THE GLUTAMATERGIC SYSTEM AND LEAD TOXICITY

~ ~ s u b n i i n d h ~ ~ ~ ~ f d t y w i t h t h e ~ s

for the D q l p of Muia of Arts

Gnduatc Deputmait 0fPsycbology

Univdty of Toronto

uisakns and AoquisTtkns ef Bi iographii Sewicss services bibliographiques %

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THE GLUTAlMATERGICSYST%M AND LEAD TOXICITY

Jaadle Catherine LeBoutiiiier

A th& submittd in conf5,rmity with the rrqukwnts for the hgme of

Mraa of Ar& Gradwte Dqmtmmt of Psychology. Univdty of Tomnto

O copyfight by Jande Clthaiiac LeBoumet, 2001

ABSTRACX

Nthough the molccuiar mdmism by which lead (Pb) producm dddaiw effkts on

wgnitive Amdion is not wdl carblidd, &dona in tâe W o n of g î u ~ c recspton

inthcdeveiop~b~havebeeaimpüatd. Tbirnrslnhcainmicdthcmof

glutamatergic womrtr rnd Wonists in nt, exposai to civonic pobiutrl Pb qoaure on

~ b e b r v i o r a l t u l P . r d m i r a r C t m t y , ~ M o n U w r t a ~ ~ r a d ~ c o Q I I

trsiwmission of food posfkaicc (STFP). At the Cpscinc dom rad M o n of Pb cirrpome

employai, the NMDA, kit mt the AMPA reccptor -un rppears to k involveci in wizm

adivity. In addition, MK-801 (O. 1- rpparsd ta k rn d b d i v e tbapait ic dosa to

d u a ~ . N o m a i n ~ o f P b ~ ~ i n t h e M W M o t t h e S T F P ~ . T b

rrseuch wwld ~~ggest tbt Pô miy bs ht- at the MK-801 site of the NMDA m o t .

This thegr dads the involvemmt ofmuiy fnends and c ~ i i e a p s at the University of

Toronto rad 1 WCIcome udr oppomrity to adaiodeclgr? th& haluable ouitn'butions. Dr

T d P d i t h r o o o a r i a i a l y ~ r n d ~ p p o r t d m y p u r n t i t o f t b U , . a d o k ~ F o t

8 numbcr of yeur rnd 1 un lpatly indebted to him. Dr Uiron Fleming, ckdù i i y o f f d

guidance uid suggestio~w t h u g b u t the reieuch ptoasr ad the Wnting of this tbaU. AU of

the gnduate studaitr who have passai thmueh this fab bave M r large impact on the

completion of th* project ad 1 pa t ly vaîue th& fiiendships. In addition, 1 am indebted to

Biendi Brown, Lucy Pickering, AM Lang, Dr Coün lhdmâ, Dr John YOUJO~, Dr James

Gurd and Dr JonruUa Fr#dmu F i s but most irnportantly 1 would iike to tbanû my nmily,

A&iao, B k s ad Paul for their limitlus love, encoumgunent and sacrifice to ttlhu this thesis.

INTRODUCI1ON ..................................................... 1 Lead Aocunarlation in the Btaia ......................................... 2 Animal Md& ...................................................... 2 calcium Depaderit Proce!ws .......................................... 3

Lead intaroton with the Ohitamatcrgic System ............................... 3 ................................................... Receptor Systems 4

Lsid and the NMDA Rcceptor .......................................... 5

L e d ~ a a ~ u i d M g a n d M a n o r y .................................... 7 .................................................. MordsWaterMaze 8

Long TamPoteatiition ............................................... 9

oiutamateqk htagonists and Agonists ..................................... 9 ........................................................... MM01 10

............................................................. CPP 12 .................................................. AMPAdNBQX 13

.......................................................... NMDA 14

......................................... GENERAL METE0DOUW;Y 23 ... 23 ..................................... .,.*.**....,...*..

