0053] -699‘/“/E30/4203-0223$02.00/O
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`]’HAnMAC0L0(;iCAi. REVIEWS
`Copyright CF?) 1990 by The American Society for Pharmacology and Flxperimental Therapeutics
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`V01-427 N0- 3
`Printed in U. S.A.
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`Antiepileptic Drugs: Pharmacological Mechanisms and
`Clinical Efficacy with Consideration of Promising
`Developmental Stage Compounds
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`‘Neuronal Excitabilitgy Section, Medical Neurology Branch, and 20/‘flee of the Director, National .’n.slit'ute of Neurological Disorders and Stroke,
`National Institutes of Health, Bethesda, Maryland
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`MICHAEL A. ROGAWSKIW AND ROGER J. PORTER”
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`I. Introduction .
`ll. Drugs used primarily in the treatment of partial seizures and generalized tonic~clonic seizures .
`A. Phenytoin .
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`1. Block of voltage-dependent Na+ channels .
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`2." Block of voltage~dependent Ca2+ channels .
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`3. Synaptic actions .
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`4. Special considerations applicable to the epileptic brain .
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`5. Clinical efficacy .
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`B. Other hydantoins and phenacemide .
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`C. Carbamazepine .
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`1. Block of voltage-dependent Na" channels .
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`2. Interaction with adenosine receptors .
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`3. Effects on catecholamine systems .
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`4. Interaction with peripherahtype benzodiazepine receptors .
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`5. Clinical efficacy
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`D. Barbiturates .
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`1. Block of voltage-dependent Ca2+ channels .
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`2. Potentiation of GABA~mediated inhibition .
`3. Relevance of GABAA receptor interactions to anticonvulsant efficacy .
`4. Other effects on voltage~dependent ion channels .
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`5. Block of excitatory transmission .
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`6. Clinical efficacy .
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`. Drugs with a broad spectrum of clinical antiepileptic activity .
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`A. Benzodiazepines
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`1. Potentiation of GABA-mediated inhibition .
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`2. Chronic effects .
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`Nombenzodiazepine receptor mediated actions
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`4. Clinical efficacy .
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`B. Valproate .
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`1. Effects on GABA systems .
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`2. Block of voItage—dependent Na“° channels .
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`3. Toward an understanding of the mechanism of action of valproate .
`4. Clinical efficacy .
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`. Drugs used primarily in the treatment of absence seizures .
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`A. Ethosuximicle .
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`1. Thalamocortical mechanisms in absence epilepsy .
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`2. Block of Twtype voltage—dependent Ca2+ channels .
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`3. Clinical efficacy
`B. Trimethadione
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`C. Phensuximide and methsuximide
`D. Acetazolamide
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`Actavis v. Research Corp. Techs.
`|PR2014—O1126
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`RCT EX. 2014 page 1
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2014 page 1
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`

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`ROGAWSKI AND PORTER
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`A. Drugs whose anticonvulsant profile is similar to phenytoin .
`. Zonisamide .
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`lmidazoles: Denzimol .
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`. Imidazoles: Nafimidone .
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`. Imidazoles: Other arylalkylimidazoles .
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`. Lamotrigine .
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`10. Oxcarbazepine .
`11. Rernacemide .
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`B. Progabide, an agonist of the GABA receptor—Cl“" channel complex .
`C. Drugs which potentiate inhibition by an action that does not involve an interaction with the
`GABA receptor channel complex .
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`1. Vigabatrin .
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`2. Stiripentol .
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`3. Milacemide .
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`4. Taltrimide .
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`5. CL966 .
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`6. Tiagabine .
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`D. Drugs that bind to benzodiazepine receptors .
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`E. Drugs that block excitatory amino acid receptors .
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`. Competitive antagonists of the NMDA recognition site .
`. Noncompetitive antagonists of the NMDA receptor~char1riel complex .
`. MK-801 .
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`'. Alternative strategies for NMDA receptor blockade .
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`F. Drugs with a novel spectrum of anticonvulsant activity .
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`VI. Conclusion .
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`VII. References .
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`
`I. Introduction
`
`Epilepsy is one of the most common afflictions of man.
`With a prevalence of approximately 1%, it is estimated
`that 50 million persons worldwide may have the disorder.
