Effects of some antiepileptic and proconvulsant drugs on kainic acid-induced limbic epilepsy in cats

1 i

Drug Development Rescarch 4191-200 (1984)

Effects of Slome Antiepiieptic and Proconvulsant Drugs on Kainic AcidshyInduced Limbic Epilepsy in Cats Carlos Cepeda Adriaacuten Martinez Mariacutea Trinidad Pacheco and Marcos Velasco

Division of Neurophysiology National Medical Center IMSS Mexico Ciacutety

ABSTRACT

Cepeda C A Martinez Ma T Pacheco and M Velasco Effects of sorne antiepiacutelepshytic and proconvulsant drugs on kainic acid-induced limbic epilepsy in cats Drug Dev Res 4191-200 19S4

I The effects of parenteral administratiacuteon of diacuteazepam (3 mgkg) DL-C-e1ylglycine (60-S0 mgkg) andketamine (20 mgkg) on kaiacutenic acid (KA)-induced limbic seizures were investshygated in c~middotts Single microinjections of KA (1-4 Ig) into the amygdaloid complex were folowed by local sustained paroxysmal discharges in the limbic system Seizures conshyf

i sisted of ton1c clonic EEG discharges accompanied by orienting-eaction lo Iheipsilateral 1 side of injeqtion and masicatory movements facial jerks and aggressive behaviacuteour Ictal

dischargesoccurred every 5-10 miacuten during the first hours after KA injection nnd then progressively disappeared within 1 wk Interictal discharges remained tar longer periods but after 3 or 4 wk Ihey were abolished Diazepam completely blocked limbic seizures bul I nol high-frequency discharges in he site of injection and the ipsilateral hippocampus The animals were protected far 30 to 60 min At the same time diacuteazepam decreased multipleshyuniacutet activity iacuten the pontine reticular formation and Ihe laleral genicufal8 nucleus and I piacuteOduced a gener21 hypotonia state DL-C-allylglycine activated KA amygdaloid focus lmiddot during the remission state and ketamine produced independent epileptiformiacuteke activity which interfered with tnal produced by KA injectioiexcl

Key words kainic acil limblc seizures antiepileptic and proconvulsart drugs

INTRODUCTION

A mode of Iimbic seizures produced by intr3Cerebral microinjectj--lDS uf kainic aid (KA) has been ncemly dcvcloped r--rinutc amounl~ of this excitatory amino acid imluce liacutembiacutec

Rcceiexclvcd final Hfcion August 11 1983 acceptcd S~p~nlbeacutef 16 1983

Address rcprint rcqucsls to Carlos Cepeda DidsioTI of lcurophysiology Scientilic Restarch Dcpanshyment Nationa ~1cJial CenlCr LMSS bull PO Box 73middot032 1xico City M(~jco 03020 -iacuteS 19amp4 AIm E Lisslne

192 Clpeda 11 al

stams epilcplicus when injecled in Ihe amygdala of mIs [Sen-Mi el al 1979a1 cal s [Velluti el al 1980J and baboons [Meacutenini el aL 1980 Cepeda et al 1982J lt has abo leen dCn1onshystralcd mat inlrahippocampal microinjections of IA proJuce ver loag-Iasting paroxysmal discharges [Schwarcz el aL 1978 Cavalhciro el al 1981 Tanab e aL 1981 Pia el al 1980J Indeed il has been shown ha limbiacutec structures are pirticulariy scnsitivc to KA [Nadler

et aL 1978J Moreover different sites as icll as diffcrcnl routes of adminisration lead to a

common histopathology iexcle dcstruction of pyramidal cel in the hippocampu 11 has been sJggestelti by sorne authors thal thi~ eommon finding ma) he dlle tu cpileptiform aClivity ami not by oacuteffusion of me toxiacuten In faet Ben-Ari el al [19790J dCiTIOiexclSlrated thJiexcl diazepam redae hippocampal daneacutege when KA is injected in the eacuteimygdala Thc faet lhat KA eacutelCt~ preferenlially on limbiacutee struetures makes the KA model a suitablc instrllmellt for the study of a-iexclepileptic and procon1l1~ant drugs

