beasley CL, Reynolds GP (1997) Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophr Res 24:349–355CrossRefPubMedGoogle Scholar
  7. Beasley CL, Zhang ZJ, Patten I, Reynolds GP (2002) Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol Psychiatry 52:708–715CrossRefPubMedGoogle Scholar
  8. Behar TN, Scott CA, Greene CL, Wen X, Smith SV, Maric D, Liu QY, Colton CA, Barker JL (1999) Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration. J Neurosci 19:4449–4461PubMedGoogle Scholar
  9. Benes FM, Bird ED (1987) An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients. Arch Gen Psychiatry 44:608–616PubMedGoogle Scholar
  10. Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL (1991) Deficits in small interneurons in prefrontal and cingulated cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 48:996–1001PubMedGoogle Scholar
  11. Benes FM, Vincent SL, Marie A, Khan Y (1996) Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 74:1021–1031CrossRefGoogle Scholar
  12. Bogerts B, Ashtari M, Degreef G, Alvir JMJ, Bilder RM, Lieberman JA (1990) Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res 35:1–13CrossRefPubMedGoogle Scholar
  13. Casey DE, Daniel DG, Wassef AA, Tracy KA, Wolnlak P, Sommerville W (2003) Effect of divalproex combined with olanzapine or risperidone in patients with acute exacerbation of schizophrenia. Neuropsychopharmacology 28:182–192CrossRefPubMedGoogle Scholar
  14. Celio MR (1990) Calbindin D-28K and parvalbumin in the rat nervous system. Neuroscience 35:375–475CrossRefPubMedGoogle Scholar
  15. Corbett R, Camacho F, Woods AT (1995): Antipsychotic agents antagonize non-competitive N-methyl-d-aspartate antagonist-induced behaviors. Psychopharmacology 120:67–74CrossRefPubMedGoogle Scholar
  16. Csillik A, Okuno E, Csillik B, Knyihar E, Vecsei L (2002) Expression of kynurenine aminotransferase in the subplate of the rat and its possible role in the regulation of programmed cell death. Cereb Cortex 12:1193–1201CrossRefPubMedGoogle Scholar
  17. Cunningham MO, Jones RSG (2000) The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. Neuropharmacology 39:2139–2146CrossRefPubMedGoogle Scholar
  18. Demeulemeester H, Vandesande F, Orban GA, Brando C (1988) Heterogenity of GABAergic cells in cat visual cortex. J Neurosci 8:988–1000PubMedGoogle Scholar
  19. Dursun SM, Deakin JF (2001) Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol 15:297–301PubMedGoogle Scholar
  20. Farber NB, Wozniak DF, Price MT, Labruyere J, Huss J, St Peter H, Olney JW (1995) Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia? Biol Psychiatry 38:788–796CrossRefPubMedGoogle Scholar
  21. Freed WJ, Weinberger DR, Bing LA, Wyatt RJ (1980) Neuropharmacological studies of phencyclidine (PCP)-induced behavioral stimulation in mice. Psychopharmacology 71:291–297CrossRefPubMedGoogle Scholar
  22. Gleason SD, Shannon HE (1997) Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice. Psychopharmacology 129:79–84CrossRefPubMedGoogle Scholar
  23. Harris LW, Sharp T, Gartlon J, Jones DNC, Harrison PJ (2003) Long-term behavioural, molecular and morphological effects of neonatal NMDA receptor antagonism. Eur J Neurosci 18:1706–1710CrossRefPubMedGoogle Scholar
  24. Honack D, Loscher W (1993) Sex differences in NMDA receptor mediated responses in rats. Brain Res 620:167–170CrossRefPubMedGoogle Scholar
  25. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Pierce MT, Stefovska V, Horster F, Tenkova T, Dikranian K, Olney JW (2000) Ethanol-induced apoptosis neurodegeneration and fetal alcohol syndrome. Science 287:1056–1060CrossRefPubMedGoogle Scholar
  26. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308PubMedGoogle Scholar
  27. Jentsch JD, Tran A, Taylor JR, Roth RH (1998) Prefrontal cortical involvement in phencyclidine-induced activation of mesolimbic dopamine system: behavioral and neurochemical evidence. Psychopharmacology 138:89–95CrossRefPubMedGoogle Scholar
  28. Kalivas PW, Hooks MS, Sorg B (1993) The pharmacology and neural circuitry of sensitization to psychostimulants. Behav Pharmacol 4:315–334CrossRefPubMedGoogle Scholar
  29. Komuro H, Rakic P (1993) Modulation of neuronal migration by NMDA receptors. Science 260:95–97CrossRefPubMedGoogle Scholar
  30. Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulates psychosis in schizophrenia. Neuropsychopharmacology 13:9–19CrossRefPubMedGoogle Scholar
  31. Leach MJ, Marden CM, Miller AA (1986) Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 27:490–497PubMedGoogle Scholar
  32. Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Neuroscience 6:312–324PubMedGoogle Scholar
