Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors

B. Yu, C. Wang, J. Liu, K. M. Johnson, J. P. Gallagher

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABAA receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABAA receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalNeuroscience
Volume113
Issue number1
DOIs
StatePublished - Aug 2 2002

Fingerprint

Neurotransmitter Receptor
N-Methylaspartate
GABA-A Receptors
N-Methyl-D-Aspartate Receptors
Pharmacology
Phencyclidine
Kainic Acid
gamma-Aminobutyric Acid
Glutamic Acid
Schizophrenia
Animal Models
Acids
Brain

Keywords

  • Chronic phencyclidine
  • Dorsolateral septal nucleus
  • GABA receptor
  • NMDA receptor
  • Schizophrenia
  • Synaptic transmission

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors. / Yu, B.; Wang, C.; Liu, J.; Johnson, K. M.; Gallagher, J. P.

In: Neuroscience, Vol. 113, No. 1, 02.08.2002, p. 1-10.

Research output: Contribution to journalArticle

Yu, B. ; Wang, C. ; Liu, J. ; Johnson, K. M. ; Gallagher, J. P. / Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors. In: Neuroscience. 2002 ; Vol. 113, No. 1. pp. 1-10.
@article{c35c17f789ac4d0484f5b3667d2acdf6,
title = "Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors",
abstract = "Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABAA receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABAA receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.",
keywords = "Chronic phencyclidine, Dorsolateral septal nucleus, GABA receptor, NMDA receptor, Schizophrenia, Synaptic transmission",
author = "B. Yu and C. Wang and J. Liu and Johnson, {K. M.} and Gallagher, {J. P.}",
year = "2002",
month = "8",
day = "2",
doi = "10.1016/S0306-4522(02)00163-X",
language = "English (US)",
volume = "113",
pages = "1--10",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors

AU - Yu, B.

AU - Wang, C.

AU - Liu, J.

AU - Johnson, K. M.

AU - Gallagher, J. P.

PY - 2002/8/2

Y1 - 2002/8/2

N2 - Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABAA receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABAA receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.

AB - Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABAA receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABAA receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.

KW - Chronic phencyclidine

KW - Dorsolateral septal nucleus

KW - GABA receptor

KW - NMDA receptor

KW - Schizophrenia

KW - Synaptic transmission

UR - http://www.scopus.com/inward/record.url?scp=0037008347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037008347&partnerID=8YFLogxK

U2 - 10.1016/S0306-4522(02)00163-X

DO - 10.1016/S0306-4522(02)00163-X

M3 - Article

C2 - 12123679

AN - SCOPUS:0037008347

VL - 113

SP - 1

EP - 10

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

IS - 1

ER -