~lany pharmacological stlldies have heen reported utilizingmiddot kindliacuteng as a model of (tTpo~al Job epiepsy [rbertson et al 1980 Albright and Bumham 1980 Bowycr and Wint~r~ 1981 Albright 1983J However the faet that eleetrical stimtlatiacuteon of lhe amygdala Ieads ir mcst ca5e~ 10 secondarily generalized seiwres makes (he interpretation of somc results difficuIt K-induced 5eizures are very reslricted lO limbic struetures alld or) rarely do the) generaize In Papio papio baboons only ver) high doses of KA produce cpikplic dischargcs in iexclhe cerebral eonex In ealS the propagati0n is more important but generalizeJ scizures are ver nre In eonsquence pharmacologicaI studies ith kainalc-imluceu scizurcs lcad 10

reliabk results iexcliexcl pnsent only fw studies have bcen devQtcd tl tIe pharmacobgy of K-ilidJc~d

liacutembic scizure5 Fuller and Olney [1979J fpund tha morphine enhaliexcl-e the ncurotoxkiry of KA In contrasl as Ve llave seen diazeparn reduces this toxic effect On (he other hand lhe wOiacutek of Fariello e aL [1982) demonstrated that homotaurine a synthciic GABA aniexcllog protected from Ihe convulsant effeel of systemically administercd KA Finally Zaclek el al (1978) testcd ~he effects of sorne anesthetics and antiepileptie drugs on intrahippocampal KA and fourid tht the attenuated the neuroLOxic effects of kainate Neverthcless a systcmatic study on theevolution of paroxysmal dischargcs and lhe effects of antiepiacuteleptic Oiacute procoilvulshysam dmgs in KA-induced epilepsy iacuteniexclats has no becn done The prescm Vork attempts to maacuteke such a study and to p~sent sorne prcliminary results on the iexclffccts of some drugs 011

K--iacutenduced limbiacutec seizures

METHODS

Surgical Procedures and Electrical Recordings

Cats of either sexo with a weight beween 25 and 35 kg ere uscd inthiacutes stuay UmJcr nembutal anegtthesia a cannula guidc was implaiexcltcd into iexclhc temporal iexclohe Vitil the ip 1 mm abo iexclhe basolttewl nucleus of the amygciexcliexclll (A = ns L = OO H - 50) Bipolar concemric staiacuterJess ~eel elcctrodcs wer( al~o implancJ in lhe entral hippocampus ]teral geiexcllIacuteulate nuclcus and pomine relicubr fOlllJion Concntioaal EEG reco~Jiiexcliexclgs from all thes ]oeiacute were compknented wth multiacutepc unit ac[iity (~1lA) intcgratiacuteon of ronrine reticular fOm1ition and lfte~al geniacutecuIatc nuumlccus Thi~ indiCHcd to liS lh( dgree of uCiexcliexclaliol1 of iexclhese Siexclf1Juures In addiacutetion stainlcss se] scrcs sercd 10 record iexclhe EEG of frontal and visu eortices ~eck muci~ actiity and ocular movemcnts c~e also rccordcJ D~tlIacutels of the tehniacuteque have been gien clsewhere [sec Vclasco et I 1(75)

lnection oIacute KA

One week af1er [h operaion mc anioJ u piexclcj in hed holder whiLh pcrmined panless fixaliacutean of teacute hcad to the stcrcluxic Iacutelstmm~middotn Once the cat was r~rtia][y irnmobishyliacutezd and Jda)tcd to iexclhiacutes condiion lile injecliacuteon aiexcluiexcl w int~oduumlccd through lhe guidc and pla~d iriexcl lhe desired positioa Thc caniexclula s UlIlTJcciexcle(~ 10 a Hamilton syringc of 5 iexcltI This -