`Although many are well controlled with available thera-
`pies, perhaps one_qua1-tar of the total continue to have
`seizures. Since the introduction of valproate in 1978, no
`new antiepileptic drug has been approved in the United
`States for the primary therapy of epilepsy. Nevertheless,
`there is cause for optimism. A large number of promising
`compounds are currently undergoing preclinical and clin-
`ical evaluation, and several of these will undoubtedly
`
`become meaningful additions to the neurologist’s phar-
`macological armamentarium. Although many of these
`_
`‘
`compounds were discovered by the time—honored ap-
`_
`_
`_
`_
`_
`proach of empmcal drug Screening: the Creatlon of 59””
`‘"31 were based 0“ rational C0Y15id‘31'3fi0nS Of the P3310“
`physiological mechanisms of the epileptic syndromes in
`conjunction with a detailed understanding of central
`excitabillty m9Ch3niSmS and 10giC31 Principles Of drug
`d9Si8'n- In the fut‘-“'9: it can be expected that Such C071“
`siderations will play an even greater role in the process
`of antiepileptic drug development.
`Our purpose in this review is to consider the biological
`
`Actavis v. Research Corp. Techs.
`|PR2014—O1126
`
`RCT EX. 2014 page 2
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2014 page 2
`
`

`
`MECHANISM AND EFFICACY OF ANTll<‘.Pl.LEPTlC IDRUGS
`
`mechanisms of action of currently marketed and devel~
`opmental stage antiepileptic drugs in the context of the
`clinical syndromes they are designed to treat. Since the
`time of Hughlings Jackson more than 100 years ago,
`epileptic seizures have been known to represent “an
`occasional, excessive. . .discharge of nerve tissue. .
`. .”
`(Taylor, 1931). Seizures are divided fundamentally into
`two groups: partial and generalized (Commission on
`Classification and Terminology of the International Lea-
`gue Against Epilepsy, 1981). Partial seizures have clinical
`or EEG evidence of a local onset, but the word partial
`does not imply a highly discrete focus; such a focus often
`does not exist. The abnormal discharge usually arises in
`a portion of one hemisphere and may spread to other
`parts of the brain during a seizure. Generalized seizures,
`however, have no evidence of localized onset; the clinical
`manifestations and abnormal electrical discharge give no
`clue to the locus of onset of the abnormality, if indeed
`such a locus exists (Porter, 1989).
`Partial seizures are divided into three groups: (:1) sim-
`ple partial seizures, (1)) complex partial seizures, and (c)
`partial seizures secondarily generalized. Simple partial
`seizures are associated with preservation of conscious»
`ness and usually with unilateral hemispheric involve-
`ment. Complex partial seizures are associated with alter-
`ation or loss of consciousness and usually with bilateral
`hemispheric involvement. A partial seizure may become
`secondarily generalized, i.e., may progress to a general-
`ized tonic-clonic seizure. if there is no evidence of local-
`ized onset, then the attack is a generalized seizure. The
`generalized seizures include: (a) generalized tonic—clonic
`seizures (grand mal), (b) absence seizures (petit mal), (c)
`myoclonic seizures, (d) atonic seizures,
`(:2) clonic sei«
`zures, and (f) tonic seizures. Although the majority of
`seizures occur without any obvious precipitating factor,
`in some patients seizures are triggered by environmental
`stimuli such as flickering light. Visually evoked seizures
`are not uncommon in humans but are rare in animals.
`
`On the other hand, certain mice and rats are susceptible
`to audiogenic (sound-induced) seizures, whereas true au-
`diogenic seizures (as opposed to music-induced or audi-
`tory startle—induced seizures) do not occur in humans
`(Niedermeyer, 1990). Seizures induced by a specific trig-
`gering factor are referred to as “reflex seizures.”
`Epilepsy, in contradistinction to seizures, is a chronic
`disorder characterized by recurrent seizures (Gastaut,
`1973). The “epilepsies” consist of a variety of diverse
`syndromes characterized by different seizure types, etiol-
`ogies, ages of onset, and EEG features; the classification
`of epileptic syndromes has recently been published
`(Commission on Classification and Terminology of the
`International League Against Epilepsy, 1989). The first
`major division of the epileptic syndromes is the same as
`that for seizures, i.e., into the partial epilepsies or the
`generalized epilepsies. Each of these is further subdivided
`into idiopathic (i.e., cause unknown) or symptomatic
`
`(cause known) and then according to age of onset. When
`possible, specification of a patient’s seizure disorder as a
`particular epileptic syndrome affords prognostic infor-
`mation that neither the seizure diagnosis nor the etiolog-
`ical diagnosis can provide and may assist in the selection
`of appropriate drug therapy.
