Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA(A) synaptic receptors.
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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABA(A) 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 GABA(A) receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.
Yu
B
B
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031, USA.
Wang
C
C
Liu
J
J
Johnson
K M
KM
Gallagher
J P
JP
D000818:Animals; D015536:Down-Regulation; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects*; D006213:Hallucinogens / Q000009:adverse effects*; D015151:Immunoblotting; D008297:Male; D010622:Phencyclidine / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D012686:Septal Nuclei / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D015854:Up-Regulation
D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine