Effects of some psychoactive drugs of electroencephalogram and brain amines of immature rabbits

Lite Sciences Vol. d, pp" iS9S-1349, 1986. Pergamon Preen Ltd. Printed in Great Britain.

~ld~ DDIII ~a Q ~l~ K>m!a d.s. leeiddr, 1. Seiaadpait d S,Z. ~ Sal,eeie8 Kata Daeaaaui 3orpital, Aai~e ~, ~{""~ " ~ b11r01

(Received a9 Jamary 1986; in ünal farm S May 1986) D~rse ~ eeerre d a~aa3aealr desi~ed te iawrl3Datt iae darala~seeß d tle

(~) d

d~

aadaes is ~ rebbity w iad tY ePP~~ to r0a~ tee dtiaaer d rar pgeeotropdr d:edr as teeea tasteau. ~ at al. (1) AreeraSaei tY Raereare d aoaupdarpreir d raaw0ada ia i5e 1a+eS: d awrbaea d adelt rd d ~aiaaa Pdire b d ]6 ieers at0ae tàe d JD-r]b (pir~l-dra~ap'1-i~easiaei .

d ]d a!/h

Ste Dersae4ap iasrea~ as boßi

aaire ia tte awbora rat wau tee wr ar te... ooeaa~rsaS in th~ rdait alti~eetl tee abrsiata alavatiaar ia tee Zdd wau L~. L tee piaaa pds, reLtirak aeau ~dralapad at ü:th ttias tee rat, teaee ia~ataer tarrd tese tie rlrar in ardaer wau egeel bFi aa aa abralsta d paa~uaalap "ada d oassldad teat tee arehora rat d lw eapeeit7 to rtere soae-~ aedaer teea tbe adeli,

aeoe obreauatS+aer t~re r~r e~+""+""~ ießeraat iaaeree .w auraapdr (!) sod soaeaaise addare iaeimton iSÎ d e tbeaupentioal~l to iataatr, adolareeatr d oü7drw .

ir i$) re dna b dalt aaiaaL

eelaa~praaasiae i. wll taoen !as itr abdlitt to ~loet er s~narre ~~ ~ iadroad t7

di :L~aa c5i +r wll r ~

(b), eaeriae (b), a~eetaedae ;(7) d ap3a~ersae (A), - b tte adelt rabbitr, 1.0 aD/lq ot eileapa~aeasiae w. aiteetire L

tle aLsf~

i~ sadaeed ~ 5.0 ~ d a~.Pe ta>d~e, oaepleta el~t d t~e p.sa1999

i33d

EFFECTS OF SOME PSYCHOACTIVE D8UG8

Vol. 4, No. 13

iadaaad ~ al~>~ wa prodreed ~ T a~/lq ellaFreaaaine (9) .

L all

tiae irtasna tia ei>~aaadr wa ad daLterad istra~oaay.

Swr La7aad alidaa rabbüa,

~m ba~ed m ralaed

ü aar laberatea~, wsa

~aad !er tüa ~~. O~aadeal ana>,sia a! i~ iasis aaa ~erlaraed ea aaiaaL oitaiaad ia ~

n

dqa arisn' :~

m a!

te adaltieod . Tbe

aedaala ~ 1~1Ld ~ deoapdtatiea, tbe bsalaa rapid>, reaeted di+ei+ded iate tyrae partat

m ~leiaa

m

ieedapieaw (eeartee:, eadate aaeLi, pataaen

m 1g2etbaLri, aitbraia m ~da17.a oil~e~a~a)s m oeri1~e11~.

~a), ba~ais ~ (tba7a>tea

T~=~+ . eer~ata 4adrüedaas

pei d tisn. tins Dra3a äddau aaa rioses aepar te]f en ael~e .arboa ai.~iee. ?ie iraia eaatearta e! aorepdaepiriae aad eesytooia ~ detersi~d an i3e aoe wple after haaodeaisation and batanol estraotian (lA). Yerapdaapbsiae nu aeaaared ~ tbe

teeboigw (11)

aad aeretoada ~ aatita llureaseeee ia etrwd ~dsoohlaa~Lo aeid (12). Y~ ß1ee. aotwda w aeiaa~ed tlr oaaeeatratieaa es tLa bieieais adra Sa tarioaa braia far~a beti ia eeeßrel

a oeatraL is a133 ea 3A~y a7d dsa~ atadi .ea m nbae~sestl~ k aere

m ~reated

saDbiEa .