`In the absence of a specific etiological understanding
`in any of the human seizure disorders, rational ap-
`proaches to drug therapy of epilepsy must necessarily be
`directed at the control of symptoms, i.e., the suppression
`of seizures. Antiepileptic drugs can control either the
`initiation and maintenance of the epileptic discharge or
`its spread within the brain. Recent advances in under-
`standing the cellular mechanisms of epileptogenesis from
`the kindling model suggest that approaches designed to
`interdict development of epilepsy may also be possible.
`Although there are a wide variety of specific molecular
`targets, all anticonvulsant drugs ultimately must exert
`their actions by altering the activity of th.e basic media-
`tors of neuronal excitability: voltage- and neurotrans-
`mitter~gated ion channels. In those cases in which drug
`mechanisms are reasonably well understood, three gen«
`eral themes encompass current views of antiepileptic
`drug action: (a) modulation of voltage-dependent ion
`channels involved in action potential propagation or
`burst generation, (1)) enhancement of GABA'l‘-mediated
`inhibition. and (c) suppression of acidic amino acid-
`mediated excitation. Because our understanding is in-
`complete, it must be recognized that these are not the
`only brain mechanisms by which currently available
`drugs could operate, nor are they the only mechanisms
`that ought to be targeted in the development of new
`drugs. Nevertheless, they do provide a useful framework
`for the classification of antiepileptic drugs and this struc-
`
`tAbbreviations: CNS, central nervous system; NMDA, N-methyl-K»
`aspartate; GABA, ~y-aminobutyric acid; CSF, cerebrospinal fluid; PTP,
`posttetanic potentiation; hm, steady~state inactivation; AMP, adenosine
`monophosphate; GTP, guanosine triphosphate; CDNA, complementary
`deoxyribonucleic acid; GABA~’1‘, GABA-wlretoglutarate transaminase;
`mRNA, messenger ribonucleic acid; THIP, 4,5,6,"/-tetrahydroisoxa
`zolo[/l—c]pyridine-3-ol; EEG, electroencephalogram;
`i.p.,
`intraperito»
`neal; p.o., oral; i.v,, intravenous; s.c., subcutaneous; i.m., intramuscular;
`GABAmide, 7-aminobutyramide; APH or AP.-5. 2~amino—’7—phospho-
`noheptanoic acid; APV or Al-"7, 2—amino-5-phosphonovalcric acid; CPP,
`3—(2—carboxypiperazin-4-yl)—propyl~1—phosphonic acid; PCP, phency—
`c lidine; PCA, 1phenyleyclohexylamine; MK-801, (+)—10,11-dihydro-
`5—methyl«v5H-dibenzo[a,d]cyclohepten—5,lO—imine or dizocilpine;
`ADCI, 5-aminocarbonyl-5H—dibenzo[a,cl]cyclohepten—5.10-irnine; LY2
`01116, 4—amino-N—(2,6~di1nethylphenyl) benzarnide; MM].-’, N-
`monornethoxymethyl-phenobar-bital; U-54494A, (i)—cis—.‘3,4~-dichl0ro—
`N—methyl1N-[2—(1.-pyrrolidinyl)-cyclohexyllbenzamidei: D»19Z"/4, 3-
`({2~amin0—6—[(4~flu1'ophenyl)rnethyllarni1‘1o—3—pyridinyl}2—oxazoli(li—
`none I-lCl); AHR—1‘224.3, 2-(4—chlorophenyl)—3H~imidazo(4,5—b]pyri—
`dlT1e~3~aCetamide; CGS 19755, cis-4-phosphonomethyl-2~piperidine—ca
`rboxylic acid; NFC 2626, Zvamino-4,5-(1,2~cyclohexyl)~”7-phosphono-
`heptanoic acid; D—CPP—ene, 1)-3—(2-carboxypiperazin-4—yl)-1~propenyl-
`1-phosphonic acid; CGP 37849, 2~amino-4—methyl-5—phosphono—3—
`pentenoic acid: CL966, [1-{2-[bis~4-(trifluorornethyl)phenyl]methoxy}
`ethyl] — l ,2,5,6~Letrahydro-- 3-pyridinecarboxylic acid.
`
`Actavis v. Research Corp. Techs.