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Urugs and Kainale Limbic EpilcpiY 193

syringe was fixed in a Harvard pump which allowed injection slowl) and at a constant rateo KA was dissolved in phosphite buffer adjusted ro pH 7A (the concentration was of 1 mgml) The dose injected varied between I and 4 Jll Infusion rate was of 1 Jll5 mino After the injection of 1JlI the EEG was observed for the appearance of abnormal activity at the si te of injection If noparoxysmal discharges werc obtaincd within 30 min a second injection was pcrforrned

Pharmacological Manipulation

Diazepam (3 mgkg) was s)stematically used as the anticpileptic drug of choice Ve 21so tested the effeets of two so-called proconvulsant drugs DL-C-allylglycine (60-RO mgkg) and ketamine (20 mgkg) Diazepam and ketamine were inramuscularly and allylglycine intraveshynously injected Diazepam was tested within the 48 hr foll~wing KA injection since it is during this period when ictal discharges were more evident Proconvulsant drug~ were applied afier this periodo Only a few times they were used sooner vhen the foells was not very active One drug was used per animal

Afier the completion onhe experiment the animals were sacrificed with a lethal dos e of anesthetic and the braios were perfused with 10 forrnaldehyde Tissue sections were stained with cresyl violet in ordcr to determine the si te of injection and e1cctrode placemeht

RESULTS

Evolu~ion o Faroxysmal Discharges

EEG abnormalities became apparent from 5 to 20 min afier the end of KA injection The EEG of the amygdala initially showed sustained high-frequency rhythms that finall) ed toparox)smal discharges Figure I illustrates the proressive appeannce of epilcptic activity at different times after the injection It must be noted that propagation of paroxysmJ1 discharges tuuml the cortex is minimal Nevertheless this propagation may become more important the followjlg day During the first hours ictal discharges recurrcd every 5-10 mir This frequency slowlydeclined throughout the second and subseguent days One week after KA injectioll only isolated EEG spikes were observable in the amygdala and tl-iexcle hippocampus Finally afier 3 or 4 ~vk parox)smal discharges disappearcd completely -~

Clinically the onset of amygdaloid seizures in cats was characterized by an orienting reaction ipsilaterai to the injected side followed by exploratory behaviour At the end of the seizure sorne mastiacutecarory movements and ipsilatcral jerks of the face wcre present Intcrictal discharges were never accompanied by myoclonus There was a chan~e in the hehaviour of the animals during the period of ictal discharges in general they beca me irritable throughout the duratiacuteon of the epileptic state Some animals even attacked during seizures- On the other

hand feeding behaviour was redllced or abolished for so me days Hippocampal discharges shocd an evolutio similar to that of ~he amygdaloid (loes

The lateral geniculate nucleus was libo irvolvcd in the pmpagatioil of limhic dischargeso In many ca5es wc haOe seen propagation to cortical regionso 1everthelcss this involvement never produced secondarily generalized discharges This contraslS with the effects of KA in me amygdala of rats Finally propagation to the ponline rcticllbr formation was rarely observed

Effect 01 Diazeam on Paroxysmal Discharges

When di3Z~pJll (3 mgkgl as injecteJ 2-6 hr after KA injeclion ictal discharges disappcared wi~iexclr 5-10 mino evcrtheicss thc EEG of limbic structurcs was not normaL showing highmiddotir-ciexcluency EEG activity instead of paroxysmal discharges (see Fig 2) The animals were pWiltcted against soizures for about 30 ro 60 min then paroxysmal discharges progressively reapxarcd At first they were only abortive limbic seizures but thcreafter they -beca me ogarized in well-dccloped seizures as seen befo re the benzodiazepine iojection With