.............................................. C h r o n i c ~ E x p a u r c 23 .................................................. B e h a v i o d T ~ 24

EXPERLMENT 1: LEAD AND THE GLüTAMATERGIC SYSTEM ........... 26 .......................................................... Methods 26

............................................ Statistical Analysis 27 Resulu ........................................................... 27

...................................................... S d h 27 CPP ....................................................... 28 NBQX ..................................................... 28 AMPA ..................................................... 29 m a 0 1 .................................................... 29

........................................................ Discussion 30

EXPEIUMENT 2: REFiNEMENT OF GLüTAMATERGIC DRUG DOSES .... 33 Mctbds .......................................................... 33 Rda ........................................................... 33

saline ...................................................... 34 ....................................................... CPP 34

..................................................... NBQX 34

..................................................... AMPA 34 MK-SOI .................................................... 34

........................................................ I>iscussion 35

........................ EXPERIMENT3= PBANDTaENMDASYSTEM 37 .......................................................... Mcthds 37

........................................................... R d t s 37 ...................................................... sahc 37

CPP ........................... ; .......................... 38 .................... ............. MK-801 (O.OSme/kg) .. ... .. 38

........................................... . MK-801 (O lm&) 38 ........................................................ Dimudo11 38

M a h o d ~ c r l Considerations ................................... 39

........................ EXPERIMENT 4: PB AND THE MK-IUBl SYSTEM 42 ...................................................... . * Metbods .. 42

........................................................... Rcalb 42 ...................................................... Salim 42

MK-801 ................................................ 42

......................... EXPERIMENT S= TEE MORRIS WATER MAZE 45 .......................................................... M M 45

Statisîicai Adysis ............................................ 46 M ........................................................... 46

- T a s ................................................ 47 -Trial .................................................. 47 V i a d Triai ............................................ 48

........................................................ Dimasion 48 Diet Effèct .................................................. 49

...................... ............ . . * . D r u g E n i .. .. 51 Probe and V d y - C u e d Trirlr ................................... 54 Fu~Directions ............................................. 55

EXPERIMENT 6t PB AND SOCIAL TRANSMISSION OF FOOD PREFERENCES3 .......................................................... M d d ~ 63

............................................ StrtiSticaî Analyais 64 Rmuh ........................................................... 65

........................................................ D i d o n 66 .................................... Lad ad Socid Transmission 66

................................. MK-801 d SOCial Tmnmi~sion 67 ................................... McthodologiicJ Considdons 69

............................................. Future Directions 70

LIST OF TABLES

Table2.. ............................................................... 60

Msin Escape Latcncy by Dkt Md Dnig across the Four Days of Testing

Table 3 ................................................................ 61 Mean initial Hcnding by Diet ancl Drug across the Four Days of Tcsting

Table4 ................................................................ 62

Roba IniW Hcaâing: Man Angie ftom the PWom per Die! and Drug Condition

Table 5 ................................................................ 62 Vi-Cued Hcnding: Mean Aagle h m the Platforni par Diet and Dru8 Condition

vii

F i m i . ............................... ....... ...................... 32 A Ovedl ~act iv i ty (mcrn~+SEM)Foroostro ludPb-expoduimulr

a d m h k t d d a u dnip fbUoWdd by NMDA (2Om&). indiates dgmDficant cîBaencer (p4I.05) between the contmf ud rapcaive Pb group anâ " indicata SipifiCant dinèrences lMtwcen Pbdfug d Pb-liüae group.

B. The #sue activity (man + SEM) ovcr time for contml and WQIposcd Wmals administered saline prior to NMDA (2ûmgkg).

Fi-2. ............................................................... 36 OvanP#inueactivity(mc~n(UiOf SEM)~rwntn,IandPb-exposcdinhnilr rdmMistCtCd wiws h g s fbIloW4d by NMDA (Zûmglk&. rn indicatm ci@cant difnmica @*O.OS) betwœn the wntrol ud rc3psctive Pb gmup ad '* indicatcr Si@c~t d i f f ~ b e t w e e r i p b r u g d Pb-* group.

................................................................ Figure 3. 41

Ovall ache activity (mean m t h ~ 2 SEM) for corn1 and Pbaxposd inimrls &hbtCitdd d a u drue, fobwd by NMDA (3ûmgk&. indicites si@- dinaonas (p4.05) ktwcca oontd rnd rripectivc Pb group.

............................................................... Figures. 57 A Mean o v d aapc Irtc~lcy (in csc f SEM) to mach the hidden platform fk each dmg

poup CO- acmm diet. . ir Pgeieamfy difféiaat 8.an di o k gm~pg (p0.000). B. Tbe &y by h g interaction fW the mean acqm la!- Cm = + SEM) oonipscd

Fi-6. ............................................................... 58

Mean initial herdug angle (in dcgrœa + SEM) for erch drug group. Dict groups were

not sienificantiy diffticat fiom cach otha b sipificantly diffsrait fiom aii otba

muPa* A. Tb probe trial mean escape iatdu Çl sec + SEM) f9r acb dnig and diet condition.