`|PR2014-01126
`
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`
`226
`
`ROGAWSKI AND PORTER
`
`ture allows the tentative categorization of the develop-
`mental stage compounds in the face of limited informa-
`tion regarding their pharmacological activity. Thus, in
`the following discussion, we often use the currently mar-
`keted drugs as prototypes and base our conclusions con-
`cerning the actions of the developmental stage corn~
`pounds on the presumed mechanisms of the prototypes.
`For each drug considered in this review, we briefly
`describe its anticonvulsant profile in animal seizure
`models because this can often give insight into its cellular
`mechanism of action. A wide variety of animal models
`are used to screen potential antiepileptic drugs (see re-
`views by Reinhard and Reinhard, 1977; Porter et al.,
`1984; Meldrum, 1986; Jobe and Laird, 1987; Lothrnan et
`al., 1988; Kupferberg, 1989a; Fisher, 1989). These include
`spontaneous or reflex models of epilepsy in inbred ani-
`mals, chemically induced seizures, and electrically in-
`. duced seizures. In addition, various models utilize chem-
`icals applied to the surface of the cortex or injected into
`the brain. Finally, the kindling model can be used to
`evaluate antiepileptic drugs. We consider the results of
`-testing with these diverse models when it is available,
`__l=__)ut we particularly focus on the data obtained in the
`maxim'al"'electrosh0ck seizure testand in the pentylene~
`tetrazol test. These two models are widely used, are
`highly reproducible, and provide a basis for comparing
`different chemical entities under relatively we1l-stand-
`ardized conditions. Results in these two models are es-
`
`"
`
`pecially apt to provide preliminary clues as to cellular
`mechanisms of action. The maximal electroshock test
`
`evaluates the ability of drugs to prevent electrically in-
`duced tonic hindlimb extension in mice and rats. Efficacy
`in this model has been shown to correlate with ability to
`prevent partial and generalized tonic-clonic seizures in
`man, and it is often" stated that this model evaluates the
`capacity of a drug to prevent seizure spread. Drugs that
`are active in the maximal electroshock test often have a
`
`phenytoin—like effect on voltage-dependent Na+ channels
`(table 1), although drugs that act specifically to block
`NMDA-type excitatory amino acid receptors or that
`increase synaptic norepinephrine levels (Burley and Fer-
`rendelli, 1984; Przegalinski, 1985) are also effective in
`this test. On the other hand, the pentylenetetrazol test
`as most commonly performed evaluates the ability of
`potential antiepileptic drugs to prevent clonic seizures
`and may correlate with activity against absence seizures;
`there are, however, several drugs that are active in this
`test but are not useful in absence attacks, such as phe-
`nobarbital. Activity in thisseizure model often indicates
`that a drug can affect GABAergic brain systems, either
`by enhancing brain GABA levels or by altering the
`sensitivity of postsynaptic GABA receptors. Specific an-
`tiabsence drugs, such as ethosuximide and trimetha—
`dione, which may act by blocking T—type voltage-depend
`ent Ca2+ channels, are also effective in the pentylenete-
`trazol test. The pentylenetetrazol model also appears to
`
`correlate with ability to retard the development of kin-
`dled seizures (Albertson et al., 1984a; Schmutz et al.,
`1988). (When activity of the drug against pentyelenete—
`trazol-induced tonic seizures is reported, the significance
`is different and is more comparable to the maximal
`electroshock test.)
`Following the discussion of drug activity in animal
`seizure models, we next consider data concerning the
`biochemical and cellular electrophysiological actions of
`the drug that may be relevant
`to its anticonvulsant
`activity in animals and man. Finally, we turn to a dis
`cussion of the clinical efficacy of the drug in human
`seizure disorders.