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-Diazcpam blocks cpilcplic seiztlrcs iacutenduecd byKA The proleclion is no long-lasting (bctween 30 10 60 min) NoteFig 2 Ihar tonicmiddotclonic discharges are rcplaccd by highmiddotfrcquency EEG aClivity in the hippocampus lntegrnted MUA of iexclhe lateral fj

gcniacuteculale nucleus is greally reduced and iexclhe cleclromyogram is hypatonie The uppcr par of (he figure soows a limbic

ciacutenlre recordcd sOllle time aftcr KA injccion (control) The bOllam iexclIlustrares Ihe effecIS of diazcpam on lilllbic ictal

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196 Cepeda el al

fcSpect to intericral dischargcs these mighl disappear or al least De reduced in amplitude Imegrated ICA of iexclhe laleral geniculate nucleus md the pOnine reticular formation decreased arrer the injectiacuteon of diazepam This decremenl in MUA was concomitant with muscular hypotonia The EEG ofthe frontal cortex showed slow vaves inlermingled Wilh slcep spindles

Effects of DL-C-Allylglycine

Three days afler KA limbic seizures become infrequent and may dis ppear conJletely If al this period a medium dose of allylglycinc (60 mgkgl an inhibitor of the synthesis of GBA was injecled limbic seiacutezurcs coule rcappear after 60-90 miacuten These seiacutezures were e1ectroencephalographically similar to those seen a[iexcler KA but they were more severe with Lnportant motor components With higher doses (80-120 mgtkg) generalized seizures were inducedGeneralized discharges appear to he dissocialed from limbic seizures since both might ocur independently For example aacute limbic seizure could follow gencralized discharges Allylglycine did not necessariY increase the frequency of iexclmerielal limbic discharges but sometimes their amplitude and propagation was allgmented (Fig 3)

Effects of Ketamine

Thi ane5thetic injected 1 or 2 clays after KA did not augmcnt the number of ictal or

iacutenterictal dicharges Paroxysmallike activity might be setn on iexclhe EEG of cortical and subcortical slruetures but a seleclive effeet on limbic dicharges was no seen Moreover this aacutectivit) blockcd amygdaloid discharges (see Fig 4) In Ihat sense it might be said th1 ktamine at ansLJetic doses showed antiepileptic propenies on limbic EEG discharges

DISCUSSION

We describeacute in this article the evolUlion of paroxysIlJ discharges induccd by imraam~gshydaloid jnjection of KA in cats Many authors have proposed thal KA-induced limbic epilepsy iigt a gO--d model for the study ofemporallobc epilcpsy [~adkr 1981j Ve have corroboratcd LCiexclC adVantages of this mdel for eacutelectrophysiological and phamlJcological stlldies Ve showcd that for small doses of J(A (1-4 ~g) Ihe severity of limbic sciiacutetres is more important during e first 24 hr Epileptic fits progressively disappear anel are replaced by interictal spikes Thc eacutesappearane o interictal spikes takes place more sloly aud i complete afiexcler 4 wk This eolution of paroxsmcJ discharglts i (ery similar to thal reported in Papio pario baboons [eL Cepeda et al 19821

The disapP~arance of epileptifqrm activity at the foeus may be explained by cclllliar cath calls~d by the toxic effects ol KA However the existnce of an active inhibitory mecharism can not be ruled out In fpct the le5ion produced by KA does not imolve all the alllygdaloid complexo Thus il may Ibe suspectcd that perilesioml neuroni are p1rticularly s-ensitive 10 proonlJsant drugs Indded we have dCmOnSIrltHed thal il i possibl~ to reactivate