Diet groupa were mt sipificantîy diffttcllt h m mch otha hdicatts lignifiant di&rum fkom JI otha graips Qsû.01).

B. The visuaiad tntl mean escape latenQg (ii sec f SEM) for mch drus and diet condition. Diet conditions w a c not sisnificltndy diffcrcnt h m cach other. * indicates signifiant diffmce h m aii other gmups @<O.ûûû).

................................................................ Filpin 7. 59

A The probe trial mean escape Irtencics (il sec + SEM) for each drug uid diet condition. Diet ~paips were not dflcantiy dünnnt &om eacb 0th

inâicates sîgnibnt diffkmm trom rll otha gmups w.01). B. The vid-cued tnil mean escape l a t d e s (ii sec + SEM) for a h h g and diet

condition. Diet conditions wem mt sienificdy ditRrrnt from a h otha. indiutes si@cant âiihmce bom aü other groups (p-4l.000).

............................................................... Figure8. 71 The mean pacaargc of targct f d collsumed by the control ad PaxpOsed groups immediatdy follo*ving aacid manctioa (O In) tftn t 24 hr detiy.

............................................................... Figure9. 72 T b mean paoalyp of target food consumed oolhpsed across diet condition fw each dnag group hu&htimmedùtdy Edowin@ sochl interaction (O hi or der a 24 hr dday) indi- signifiant di&rrncc -.OS).

............................................................... Fi- 10 73 T h e ~ t o f ~ f b o d c U a u m c d b y t h c c o n t t o l r n d P b Q l p a ~ g m u p f o r d dnig trertment rt: A The rao thne condition, B. The 24 hr time condition.

Tb c f E i r of Iead (Pb) a<posure on our Mth b kai an uri of intense

amuhtion by aiiny rtsearchen. DevdopmcDtrl Pb crpoauro in hUMN h b w n to disnipt

naml ddopment and wgnitivcr ciprdtia in a dose dependent m ~ i a with hi* levels of

expoaure assoCiated with enaphdopathies, anâ m d rrrudaton, and Iowa levds

sd&idy bigh cowxntmtiom (se H m h q , 2000, for d e w ) .

N~~t~pathologicnl shidics have geaaiEly Md to & any moipho10gid impuct fkom

Pb -sure Qtapt at vay high levdr asdatai with amte Pb powning. The abseme ofrny

neuropitho1ogical aiplraition su- that bioJlanical or nain>chemid alterations m y

underlie Pb inducd k h v i d toxicity. aunnt rrseveb todry hams on the low to vay low

I d ofPb -sure in rn attunpt to deeat tbe limita fbr safè aipoauq determine possiik

tbarpaitic tmtmmts to Pb conditions, rad utiiizc Pb u r navobiological tool to

Qliminaind~therdes~f*divrl~crti~~~iadionnarl~em.

Swanson, Aracava & AIbuquerque, 1996). Under n o d conditions, the hippocmnpus, wtiich

comprises ody rbout 13% of the ftah biia dght in a rat, oonsiiar 5(Wi of the total Pb with

the hi- coIICCllffation in die hüur of the dentate (Danscher. F j d n s M , F j m h g s t d

& Fredtlw, 1976; 4cdqsta4 DMSCbCt,& Fj- 1974). Lead &ers the uutomy of the

bippocampus, and the bdiaviom mediated by the hippoampus (Aifàno & Petit, 198 1; Ki* &

Jonm 1982; Peîit & Ahno, 1979; Petit et al., 1983). Wbile not dl b& regions have been

speafidy examhd, 0th regions in tbc rat wbich hve h w n sisnifiant ummuîation of

leaâ indude the hntai Gort- corpus rtriitum rad Ottcbdlum (Fion & Seth, 2ûûû).

S i i t i e s in the h & y p of eariy li& Pb n p o ~ a h m human Pd animai work have

ben grestest whcn complut procemes uch u copition rnd 1- hva been aeimiaed (ag.