~e neae

relbdta !~ wre cbtaiasd paier

~ tar

sa lellon :

in aar litter oi

6 r~bdt. l0 dqs es ap, Z wre vaed sa eeoctroL . iaeh .a! tLe otDer $ aaiaala raeei~ed k iatrapeariteaaal injeotieaa o! trauu~.leZpsaalae (2 ad/!q) at 2-boar iat~errala

m naa

asr!lieed Z ioare alDer tie last igjeetim.

L aaetber litter e! 6 aoiaala aLo aeettreL

m eaeh

dqa old, t wre apin ~ a,

d tbe etiar k reeei~ad 2 iatraperitaaaal iajeotims o!

s+aaeapiae (2 ad/b~) ~ boara apart aaat i~1..tiea.

lo

m wa

aaorüi+eed

h

bdo:. after the

Vol . 4, No. 13

EFFECTS OF SOME PSYCHOACTNE DRUGS

1335

SLleer aleetredea ~ L4Lded sirad+eal7,~ ia !k sa~lYaes alidae raibdte aesee~is~ te tie a.liaa ~~ d~ ~ leta~eraa .A al. (7,~) d a ietal d ],!k ~ reeaeL wse etit~dsed.

baselisp âw tia !lrsd.

d eaai~ital araaa wea sde ~ a paaried !l~ea 1 t. !~ ~ d ap w as 8-aèaaeal ~are III D istltiaee d

L oslee to ssL wt tia atits7.t w tàe ~, tia istesd~ d aeise d

lighi is tie reoeei3tg ra~ .t~ btt to a adaia~. ~adaali ww plased .w tis lat d o aadatast !ee aattsart d taraLi. Zie aaaiatd d acted eiaagea is tie asisal~a tietariee te iater~dsa tis dt. d eeraioas~eaaa aad to raL d psaaliL rwrat artilaeta dLi adsi~

w istsar~eeted

y laala taTea . DarSai tie raear~iag peried arttratiwal eiopa iaa~=+±

lirat atpearasaa~a e! aLep d tablalsaaa tore a tad d tie aieatasawa ioae e! eil~reas:d n.d te di eert3aal ~i aleelia~ te td atiaeli wa istss~d. Or adrl !!rw eaei litter a tsd aa a drel

das reeeiria~

tio di . >i additiss, eeatrel ~ reaeela wea eitaisad w eari ralbit

~T p~a ~ ds Wdddti~ hL atiwli wre peodased b ~Lsisg tie rlgit :dsd leot as tie adsal is d wtse (55~5db) !ee a ~es~ied el 5 aaada. Chlee~ewaaisa ~ äaaelrad ia äatill ed wtar at a eessastratien e! lA sg/1 sl d addatersd aaiaataaaoea>T is ~eaasea itsa 5.0 te ~9,0 sg/~, i~es larger deaea wre divs, tis it jeetiwa wre d is dirided ieaea. tolleaisg ~ adaddatratiw tbe ~wsg asisala wee retarsed te a earr~ieg d ad ioRt taes ~ a wsll. Lat . ~ ister~al ss 30 to 60 adsatea olaaped ietwes

d tis Brsg d tie e~peri~

wd ~ roea~Qiag. Zo reL d eiresia efleeta d eilsepeaaaaiaa, 3 t. 5 dqa eLpaed iettioes rateated ea:er3aasta aa tie asse aaiaal . L oadsr to sa~pare tis doaaps o! eilertra~3se re~ait~d te traeerd pds-daaaaod ~f1 alaeti~eg is 3aatsre rabbits ,dth tioae regetrw !ae tr ,adalt, k pilot esperisamts ~:r periorsed w greaa. raèbita giraa aajei. taeeoea isjeetiaes e! tiat dg" ?ieae astsro atisaL wre