`
`II. Drugs Used Primarily in the Treatment of
`Partial Seizures and Generalized Tonic-Clonic
`Seizures
`
`A. Phenytoin
`
`The ideal antiepileptic would Prevent seizures without
`producing side effects that adversely affect the patient’s
`quality of life. The discovery of phenytoin (fig. 1) dem-
`onstrated that this ideal was approachable. At normal
`therapeutic serum concentrations of 10-20 pg/ml (40-80
`[.LM), phenytoin protects against seizures without causing
`sedation or otherwise interfering with normal CNS func-
`tion in most patients. In addition to revolutionizing
`epilepsy therapy, the introduction of phenytoin set a
`standard against which to measure potential new antic-
`pileptic agents. Phenytoin was the result of a search by
`Merritt and Putnam (1938) for a nonsedating analog of
`phenobarbital capable of suppressing electroshock-in-
`duced seizures in animals. The -drug has very specific
`effects on the pattern of electroshock seizures in that it
`completely abolishes the tonic phase (usually scored as
`hindlimb extension; ED,-,0, 9.5 mg/kg, i.p., in mice) but
`may enhance or prolong the clonic phase of the seizure
`(Toman et al., 1946; Swinyard et al., 1989). In contrast,
`phenytoin is ineffective against seizures induced by
`chemoconvulsants such as pentylenetetrazol, bicuculline,
`picrotoxin, penicillin, and strychnine (Swinyard et al.,
`1989; see Eadie and Tryer, 1989, for additional refer-
`ences); it is weak in protecting against myoclonic re-
`sponses in photosensitive baboons (Meldrum et al., 1975)
`and generalized seizures in alumina cream-lesioned cats
`(Majkowski et al., 1976); and it has variable effects
`against amygdaloid-kindled seizures in rats (Callaghan
`and Schwark, 1980; McNamara et al., 1989). Phenytoin
`has been shown to limit the propagation of epileptic
`activity from regions of epileptic cortex, even though it
`may actually increase the frequency of spiking in such
`foci (Morrell et al., 1959). As a consequence, it is often
`stated that phenytoin inhibits seizure spread but does
`not stop the initiation of epileptic discharges.
`Phenytoin is known to exert a wide variety of phar-
`macological actions on neurons many of which are com-
`patible with anticonvulsant activity. However, the chal-
`
`Actavis v. Research Corp. Techs.
`|PR2014—O1126
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`

`
`MECHANISM AND EFFICACY OF ANTIEPILEPTIC DRUGS
`
`TABLE 1
`
`Anticonoulsant potencies and proposed cellular mechanisms of action of
`Mouse anticonvulsant screen
`(ms/ks. i-1:-)
`
`Seizure type/
`antiepileptic drug
`
`Voltage-dependent
`N51* channels
`
`ototype antiepileptic drugs*
`'l‘~type voltage-
`dependent Ca“
`channels
`
`GABAK
`receptor
`mechanisms
`
`+ +
`
`7‘
`
`Generalized tonic-clonic
`and partial seizures
`Phenytoin
`Carbamazepine
`Phenobarbital
`Broad spectrum
`Clonazepam
`Diazepam
`Valproate
`Absence seizures
`Ethosuximide
`Trimethadione
`
`No protection
`Potentiation
`13.2
`
`0.18
`0.17
`149
`
`130
`301
`
`92.7
`19.1
`272
`
`>1000
`.
`‘
`
`"‘ Abbreviations: MES, maximal electroshock (tonic) seizure test; I-""l‘Z, pentylenetetrazol (clonic) seizure test; E1350, median effective dose.
`Adapted from Porter et al. (1984) and Swinyard (1989).
`T The metabolite dimethadione was tested.
`
`ceptance, although some investigators have also impli-
`cated effects on voltage~dependent Ca2+ channels. We
`will consider the experimental observations supporting
`the idea that phenytoin is a selective blocker of voltage-
`dependent Na+ and Ca2+ channels. In addition, we will
`briefly consider data regarding the synaptic actions of
`phenytoin, including its ability to block neurally evoked
`excitatory transmitter release and its effects on excita-
`tory amino acid-induced excitation and GABA-mediated
`inhibition. When evaluating any of the diverse pharma-
`cological actions of phenytoin, one must always consider
`the data in light of the actual levels achieved in patients
`adequately treated by the drug. Although the usual ther-
`apeutic serum levels are 40-8O itM, phenytoin is highly
`protein bound so that only about 10% of the total is free
`and available to equilibrate with the CSF (Woodbury,
`1989). Most investigators have considered the CSF levels
`to be a reasonable estimate of the drugconcentration at
`the physiologically relevant acceptor site(s) because they
`are presumed to reflect the level in the extracellular
`compartment of the brain. We will follow this convention
`and focus on drug effects that occur at concentrations
`near the therapeutic CSF levels (approximately 4-8 ;M).