Cobn, Cox Coy-Slechta, 1993; Rica 1993). The towut lavdr of Pb ~ ~ p o n a at which

obsuvable sgcctr hvc been reportad w riaiüu iaorc @a: lOlS ug /dl wbde blood in

c b ü h m a c& ai., 1991). < 1SugId in phut- (Rice ud Kuplarlti 1988) and, 20 ug/d

in rodw (Cary-Slcobq W ~ S S & Cox, 1985). TI## h d h g ~ iadi~att tbit rencitmty to th

& McNmm, 1990, Youw & F- 1990). NMDA rrccptors arc oompod of assunôlia of

NRI *ukimtr rad NR2 subu&, *ch a n be one of fbur q m t c gaie produ& t c f d to as

NR2A-D. The expression of ôoth aikniirr ir rcpuirsd to fônn h c t i o d channds. To date, the

rtoichiomcby of thI subunit oomposition ad nimba of b i i dtcs in the NMDA -toi are

not known. The NMDA tcccptor cham& are b i d e d by Me ions at rcstin8 munbnm

potentiai and dow the flow of moaonknt cations (NI' rad K*), as wdl as dident Clh ions,

with depolarizstion. N o d W o - of the NMDA receptot cornplex dependr on r dynmiic

equili'btium mong the various componaits. Loss of qW1i'brium may result in the expression of

cxatotoxiaty (Sombati, COUIter & DeLomzo, 1199).

Lcss is known about the AMPA teaptor cornplair and its rPsooated ionophan.

El~physiologiul studier on the glutamatmgk system bave shown tht most rapid rynaptic

excitatory nauotrarwmission is mediated tbmugb the AMPA m o t complut which conducts

mriiily Nd aiirrps.. wMe the NMDA -or complex âhplays vo1tage dependent c.h

pumeabiility wbich d t s in dow transmission (sœ Bettler & Mdc, 1995 for miew).

Biocheniical and/ot conformatiod chan- at the giutcunatqic receptor cornplex may inducc r

dekit in leYning and mcmory (Hmiq et al., 1984; Monaghan and Cotman, 1985; Luley,

PoLn-CurUin & Armstrong 1993; Cupaitct, h h t t h w q Purwr & Hori, 1994).

m Lmd b a dective non-conipetitive mta@st of the NMDA rcceptor. Biochemial

and electrophysiologicirl studios have shown tbrt Pb btmact8 witb the NMDA receptor

oomp1u and inhiiits receptor rotintion (Gubrte, Mali & Jett, 1995; Guilarte, 1997r)

rlibougbtbenibrite~Pbbiadrdbowbrinlp'bitory~m~tatdIrmtnilly

Uoderstood. Gutowski et d., (1998) ai- that NMDAdqmdatt f o m of ryniptlc plubcity

ducing the induction of LTP. and the fimcticail PropsrOies of NMDA reœptom

(Whm, AUmndoq Montes & Albqucrpue,l995; MurChiori et d.. 1996. ûmelcbko Nelson,

Muiao & Men, 1996; Gibm a al., 19998). L d by bmn show13 to induce r ddopmantrlly

dcpadmt Compensrrsory upegulrsion 0fNMDA i s c e p o t ~ rhhough PCP nsaptOr8 me

Iirsay uirfftçtod (Brooks et al., 1997; Bsodq Petit, Lcaoutillier, N o h p & Jan& 1993).

6

- ~ ~ ~ a r p o a u r i r r b ~ ~ m o ~ t ~ i a d w a ~ ~ ~ t a ~ ~ ~ ~ ~

seinues (Petit, LeBoutilliu & Brooks, 1992). Wbüe little naarcb Iils #Imincd the

interactions of Pb ad the MiPA aystan, recmt Whgs ôy Ch, Ma a d Ho, (2001) auggest

tbat aitacitions in the AMPA mceptor -an may posably contribute to Pb-induced deficita in