1~8

EFFECTB OF 80~ PSYCSOACTIVS D~tII(lB

Vol. ~, No. 18

>etar atier ad lwal pon~ar areiieeiy "ar"rised d .*t~r+ .+_i swplsyd pa~iee te ßie

d da7p. Cartiwl esd wisearC3+sa1

elrstrodaa ~~ iapla~wd 3a tie sataaiam oaa~aa: (lbtaa") r a+~ialar oar~ ~ ear~ ili~)r üpposa~~ r ~~ c~û ~d arLies]ar wiramse aeooadia~ to t~r wM d ~ager et al. (lk) . 4re "! tiaw aseL~lr !

dwee d ehlAa~arssiae w~rt ~trn te wah ral~dtt !A ~,/lqr ~ a~/lq sad ]D R~" 9arlag t1r ooaree d weh as~a~3ratr a Mad !w0 d tie rabbit ~ pLoed ü wter ~r,Lti~ a tae4aeatara d 55~58eb. !ar 5 weade, ?ia eaaoestsrdt hrai~ at rariau ape ia aiaas ia risara 3l ad ]3, !ie eaaaaatratiaa, d ~ aai~ea iaeswaad lSrea hir h to aiaat jD i~s ia tra i~aia eta>s aad to ieiwea j0 m 50 +qe ia üe iadalie~eer rierear tie Aearialh aiewd ~ aedaaste rarlati,an tiragiaat tie swtid apa~

laàaw ia Dra~eated ~aimta. lrwta~d ad tlr 3A-i~q eyi raülta dti t>r~tplypardae elnated ti,

d wee~ada aai ~>r

ia tie hraia e0aa to a~awsLrte~ 340~ wd l~ d tir eaat:aL ree-

éwti~,T i=alrlr 1), ißth raaa~pdaer eesvtwia lell t. meot ~ d tie eaatrol aad aoar~iaepln~iae to ]~. aird]at eàaspe wa+a eiwrnd ia tie ~epiu+aa aad easabrl]~aa Ust tie eeatral ralaae d tia its aeaeadaat hwa~e teo ler ia tiew iaaiz ~e to readear ~antitat3~e "oepariare ral~. ~T Q ~d Cf ~a 11®d " ~ " a ]A ~ ® ~

5r~ 0 ~~

~

~¢8~i8

5gr

~

~m[ 5~ s

z,50

,d2

,if

.:7

,17

.3E

.T3

.63

.28

.tl

.12

,i9

.Og

,0!

.]3

.12

.2d

,06

Vol . 4, No. 13

EFFECTS OF SOME PSYCHOACTIVE DRUGS

FIGURE

1337

1

A SEROTONIN CONTENT OF RAIT BRAIN

L: 1.0~

011AAUSTE~1

_ .A" IIEwrsPl~l~s

.21

cER~LLUw

-10

O

10

20

JO 40 AGE IN QAYS

30

e0

'TO

t

~AJOIM.T

B NOREWNEPHRINE CONTENT OF RABBIT BRAIN

1.2r LO

LRAINS7

W

f ~1 FIE~gSPNEREs

.2 O'' -10

CENE~Llllrtl

. O

10

20

JO ~O AGE IN QAYS

30

ô0

70

~D!!LT

1338

EFFECTS OF SOME PSYCHOACTIVE DRUGS

~ =ttaot ot

'in haatsre Babbits.

Vol . 4, No . 13

~} reeeedinHe wra

obtaiasd et 3i4 nasborn alidno rabbits irat 1-5 days et aaa, aa 11 et thsae ttut 6-8 dqs at aHe dth aa additiaoal ~0 at 9.1h daTa .

yam 1~ dqs

attar MrCh, betosa tha dittarsnoes iatwsa elaep aad amoval pattern aoald ba a]ioited in aaaaatal rabbits, tha attaot o! oèlerp~tataaine aH/1rHj wa to di~~ "~ tlr aaplitada et tha 1~ (yiHara L) . eblaa?a~ataaiaa

(s~ ~/~)

(S

8abociansoas

P~ai ~~ ~ tba >~ aroaaal raspmea

to paia it 6-8 VP eld aaitala (yiQara 2H), whiL ].arsar dessa (20-:1o aB~) pmsmaatad tha aroaeal s+aaotioa at 9~k d4a ot aia (yi,Hare 2C) .