f 211 apparently extinguished limbic focus by systemic injection of t3-carboline a benzodiazepine antagonist [Cepeda et al 1981J DL-C-allyiglycinc is capable of reactivating an amygdaloid focus However the effeet is less specific lhan for iexcl3-carboline since with the former iexclhe excimbilityof man) brain structurcs is alttred Diazepam has demonstralcd its effieacy for inhibiting the spread of epileptic activily from the amygdaloid focu~ This is in agreelllenl ilh Dan) inve~ti~atoiacuteS levertheless iexclhe protcctivc efkct with the dosc we uscd Vas not long- l5tin Thi~ cont~ts Wil iexcloe effiexclts of di bull lZcpml on foc motor SiZUreacuteS iacute1duclu by 2uninJ criexcliexclm fVelasco aL 1977] in which th~ prolltction obrainec1 is much loner Our re~ult s-eems to cuumlnfirm iexclhe finding of Albrighl and Burnham [1980J who demonSlrated tha amiconshyvulsam drus SUiexclPI~S more easily cortical lhan amygdaoid foa discharges Wilh respccl to ketamine we f2iacuteled lO replicate iexclhe proconvulsanl efkcls of iexclhis drug found hy sccrt1 -i1estigatos [Wimers 1972 Ferrer-Allado el aL 1973) In [ael we fOllrd a blokade of lL-nbic pJ~O(ysii1 di~chargLS Thi~ agrees with Ihc rcport of Arfel et al [19761 wha

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fig 4 KcllIlIinc WIS injlctcd IR hr allcr KA injcctioll (2 J-lg) Thc foacutecus was not very active hUI showcu isolalcd spikcs anu shor1middotlasting scizures The druumlg injcclcll dicl not facililatc amygdaloid scizurcs nor intcrcital di~charges Inslcad il rroclllccd epilcpriforlll acriviry in lhe COrlcx (visual corlcx in this case) and lhe all1ygdala (R Am) whieh blocked lhlf inUIlCCU by KA iniCCljon

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I Drugs and Kainate Limbic Epilepsy 199I

I demonstrated a dominant depressant effect of ketamine -onparoxysmal discharges iacutenduced

I through air emboli in Papio papio baboons Jt is interesting that recently Bovyer and Winters [1981] showed that ketamine inhibits amygdaloid kindled seizures al anesthetic doses

I The obseratiacuteon of profound alterations in the behaviour of the anlmals is worth

stressing As we han~ seen during the epileptie state the cats become irritable snd aggressive In contrasto in Papio papio baboons the epileptic state is aecompanied by a marked dccrease of

I aggressiveness [~iquestruumlniacute et al 1980 Cepeda et al 1982J This difference is hard to explain It is possiacuteblc th1t mere exist functional differenees among amygdaloid nucelor that the same

I nucJeus may hase different functions in cats and in Papio papia We can also consider that sl~p disturbances induced by the epileptie state affect both species in a distinct manner In any case this discrepanc) obliges us 10 be more careful ifwe want to generalize our results ievertheess many other behavioural changes during the epileptic statc are similar in different animal species chis is troe for fceding behaviour for the release of exploratory bchaviour during the seizure ror the existence of oral aUlomatisms md so on

A last poim merits Ouf attentioll It iacutes the faet of iexclhe absenee of propagation of cpileptic actiity lO the pomiacutene reticular formatiacuteon This observatiacuteon is in accordance Vith Trcmblay et al [19831 who found that this structure though rcceiving massive projections fmm the amygdala d()s root inerease its rate of glucose eonsumptiacuteon after intraamygdaloid KA This

j i fiding may haC~ important implications in Ihe eomprchensiacuteon of slcep-epilcpsy intcractions arJ in the remission of limbic seizurcsI

--1 ACKNOWLEDGMiNTS

I The authors want to express thciacuter gratiacutetude to Mr Humbcrto Rangel for his expert ttchnieal assistnce

j

1 REFER~NCES

1 Aibemon TEbull Peiexclerson SL andSIark LO Anliconvulsanl drugs and Iheir anlagonism of kindlcd

amygdiexclJo ceiztres-ln rats Neuropharmacology 19643-652 130 Altright P_S Efecls of carbamazepiacutene clo~azepam and phenyloin on seiacutezure Ihreshold in amygdala

and conexo Exo leurol 79lIacute-17 1983~ ~brihl PS B~rrLla~ VM Devclopmeflt of a new pharmacological seizure model Effects of