1earning acquisition of a'bitory avoicbm in nir. The ttstarch findings rcviewd ibow

suggest Pb may arert its deleterious neudmhaviod effkcts by âimpting the ghitamateqic

systcm during devdopmc~t

Lead Exposure and Luraing and Memoqr

Leuiyne and memory q W t e s the amdhg. dorage and mbsequent iotivation of

information in the bnia The hippocampai formation Y WU situatad for a role in leaniing rid

munory, 6 t h recipcooil connections to mrny o k cortical regions. Law tmn potaniation 'is

a proposeci ceiiuiar d e l system For lemhg ad maaory characteruad by a persistent

hcmae Li aynaptic di ioacy folowing ddiyory of bnef t d c stimulation (sœ B ~ e r , 1995, h r

rcview). Hippocampal LTP has b e a theoratidy linltd to various Onds of lem@, iad has

kai clody Wed to spatial l e . S e v d iswrrcha have rtited that the hippocampaî

f o d o n is required for spatial i- in nu (Tonegawa et d., 1996; Hargre8ve8, Cote &

Shapiro, 1997) and tbat roâw rvitb bippoc~~pai Iesiona arc impaired in a variety of spatial

Law tcrrn potentiation is &O b w n to be disnipted ôy kid (Hori, Buadkg ,

Matthcwa, Parsons & Cupaiter 1993; Ladey et al., 1993; UjiJüw & Albuquerque, 1992;

Gilbert & Mack, 1998; Ni et al, 2000; Ziim & Miletic, 1997). The llcutologicai bases of

LTP hippocmpai synaptic pliuticity and remnt on the d u l a r actions of Pb have

indicateâ target sites where exposurt may act to intdén with the processer unâerlying the

piasticity. NMDA m o t mcdidted synaptic pîasticity is mcamry for the propet

repcibscntafion of rprce ia the CA1 region of the hippocunpus that NMDA receptor

depeadent LTP unddes the accpiskn of new mcmories (Tonqawa et ai., 1996, Cdn, 1998).

Howevcr, iItbougbWbsrkcnreportdto~'bitLTP.tbismiynotoca~roklytlirai~itr

actiom on the NMRA rcceptor cornplex (Hori et ai., 1993). In addition to Pb's abiüity to i a h i

LTP, Zhao et al., (1999) .Ise ObScrvtd inh'b'ion of 104 tam depression (L'ïD). Takm

to8ether. the inhibition of LTP anâ LTD muha in r damsed range of synaptic plrdicity in Pb-

expod*.

In gannl. basdine synaptic phydology does notappcar to k d t d in Pbaxposed

animais (Ahmann et al., 1994,; Ciilkrt et al., 1996; Grovu& Fryq 1996, Oilkrt et ai., 1999)

rad or@ ruponscs to more canplcx patterns of ahdation aidi as L W dcmoiwtrate cl-

dctincd clBhmxa. Mont mearckm biw obstmû c l iahbd potentiation as r result of Pb

exPo-

GIibai tergk Anbgonbb and A p i M i

nKNMDA~~~comptt~ir~Ckmemoryudrraool~dq~~ll~t

aiggesting an inte@ d e of NMDA receptom ia phce IcuNn8 (McNuwr & Skdton, 1993;

N i & OuiLrte, 1999). Whib the de MCI mechdan of action may diffa for potmt NMDA

autagoairts, inhiion of the induction of LTP k at the rcbffar ooUaterai-CAl pymmidJ cd

synapse with very fm uceptions (Abcmi, Masti & Muder, 2000).

MKi80_1

NU~CIOIW -dies bavs fonurcl on tb efsbctr of MK-801 in l e Md m c m ~ q Wtiich

are b w n to bc dcpcadcnt on the intwty of the bippociunpus (Canmanos & Shapwp 1994;

Ma, C h , Lim, Huma & Ho, 199%. McLimb et ai.* 1990) Wtthin the ion cbannd MK-801

&as bœn shown to ôe a powaftil non-compcthk ~ o n i s t acting a! the phncyclidine bindng

&te, blocking the d a t a i chinad rnd subsequeat ion Mux (Won& Kniat & W M

1988; Sukhotina, Dtavolina & Bespdov. 1998; hh, Chen, Chang, Hwne dé Ho. 1997~ Ma,

Chen, Lim. Hume & Ho, 199%).

MK-801 t imown to dimpt LTP d impair leamhg in a variety of tasks

(McNam~rr & Skdt011,1993; Co~~-Slschy -rouai & 1997; m m

Cote & ShapPro 1997; Ma et ai., 1997; Cain, 1998). MK-ûûl doses m@,g h m 0.0 1 mente to

0.1 m@g wem fama to d o S 6 d e p a d a i t f y i n i p i i r ~ of qmtM leamhg trrh. with 0.1

a total b l d d e of aquidthn uui 0.05 base the threshold dose with r

Sigd3cmr rcpuiritioa* m p h m t of rpitLI 1- (MLada, Mirme, Scbott & Qyea, 1999).