  33. Lipska BK, Luu S, Halim ND, Weinberger DR (2002) Behavioral effects of neonatal And adult excitotoxic lesions of the mediodorsal thalamus in the adult rat. Behav Brain Res 141:105–111CrossRefGoogle Scholar
  34. Loscher W (1999) Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 58:31–59CrossRefPubMedGoogle Scholar
  35. Malhotra AK, Adler CM, Kennison SD, Elman I, Picker D, Breier A (1997) Clozapine blunts N-methyl-d-aspartate antagonist-induced psychosis: a study with ketamine. Biol Psychiatry 42:664–668CrossRefPubMedGoogle Scholar
  36. Maurel-Remy S, Bervoets K, Millan MJ (1995) Blockade of phencyclidine-induced hyperlocomotion by clozapine and MDL 100,907 in rats reflects antagonism of 5-HT2A receptors. Eur J Pharmacol 280:R9–R11CrossRefPubMedGoogle Scholar
  37. McPhalen CA, Sielecki AR, Santarsiero BD, James MN (1994): refined crystal structure of rat parvalbumin, a mammalian alpha-lineage parvalbumin, at 2.0 A solution. J Mol Biol 235:718–732CrossRefPubMedGoogle Scholar
  38. Mechri A, Saoud M, Khiari G, d’Amato T, Dalery J, Gaha L (2001) Glutamatergic hypothesis of schizophrenia: clinical research studies with ketamine. Encephale 27:53–59PubMedGoogle Scholar
  39. Metin C, Baudoin JP, Rakic S, Parnavelas JG (2006) Cell and molecular mechanisms involved in the migration of cortical interneurons. Eur J Neurosci 23:894–900CrossRefPubMedGoogle Scholar
  40. Millan MJ (2005) N-methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insight and clinical perspectives. Psychopharmacology 179:30–53CrossRefPubMedGoogle Scholar
  41. Moore DB, Quintero MA, Ruygrok AC, Walker DW, Heaton MB (1998) Prenatal ethanol exposure reduces parvalbumin-immunoreactive GABAergic neuronal number in the adult rat cingulated cortex. Neurosci Lett 249:25–28CrossRefPubMedGoogle Scholar
  42. Moy SS, Breese GR (2002) Phencyclidine supersensitivity in rats with neonatal dopamine loss. Psychopharmacology 161:255–262CrossRefPubMedGoogle Scholar
  43. Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007PubMedGoogle Scholar
  44. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, USAGoogle Scholar
  45. Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev 25:192–216CrossRefPubMedGoogle Scholar
  46. Plogmann D, Celio MR (1993) Intracellular concentration of parvalbumin in nerve cells. Brain Res 600:273–279CrossRefPubMedGoogle Scholar
  47. Roberts GW (1991) Schizophrenia: a neuropathological perspective. Br J Psychiatry 158:8–17PubMedCrossRefGoogle Scholar
  48. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11:157–198CrossRefGoogle Scholar
  49. Sadikot AF, Burhan AM, Belanger M-C, Sasseville R (1998) NMDA receptor antagonist influences early development of GABAergic interneurons in the mammalian striatum. Dev Brain Res 105:35–42CrossRefGoogle Scholar
  50. Sato M, Chen C-C, Akiyama K, Otsuki S (1983) Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis. Biol Psychiatry 18:429–440PubMedGoogle Scholar
  51. Seiler N, Grauffel C (1992) Antagonism of phencyclidine-induced hyperactivity in mice by elevated brain GABA concentrations. Pharmacol Biochem Behav 41:603–606CrossRefPubMedGoogle Scholar
  52. Sircar R, Soliman KFA (2003) Effects of postnatal PCP treatment on locomotor behavior and striatal D2 receptor. Pharmacol Biochem Behav 74:943–952CrossRefPubMedGoogle Scholar
  53. Szeszko PR, Bilder RM, Lencz T, Pollack S, Alvir JM, Ashtari M, Wu H, Lieberman JA (1999) Investigation of frontal lobe subregions in first-episode schizophrenia. Psychiatry Res 90:1–15CrossRefPubMedGoogle Scholar
  54. Tiihonen J, Hallikainen T, Ryynanen OP, Repo-Tiihonen E, Kotilainen I, Eronen M, Toivonen P, Wahlbeck K (2003) Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 54:1241–1248CrossRefPubMedGoogle Scholar
  55. Vriend JP, Alexiuk NA (1996) Effects of valproate on amino acid and monoamine concentration in striatum of audiogenic seizure-prone Balb/c mice. Mol Chem Neuropathol 27:307–324PubMedCrossRefGoogle Scholar
  56. Wassef AA, Dott SG, Harris A, Brown A, O’Boyle M, Meyer WJ III, Rose RM (2000) Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol 20:357–361CrossRefPubMedGoogle Scholar
  57. Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H (1998) Involvement of γ-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharmacol 341:45–56CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Tomohiro Abekawa
    • 1
    Email author
  • Koki Ito
    • 1
  • Shin Nakagawa
    • 1
  • Tsukasa Koyama
    • 1
  1. 1.Department of Psychiatry, Graduate School of MedicineHokkaido UniversitySapporoJapan

Personalised recommendations