- anticon1lsam5 on cortical- and amygdala-kindJed seizurs in Ihc rato Epilepsia 21 6SI-6S9 1980

Anel G bull Lavardiquestgt M de PomTIJery J de and Pommcry H de AClion de la kelamine $ur le~ deacutecharge5 p~r0xysliques provoqueacutees par embolie aeacuterique chez le babouiacuten papio-papio Ekclrreiexclshycephalor Ciexcl~ Neuroiexclihysiol 41357-366 1976

Sen-Ari Y lr~mtgtay E and Oltersen OP Leacute~ion5 ceacutereacutebrales primaircs el secondlIacuten produilcs par des iecuumlols (iexclacide kainiacuteque che tI raL CR Acad Seiacute rD) (Pariacutes) 288middotQ()iexcl-994 1979a

B~n-Ari Y Treoacutelay E bull Ouersen OP and Nlaquoqucl R Evidcnce suggesJng ~ccondary cpilcpfogcnic leio ~iexcl kainic acid Prclreatment with diazcpam rcduc~s distant huI nOI 10(al hrain dama Brain Re i65362-365 1979b

Boer JF iexclJ ViDrcrs VO The effccls of various ancstncliacutecs 00 iexcliexclmygd~loid kindlcd scizurcs NeuropbrD~coogy 20199-209 1981

Czalhciro E Ri~hc D and Le Gal La Salic G Long-Ierm cffce of intra-hirpocampal kainic acid 1 jI ra A mClhod lor iacutenducing sponlnneous reCurnm cilllrc~ EIelroencphalogr

Cq)~da C Tiexcluacute T Bc~li~Yr~ R_ Porcr P 0UQU1 Rbullmd Rbiacuter J Pw(on ulsan CfCL

in bgtv)- ( 3-carb01ne a pntic ciexcluacutecnou ligand for bcn7odiazcpinc rceplor NeurosCIacute Len 2-453-57 19S1

Ccpeda c T2~iexcl2 T Riche D aod qucl R Limbie ~aIUS cpilepliacutecus anel sleep altcralion after iacutemra-2m gjiquestjoid kaiacutenic acidmicroinjeciacuteons in p3pio papio haboon~ Elcctroencephalogr Clio -t-eurorlioL 53603-613 1982

J

1

200 Cepeda el al

Fariello RG Golden GT ad Pisa M Homotaurine (3-aminopropanesulfonic aCld 3 APSj prOhCl~ from iexclhe convuls3nt ad cytotoxiacutec effee of syslcmically adminislcred kainic acid Ncurology i (11 322-11-245 19S~ iexclFerrer-AlIadiexcliexcl Th Brechncr VL Dymond A Cozen H and Crandall P Ketamiacutene-indueed electroconvulsive phenomcna in iexclhe human liacutembic and thalamic regions Ancslhesiology 38333shy3-1-1 1973

Fuller TA and Oloey JW lorphinc cnhances and diazepam suppresses the neurotoxiacutecity of s)stemically admiacutenisiexclereJ kaiacutenic acid So Icurosci Absiexclr 556 1979

Meacutenini eh 11eldrum B S Riche D Sihmiddota-Carnte C and Sutzmann JM Sustaiacuteicd Iimhic seizures induced by iacutentr3middotiexclmygdaloid Lililiacutec acid in the bahaon Symp10matology and ncurologishycal consequcnces Ano euroi 8501-509 1980

Nadler Jv Kaiacutenic acioacute as a tool for the study of temporal lobe epilepsy Life Sci 292031-20-12 198 t

adler J Perro B and Cotman c Intravcntricular kainic acid preferentjally destroys J hippocampal pyrariexcldl cells ature 271676-6771978 iexcl

