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Psychopharmacology

, 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

Abstract

Rationale

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).

Methods

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

Results

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.

Conclusions

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.

Keywords

Prenatal MK-801 NMDA receptor Parvalbumin PCP METH 

Notes

Acknowledgement

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.

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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

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