`However, it is of interest to note that the brain concen-
`tration may be substantially higher than the CSF con»
`centration, presumably because of binding to brain pro-
`teins and lipid (Goldberg and Crandall, 1978). Thus, the
`actual brain concentration is one to two times the total
`serum concentration (Wo0dbury, 1989) and the multi-
`tude of drug effects that occur at concentrations near the
`serum levels cannot therefore be discounted completely,
`although the physiologically relevant concentrations are
`presumed to be closer to the free brain concentration
`which is thought to be equivalent to CSF levels.
`1. Block of voltage-dependent Na"' channels. Investiga-
`tions of the cellular actions of phenytoin‘ lagged by more
`than a decade the original accounts by Putnam and
`
`H
`
`_
`
`.
`
`_
`
`NYC
`O o H
`N
`
`I
`
`-
`
`H
`
`NYC
`\
`N
`
`o
`
`PHENYTOIN
`
`MEPHENYTOIN
`
`HZNYQ
`N
`0
`“
`
`H N
`
`Y0
`N
`0 L.
`
`ETHOTOIN
`
`PHENACENIIDE
`
`FIG. 1. Structures of succinamide anticonvulsants and phenacw
`emide.
`
`lenge for researchers has been to explain its relative lack
`of neurological side effects at therapeutic doses. For
`example, in mice, phenytoin’s TD50 (dose at which 50%
`of animals exhibit toxicity) in the rotorod ataxia test is
`66 mg/kg so that its protective index (TD5o/ED50) is 6.9.
`Numerous excellent reviews of phenytoin’s diverse neu-
`ronal actions have appeared (e.g., Yaari et al., 1986;
`Selzer et al., 1988; Eadie and Tryer, 1989; De Lorenzo,
`1989) and the present account will focus on observations
`leading to a molecular understanding of its antiepileptic
`action. In recent years, it has been elegantly demon-
`strated that phenytoin can interact with the voltage-
`dependent Na"“ channels that are responsible for the
`action potential upstroke in a highly specific voltage-
`and frequency~dependent manner. This is the only
`known action of the drug that can easily explain its
`ability to suppress seizures without causing a generalized
`depression of the nervous system. Thus, the theory that
`Na* channel blockade is the mechanism underlying
`phenytoin’s clinical efficacy is gaining widespread ac-
`
`Actavis v. Research Corp. Techs.
`|PR2014—O1126
`
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`
`228
`
`ROGAWSKI AND PORTER
`
`Merritt (1937) of its ability to protect cats from elec~
`troshock-induced seizures (Merritt and Putnam, 1938).
`However, the first such report (Toman, 1949) was strik-
`ingly prescient in foretelling the conclusions of an addi—
`tional 4() years of research. Frog sciatic nerve, when
`stimulated with a suprarnaximal shock, was shown to
`respond with an action potential followed by a second
`“rebound” spike. Phenytoin at near clinically effective
`concentrations (50 nM) prevented the rebound spike
`"’ without altering the initial spike. Thus, phenytoin could
`' produce a selective blockade of high-frequency repetitive
`neuronal firing; the obvious inference was that a similar
`action in the brain accounted for its ability to specifically
`block the spread of seizure discharges characterized by
`high-frequency neuronal activity. The lack of effect on
`the initial spike response was interpreted as reflecting
`the failure of phenytoin to cause a general depression of
`neuronal firing.
`Blockade of PTP, one of the best documented and
`most robust physiological actions of phenytoin, may
`' underlie the_ capacity of the drug to prevent seizure
`spread. "PTP refers to the_ability of high-frequency re-
`petitive synaptic stimulation (tetanus) to transiently en- -
`bance the responsiveness of that pathway to a single
`__stimulus. It has been suggested that PTP may be a
`mechanism that reinforces focal discharges by positive
`feedback and facilitates the spread of high»frequency
`impulses occurring in these foci to synaptically coupled
`cells in distant areas. In several preparations, phenytoin
`at low doses has been shown to prevent the augmentation
`of synaptic responses produced by a tetanizing stimulus
`(Esplin, 1957; Raines and Standaert, 1966; Selzer et al.,
`1985). For example, in the in vitro hippocampal slice
`preparation, PTP can be produced by high-frequency
`(100 Hz, 1~~2 s) stimulation of the Schaffer collateral/
`commissural pathway to CA1 pyramidal cells or by stim~
`ulation of the mossy fiber input to CA3 cells (Griffith
`and Taylor, 1988a). Phenytoin (l0e80 ram) accelerated
`the decay of l"’