Pisa M Sanberg PR Cororan ME and Fibiger HC Spontaneous recurrem scizures afteri imracerebral iacutenjectiofS oi kaioic acid io rat A possible model of human temporal lobe epilep~) Brain Res 200-ISI-iexclS7 1980

Schwarez R bczek R aid Coyle JT Miacuteeroinjection of kainie aeid into iexclhe mt hippocarniexclms Eur j Pharmiexcl~ol 5009-120 1978

ITan3ka T Kaiiacuteiacutema gt1 Diacutetiexcl G Ohfami 1 Yanemasu Y and Riche D Electrottillical fciexcltures t of kaini~ acid indJcl status cpileptiacutecus in freel) moving cats Microinjcction to Ihe dorsal

hippocampus Eletflncephalogr Clin Jeuroph)siol 54288-3001982 Trcmbll E Oil~r~en O Rovira C and BenmiddotAri Y Intramiddotamygdaloid injectiacuteons (lf kainiacutec iacutecid

Regional mctiboliacutec c~anges and iexclheir rdmian to iexclhe pathological altcrallOns Neuroscience 8299shy315 1983

Velasco F Vcbsco 1 Eiexclr~da-Villanucva F and Machado JP Specific and nonmiddotspccific multiple uni a~timiddotity during the ooset of pcntyknctetrazol scizures L lnlct animals Epilepsia 6207shy21~1915 bull

Veseo 1 Iasco F Cepeda C and Anda AM de Effect of diazepam on pyramidal and ekctromograiexcl-~ic r-Jltiplc unit activitiacutees of calgt with chroniacutec epileptogcnic fociacute Neurophalillashycology 6299-301 1977

Velluti JC Diacutemov S ~aquet-R and Riche D lntra-amygdaloiacuted Iainiacutec acid iacutenjection in iexclhe cat Ele-trnc1iacutenical nd neuropaiexclhological conscquences Neurosci Len (Suacuteppl) 5331 1980

Wiacutenters WD Epilepgty or anesiexclhesia with kelamiacutene Aneslhesiacuteology 36309-312 1972 Zacz~k R lebon iacuteF ~1d Coyle JT Effccts oC anesthetics and ulticol1vulsarlls on iexclhe actIacuteon of

kaini~ acid in the ro hippocampus Euf J Pharmacol 52313-327 1978

-

J

192 Clpeda 11 al

stams epilcplicus when injecled in Ihe amygdala of mIs [Sen-Mi el al 1979a1 cal s [Velluti el al 1980J and baboons [Meacutenini el aL 1980 Cepeda et al 1982J lt has abo leen dCn1onshystralcd mat inlrahippocampal microinjections of IA proJuce ver loag-Iasting paroxysmal discharges [Schwarcz el aL 1978 Cavalhciro el al 1981 Tanab e aL 1981 Pia el al 1980J Indeed il has been shown ha limbiacutec structures are pirticulariy scnsitivc to KA [Nadler

et aL 1978J Moreover different sites as icll as diffcrcnl routes of adminisration lead to a

common histopathology iexcle dcstruction of pyramidal cel in the hippocampu 11 has been sJggestelti by sorne authors thal thi~ eommon finding ma) he dlle tu cpileptiform aClivity ami not by oacuteffusion of me toxiacuten In faet Ben-Ari el al [19790J dCiTIOiexclSlrated thJiexcl diazepam redae hippocampal daneacutege when KA is injected in the eacuteimygdala Thc faet lhat KA eacutelCt~ preferenlially on limbiacutee struetures makes the KA model a suitablc instrllmellt for the study of a-iexclepileptic and procon1l1~ant drugs

