/ 2a36 2266 Mp 297 Monday Jan 13 08:45 AM EL–BRB (v. 42, no. 4) 2266 297 Brain Research Bulletin, Vol. 42, No. 4, pp. 297–302, 1997 Copyright  1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/97 $17.00 / .00 PII S0361-9230(96)00268-7 The Effects of Anticonvulsant Drugs on NMDA-EPSP, AMPA-EPSP, and GABA-IPSP in the Rat Hippocampus GLADYS YI-PING LEE KO,* 1 LAURIE M. BROWN–CROYTS† AND TIMOTHY J. TEYLER* 1 Departments of *Neurobiology and †Pharmacology, Northeastern Ohio Universities College of Medicine, 4209 State Rt. 44, P.O. Box 95, Rootstown, OH 44272-0095, U.S.A. [Received 4 June 1996; Accepted 1 August 1996] 1 To whom requests for reprints should be addressed. Gladys Yi-Ping Lee Ko or Timothy J. Teyler, Neurobiology Department, N. E. Ohio Universities College of Medicine, 4209 State Rt. 44, P.O. Box 95, Rootstown, OH 44272-0095. ABSTRACT: The effects of phenobarbital, phenytoin, and val- proic acid on pharmacologically isolated NMDA-EPSP, AMPA- EPSP, and GABA-IPSPs were examined in rat hippocampal slices. Phenobarbital (0.05 mg/ml) had no effect on the NMDA- EPSP, but decreased the slope of the AMPA-EPSP by 13.4% and facilitated the GABA-IPSP slope by 77.12%. Phenytoin (0.02 mg/ ml) had no effects on the NMDA-EPSP, AMPA-EPSP, or GABA- IPSP. Valproic acid (0.1 mg/ml) decreased the NMDA-EPSP slope by 14.3%, increased the GABA-IPSP slope by 54.34%, and had no effect on the AMPA-EPSP. These data suggest that the mechanisms of action of these anticonvulsant drugs may be via their actions on different neurotransmitter systems or ion chan- nels. Copyright  1997 Elsevier Science Inc. KEY WORDS: Valproic acid, Phenobarbital, Phenytoin, NMDA, AMPA, GABA. INTRODUCTION Epilepsy is a disorder of brain function caused by abnormal syn- chronous and excessive discharges of a large group of neurons [17]. Epilepsy is not a uniform disorder [21]; consequently, most anticonvulsant drugs affect each disorder subtype differently [21]. Understanding the cellular and molecular mechanisms of different forms of epilepsy will help improve their treatment [16]. Similarly, understanding the mechanism of action of anticonvul- sant drugs will improve our knowledge of the pathophysiology of epilepsy and lead to the development of better anticonvulsant drugs. The idea that reduced inhibition results in epileptic seizures has been prominent for some time [7]. Disinhibition facilitates the synchronization and propagation of epileptic discharges [21]. Localized chronic infusions of GABA into motor cortex have powerful anticonvulsant effects in naturally photosensitive epi- leptic baboons [20]. Benzodiazepines (BDZs) and phenobarbital are currently used anticonvulsant drugs, and there are binding sites for both on the GABAa receptor complex [21]. BDZs and phenobarbital enhance GABA-induced inhibition through the en- hancement of GABA-receptor mediated ion currents, while BDZs also facilitate the binding of GABA to its receptor [21]. NMDA receptors are also able to generate and propagate the excessive neuronal discharges of a seizure [17], and the synaptic activation of NMDA receptors is strongly facilitated during the tonic phase of a seizure [25]. Some of the newer experimental anticonvulsant drugs can suppress NMDA receptor-mediated ex- citability [21]. The NMDA receptor antagonists CPP(3(2-car- boxypiperazine-4-yl)propyl-1-phosphonic acid), MK-801 (5- methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate), and ketamine are effective in suppressing behavioral and electrographic seizures [2,23]. Other anticonvulsant drugs like FBM (2-phenyl-1,3-propanediol dicarbamate) and GBP (1-(aminomethyl)cyclohexaneacetic acid) decrease NMDA re- ceptor-mediated excitability [15]. In hippocampal CA1 pyrami- dal cells, the bicuculline-induced acute epileptiform response is used as a model of complex partial seizures [24]. This bicucul- line induced seizure is significantly suppressed by the AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-di- one) [24]. Recently, it was reported that phenobarbital, phenytoin, and valproic acid inhibited NMDA-stimulated [ 3 H]norepinephrine ef- flux from rat cortical slices [3]. It is not clear whether these an- ticonvulsant drugs act directly on the NMDA receptor, or mediate their effects indirectly via their effects on AMPA or GABA re- ceptors. In this study, we examined the effects of phenobarbital, phenytoin, and valproic acid on pharmacologically isolated field EPSPs and IPSPs of CA1 hippocampal slices. MATERIALS AND METHODS Male Long–Evans rats (2–3 months old, 200–250 g) were used in this study. Animals were group housed and maintained in a temperature-controlled environment with a 12/12 h light- dark cycle. Transverse hippocampal slices (400 mm) were pre- pared by the method of Grover and Teyler [6]. Slices were main- tained in an interface chamber at 32°C and perfused with normal medium that contained (in mM): NaCl 125.0, KCl 3.35, NaH 2 PO 4 1.25, MgSO 4 2.0, CaCl 2 2.0, NaHCO 3 25, and glucose 10.0 at pH 7.4. The perfusion medium was bubbled with a 95% O 2 /5% CO 2 gas mixture. Extracellular field potentials (EPSPs or IPSPs) were recorded using glass micropipettes containing 0.9% NaCl, and were amplified (10001), bandpass filtered (1 Hz to 10 KHz), digitized (5 KHz), and stored for later analysis using the Labman system [6]. A bipolar stimulating electrode was used to activate the Schaffer collateral/commissural fibers 2 – 4 mm from