Doriag

tbis tiaa iatersal, n olvmge ia aaplitade ot tba ~ß aftor ohlompa~otaadaa w aotad.

L 3 adelt ntbdts, eblaaRronaaLr ia saboitaneoas dosas at 20 ai~,

1S

4% ~ ~ ~~ atteeti~el, bleobd paia aati~atian indvad ly bot

satar .

Ia anotbem adelt nital, hansar, a saeatd oises~atian at 1D R~

an]y oertieal aLrting sas pms~antad si~le tba sabeomtieal sitaa rsnaled tbt vaal ~f! aetiratien ia rsapataa te paü . Habarisral 1taaDOtsas ef Iaatara àabbits aa Kadieatiws .

tat "dq eld

rabbits traatad sitb rassrp3aa aa~ibitad lessetad saea7.laatiea asd radaoad aotid~ to tbs aztant et tost p~eaad dapmasd .an sbiL ihwa raeeStiM tba aoaoadae esidssa inhibitam Tooalioed aems tban ssoal a~ had trators ot all team eztretitias as soll u hypsraotidtJ,

Yith ohlaxpmota:ina

w wra unabla te detartiaa afiatisx~ am aet the daeraaea ia >QH} arplitada ebsarrad

irea .lr5 dqs

ai'tam birtb soa rslatad to a tall in blood prassara,

n se .did not detaraina that paratster in oar narastraivd nbbita . ~~Tr ~s tbaa" aeaoatal ~ wrn ~~ rmd oeeasianal]f pain tailed to sseia aebem raspemss .

Ths older iaatora rabbita aLo

~od7lbited sats da~sw ot sedatioa, bat oar iadioation tar ths etteotirsaaas et ohlm~parotadas sas tha dose aaoeseary te prsrent bahariemal aad HHH respaoaas erobd by psin, and tbaes ohaades sen prodsoed at a tiaa shen ths ~nrsstnined rabbits retaiasd !1~].],7 their ability !am looatotien a~ ntlez is0l~ity .

Vol. 4, No . 13

EFFECTS OF SOME PSYCHOACTIVE DRUGS FIGURE

2 IN 3-QAY OLD RABBIT

EEG EFFECT OF I. CoNTRa -sLEEP

1399

s. 4s' AFTER a "9/k9 ~o~owAr

:. RuN srawuLUS

A. R .OGpP1A1L

tw-~u-i so w L~ aaa . worr LACR or orrrrAdru~rwr ~crwrd nca two Al10UUL w~rrrds ao orar~sE w A~ruruoc ~R iwxcnou or aao~r~or~+c .

EEG EFFECT OF CHLORPROAUZMIE OH AUH STIENR.US RV 7-d1Y OLD RABafT L GOwITROI -SLEEP

2 R11N STIIIIA.ILS

.

STRII1L14S 4S' AFTER ~ ~~ ~_p ~~ - .r Y+ v~

L . FRONTAL

B.

so irvLF~

st_ns,e

Narc oirrrndrwnoN arrrd um MO ~uo~aAi R~rrawr aS nocK ro Aw wra ~,ranow of a~o~rROrA~c.

EEG EFFECT OF CHLORPROMA2MIE ON RUN STIMULUS RY 14-d1Y OLD RABBIT L OONTROL -SLEEP

2.RWV STIIRILUS

3RIR1 57 "111115 IS' AFTER ~"~ ~!~/

L . FRONTAL ~~~~

c.

R.FRONTAL~~

~~

~~y~%~1,(1

i .occ~7AL R.000IPITAL~~,~,~VBÎ~y

M~~N~%l~/`~^~%rVy~

~r~ ~ ~orc ~ouar cra R~rrcaa ~NO w.ou to Aiwl Arra xrrarrow or aaoia~or~zrr.

1340

~FFECTB OF SOME PSYCHOACTIVE DRUGS

Vol. 4, No. 13

Disousaioa DR~ Stedies an Hrain ~ara.