~lany pharmacological stlldies have heen reported utilizingmiddot kindliacuteng as a model of (tTpo~al Job epiepsy [rbertson et al 1980 Albright and Bumham 1980 Bowycr and Wint~r~ 1981 Albright 1983J However the faet that eleetrical stimtlatiacuteon of lhe amygdala Ieads ir mcst ca5e~ 10 secondarily generalized seiwres makes (he interpretation of somc results difficuIt K-induced 5eizures are very reslricted lO limbic struetures alld or) rarely do the) generaize In Papio papio baboons only ver) high doses of KA produce cpikplic dischargcs in iexclhe cerebral eonex In ealS the propagati0n is more important but generalizeJ scizures are ver nre In eonsquence pharmacologicaI studies ith kainalc-imluceu scizurcs lcad 10

reliabk results iexcliexcl pnsent only fw studies have bcen devQtcd tl tIe pharmacobgy of K-ilidJc~d

liacutembic scizure5 Fuller and Olney [1979J fpund tha morphine enhaliexcl-e the ncurotoxkiry of KA In contrasl as Ve llave seen diazeparn reduces this toxic effect On (he other hand lhe wOiacutek of Fariello e aL [1982) demonstrated that homotaurine a synthciic GABA aniexcllog protected from Ihe convulsant effeel of systemically administercd KA Finally Zaclek el al (1978) testcd ~he effects of sorne anesthetics and antiepileptie drugs on intrahippocampal KA and fourid tht the attenuated the neuroLOxic effects of kainate Neverthcless a systcmatic study on theevolution of paroxysmal dischargcs and lhe effects of antiepiacuteleptic Oiacute procoilvulshysam dmgs in KA-induced epilepsy iacuteniexclats has no becn done The prescm Vork attempts to maacuteke such a study and to p~sent sorne prcliminary results on the iexclffccts of some drugs 011

K--iacutenduced limbiacutec seizures

METHODS

Surgical Procedures and Electrical Recordings

Cats of either sexo with a weight beween 25 and 35 kg ere uscd inthiacutes stuay UmJcr nembutal anegtthesia a cannula guidc was implaiexcltcd into iexclhc temporal iexclohe Vitil the ip 1 mm abo iexclhe basolttewl nucleus of the amygciexcliexclll (A = ns L = OO H - 50) Bipolar concemric staiacuterJess ~eel elcctrodcs wer( al~o implancJ in lhe entral hippocampus ]teral geiexcllIacuteulate nuclcus and pomine relicubr fOlllJion Concntioaal EEG reco~Jiiexcliexclgs from all thes ]oeiacute were compknented wth multiacutepc unit ac[iity (~1lA) intcgratiacuteon of ronrine reticular fOm1ition and lfte~al geniacutecuIatc nuumlccus Thi~ indiCHcd to liS lh( dgree of uCiexcliexclaliol1 of iexclhese Siexclf1Juures In addiacutetion stainlcss se] scrcs sercd 10 record iexclhe EEG of frontal and visu eortices ~eck muci~ actiity and ocular movemcnts c~e also rccordcJ D~tlIacutels of the tehniacuteque have been gien clsewhere [sec Vclasco et I 1(75)

lnection oIacute KA

One week af1er [h operaion mc anioJ u piexclcj in hed holder whiLh pcrmined panless fixaliacutean of teacute hcad to the stcrcluxic Iacutelstmm~middotn Once the cat was r~rtia][y irnmobishyliacutezd and Jda)tcd to iexclhiacutes condiion lile injecliacuteon aiexcluiexcl w int~oduumlccd through lhe guidc and pla~d iriexcl lhe desired positioa Thc caniexclula s UlIlTJcciexcle(~ 10 a Hamilton syringc of 5 iexcltI This -

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Effects of Ketamine



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Effects of Ketamine



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Effects of some antiepileptic and proconvulsant drugs on kainic acid-induced limbic epilepsy in cats

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Transcript of Effects of some antiepileptic and proconvulsant drugs on kainic acid-induced limbic epilepsy in cats