Abstract
The effects of the antipsychotic drugs haloperidol and clozapine on N-methyl-d-aspartate (NMDA) and non-NMDA receptor-mediated neurotransmission were examined and compared in pyramidal cells of the medial prefrontal cortex in rat brain slices by using the techniques of intracellular recording and single-electrode voltage-clamp. The bath administration of either haloperidol or clozapine produced a marked facilitation (300–400%) of NMDA-evoked responses in a concentration-dependent manner. The EC50 values of haloperidol and clozapine were 38 and 14 nM, respectively. At concentrations of ≥100 nM, clozapine, but not haloperidol, produced bursts of excitatory postsynaptic potentials (EPSPs), which were blocked by glutamate receptor antagonists, suggesting that these EPSPs were the result of increasing release of excitatory amino acids. Haloperidol, but not clozapine, produced a concentration-dependent inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced current with an EC50 value of 37 nM. Haloperidol significantly decreased the amplitude of EPSPs evoked by the electrical stimulation of the forceps minor, whereas clozapine increased the amplitude of these EPSPs. The study of current-voltage relationship indicates that clozapine preferentially potentiates NMDA receptor-mediated transmission, whereas haloperidol depresses the non-NMDA receptor-mediated response, which probably obscures its potentiating effect on NMDA receptor-mediated EPSPs.
Footnotes
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Send reprint requests to: Rex Y. Wang, Ph.D., Department of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook, Putnam Hall, South Campus, Stony Brook, NY 11794-8790. E-mail: rex.wang{at}sunysb.edu
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↵1 This work was supported by United State Public Health Service Grants MH41440 (R.Y.W.).
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↵2 X. Liang, V. L. Arvanov and R. Y. Wang, unpublished observations.
- Abbreviations:
- aCSF
- artificial cerebrospinal fluid
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- d-(−)-AP-5
- d-(−)-2-amino-5-phosphonopentanoic acid
- APD
- antipsychotic drug
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- AM
- acetoxymethyl ester
- CNQX
- 6-cyano-2,3-dihydroxy-7-nitroquinoxaline
- CSF
- cerebrospinal fluid
- EAA
- excitatory amino acid
- EPSC
- excitatory postsynaptic current
- EPSP
- excitatory postsynaptic potential
- FS
- fast-spiking
- GABA
- γ-aminobutyric acid
- IB
- intrinsic bursting
- IM
- intermediate
- mPFC
- medial prefrontal cortex
- NMDA
- N-methyl-d-aspartate
- ROB
- repetitive oscillatory bursting
- RS
- regular-spiking
- TCP
- tenocyclidine
- TTX
- tetrodotoxin
- Vh
- holding potential
- Received January 17, 1997.
- Accepted June 2, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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