The ioorsaaee of awiaes fomd 1a ths brain

stsa after tra~gloyprasiine are ~1~ u lame u those is .the adult rabbit, if sat Lrges. The brass stesi of the lD~dq old rabbit oaa aLo bs dseplT depleted of seines ~ as aaosmt of :.~ egoisaLmt to that eaplord is adult rabbits. It appears that an sarl,T satuaticn of bioahgiioal getaas geTSraing aoecaaias rtabol+ ° is reepamae to these tre drags, oocnra is the rabbit . It is, howersr, a possibility that iratnre rabbits say be either mots or lees esmeiti~e to both drags, In the rabbit 5 ag/lq~ of rsaerpine L a dose oa~on],7 need to deplete asdass, our divided doses of 4 ag/ig are thsrsiare roogh>J egoiTalent to that used in adult aniea].s. On the other hand in our lA~y old rabbits a dose of 8 ~~ of tranylcypredns wa used rhioh is larger thaw the usual 2~ ag/ig doses tiled to elicit iacreue is brass adnsa. ifith these fro drags, honner, w were interested ears in aa:isial ospability of the brain tisane to raPrd than dstersiaing efteatiwe doses. The ap~pearanoe of tro asjar daeslopoental features of the rabbit ~Q, alerting at 5-8 days and approach to a astnre ~ patters bt 9-lh dqs ooowrs at a tir rhea the brass ]ewsls of adnes are about 506 0! their aasiaal relue . "ocordisg to Leget asd Dsl,hge (1,5) the rabbit ~ is oaapLte],~r emus b7 the 2l~th day of life.

Therefore there ie a lag in

the derelapr~ of the bran biogesio rides rlth respect to the n50 in the rabbit, =tteot of Ohlor~urosrains m ~3. She failure of ~ alerting to pass is rabbits irca lr5 days of age precluded the possibility of obssrring a blooldag notion of chlorproaaaine although its +w~+~ s is dsaomstrated by a daorsesat is the awplitude of the ~ß b! 5 ag/lcg of that drag.

In

the 6-8 dq asiaal.s, holster, the des~nchrardsisg responses to aooioeptire atiaali wrs blodoed by ch]Arprc~asias at 5-10 ag/'hg, and in 9-14 day old rabbits even larger dosages, 20,l~0 ag/1gg were seeded,

Vol. 4, No . 19

EFFECTS OF SOME PSYCHOACTIVE DRUGS

?hs oharaoteristio ßf1 blocüsg effeet of ohlarpresasiae seas at

1941

6-d

dqs as age is, w be]ieve, the earliest ties that this aetien has bees obssrasd is the rabbit .

?abn in oagfimotian with tis affects of

trasglo?praaiae and rsssrpdaa ad brasa mica is this species this suggests that ~ 11s d+4s of age the ceectnl aas~oas 4sCea is capable as ?leldisg ü.ooiresioal and plQaiologieal respmse eharacteristio aS the adult. It is diffiealt to s~b geantitative ocsparisona of the doses of oblorpro~asise required to block pass-iadnead alerting bat~wam adult asd issature rabbits becasse this drag has bean addaistsred aLost emols
HOl~er, it is Olear that the ~ ~ ~

required oansiderabl,7 sore ohlorproaasine to block the ~ß response

to pain than did the 6-8 daf old aaisla. Also, 10-20 ag given sabentanevasly to a arll mbar

or

or

ehlatprasaaiae

adalta was effective whereas

200 ag was required in the ].!a-dal old rabbits. Ye aq aLo eespare the dirrere~ mates as aa,d niatratiaa of ohlarprosasias in adult rabbits.

?ir

highest intravamoas dose required to block alerting das to peso is 7 sg~ig which is sosewhat ].user than LO ag/1rg, the ].onset asosmt regairsd far the sale effect when given anboataasoaslf. ?heee findings dasoostrata that the ssnsitivitT

or

rabbits to ehlorpros~adne ohteiges with age. tilrther thin

is due to setabolio factors iavolviag atsaages in the aotivit,T of drag setiboliaing s~yses or the altered reaotivit~ o! the nsrroas eTstas with age is not apparent, In addition, we ors ispreseed b7 the reLtive~ high dosage which the issatnrs rabbits seen to bear with iapusitt in contrast to the taadoitT is adult anissls.

A+++wiei

and Hisrioh (5) fouad that 10-20 sg~g

ohlorpreaeaaiae loses ita bloc]dag effect cad instead causes oaotianaas â~3 alerting .

?Ioreor~er, the adult rabbits ezhibited edges

or

taudait~ with these

doses, bet even higher era in the 9-1lt dq old rabbit did not farce! atp apparsat ill etfeets.

19~l4

EFFECTS OF SOME PSYCHOACTIVE DRUGS

Vol. ~, No. 19

t e~+~+~~ eetnterpart os ear ybte~atiaat ir . teea ia tie treatnant d p~e],7 di.etaried obdldren ~dth eiler~anaaine elieh ragatret lar~ee detet m a wishb bada tim tiat eapl~od ier etaaa~e~ di~tarbed adoltt. Dapite ~ deta tbe eül~ eabiidt renarlrah~ !s tide etieott r taaia raaetient in eotpritaa ~dtà rtmy adslta (16) .

~ tlr ba~ain thr and iedtAinsw tie eaaee~lea as ~ atredd~i~rist aed eerota~s inoreated Qadaal3P ad adult LwL wre aot attained ~atü tartine betwan tie ~ and 50tà dq ~et li~e.

In eaatiwt the sm

dmlaped a~+e rF~T iwi~ a]artia~ patternt ~ 6~ dqt and rntier aatare eiaraete~it~3ot at 9~h dyt~ i6eterpiae and tra~leppra~dne wze ieaed te ~ thds astiant w terotania and aarepdnepirir in ]~-daT o11 rabbdttt trea~leppeaaiae to ratte tidr eoneeatratiaat ia tie brait end reserpi>t to la~tea~ t1es. Chlasproaatir aLo

bleab pdn-dadoeed

~ aLrtiad bediaalaB at 6 dapt ad ap, i.e. ibe earliaat appsaranoe et. alaxtia~ in tie awbora rabbit . Babbita 9-lk dqt at ade ragaired iidisr doeet d eh].aepranaaine to pa~erent ~ ala~tinB in repaee. te pain tàaa eitber Paa~er rabbitt r adult oaet. Bstea~woet 1, B. =iBII, 8. ~l9~ aad B.B. B10~i, J. Bearoehr. i, 53 (19~) . 2. L. B®0! and Q. T~l, D~Le. ïart. â~tt. ~ 110 (19~) . 3. ]LJ. ?1180?, J8. lm. ï.z.. "oad. aei. 61, 198 (1955) . 1, B. PIBH, Osrrant atrattaa, ew

frire Tàe

Fiat

p. 82, Pol. 3, Qror and

5.s. ~ur~a eid g.s. ~r~H, n~it. serr. 8stt. 1-'6 3 (1~55) . d. v.a. ers~ and H.s. BnarncH, eeiooae. 1~6, 973 (1962), T. P.B. BBd~~ and L.J. B1BCS~ IIaotroenoeeh. Olia . ïsa:'oDl4eiel . f, 191 1~957) .

EFFECTS OF SOME PSYCHOACTIVE DRUGS

Vol . 4, No. 13 8, !.

La,

a . Hi~, Y. HQdYM~? and P. x.a. armr~ and H.s . ~sr~,

J. se~ .. x..t. DL . 1~ 277 (19s3).

11.

P.l . HHaHE and

12 .

D,P . HODd11fSâI, H. 1~SSBICH ayd

~.

J . P3T:~, 8. DI PH$RI and

3~4.

a .H. 8ixlHS, J .x. SYIItII'T and J .D.

i5.

~ 52 (~961) .

dLD, J. ?àaraaaol. asD. tàar. ~

(1957) .

a.

x.l.

H~~aiol. ~,, 557 (1161+) .

j3,

IIDHHPIt~,

295 (1958)~

ôh~. J_1

is 272 s

®~H, IIaotsbaeaaph. elin.

387 (195h).

ciHm, l1a

b. ?JR~ and H. DII~Ii, 1~aivalüe~ lteoro Yol, Maaaon, Hd ., ParL,

i6. a .

(1950 .

DII~L, . ôr. HsD . Paria. ~O, ~

J .1.3. 1~D and t h . ~., Dl.eahaa. Pàarreol .

J.B.

1343

h,

?J8a1~, lersooal ca~aoiAatian .

iroh. 101o

Hearol. P~obiti . p . 259,