Evaa foUowh~ rpiieie dnanidirti 0 *on of MK-8ûI (10 mg@@ long Whg bpahmib in tbc

--- .. wonnuice ofrats in the wrta ta& h w been rcpoctcd (Lukoyurov & Pauia-Barborir,

2000). McLamb et al., (1990) have sbawn however tbit aithough systanic dmiiiLltnti . . 'on of

MK-801 to ad& rats h t d d with the rate of l d g of a spatiaî tasic, the nt, mnbililly

leamed the task i n d i e tht MK-801 trcatd rats are capable of learning. Raamâ badisg

in mica and rats using dic~tnt spatial tukr miaests that MK-801 Scctr the rate of acquisition

of a ncw spatial but does not pproduos alterations in the abüity of the abject to d

p m h d y ieMnd idonnation (Woznill a al., 1996; Lukoyanov & P d - W s a , 2000).

MK-801 rnay impair spatial leamhg by uther d ' i y or induectiy Ctducing the likelihood of

synaptic plasticity in the nt bippoampus ~ v c s et al., 1997). Th dt'ks of NMDA

blocketrr on rats in the foimation and retention of m o r i e s for new foods within a d

contcxt have dao ben amminui (Myhaî & Fl- 1990). Th& msults iadicate that at high

ooncentrations, MK-801 produces a conâitioneû aversion and at low dom it acta 10 p m m t the

aquiaition of a conditioned food p d w .

Pretroatmat of MUnals with MK-801 bac ken & O W ~ to si@antiy d u c t the

nmba of seizwes per uiima and the totai seizure duration induccd by NMDA (HSrk et ai.,

1993; FolbaIgovB, Haugvicovi, & Ma& 2 0 ) . A PmiLr p u p of studics rrpocied tbu acute

MK-801 administration protactecl 7 day old rats h m peirtytenetetrau,I and piaotoxin-inducd

reinirrr. and 9 &y old rats h m flurothyi-inducal rciaaor (VaUdr et al., 1995; Vdkk,

Vcrcsova, Povisova & Marcs, 1991; Vcliskova & Vdisdg 1992). Reaoatly, Kdsq, Siodacai

& Frye (2ûûû), have reportal that a hgîe injection of MK-8Ol(l .O mgîkg) immediatdy prior

to psrforant path stimulation raiucai sehum anci mhm-iiccd ddcits in mipping in

t h e M o n W w a t e r ~ .

In Ppnud with tbc bhaviomi ch@ autondiographic lnrtyris of kim d o n s have

11

ocain in the CCtCbd 00% corpus rtrlltum risd mdub-pons. Wüson a al., (1998) mportd

ht tb of NMDA -OC =bunit mRNA d k MK-801 -rait in lld0118fBf ntr

w u i n d by NMDA rrcepdor antagonists causing toxicity, ancl dccnr#d ôy agonista to

bcncficially enhancc NMDA receptor fiincton.

Severd r e s c d m have exuninad the Wmctbn of Pb and MK-ûûl. The interaction

with Pb hrc bcai reparted to inhiii the b i i of MK-801 to itr site within the ion chiand

(Akondon, Costa, Radhihihan, Arondlim & Alkiqurnque, 1990, Ouilme & Mioeli, 1992;

Schuite, Muller & F r i a 1995). This inhibition of MK-801 laub to r compauatory u p

regulation of MK-801 b- itea (GuMe a 4.. 1993; Jan & GWlarte, 1995). Ma et ai., '

(199%) h w d-nstntd that w3m-801 b m m het- disbr'butd

tbroughait th nt bmia uid tbit chronic Pb a t p o ~ produces maCuCr w - 8 0 1 bindmg

in the hippounipai brmation and cacbnl cortical amas. Behaviod cvidence Jso exists

suggestin~ a mbseasitivity to MK-801 Mlowing ddopmcatrl Pb acposure (Cory-Slechtr,

1995). This w 4 d niggcst that men in the pmwm of h c m d production of MK-801

bmding sites, these sites may bc baud by Pb, ud thsreEore mt M o n i n 8 n o d y . Thus,

w h k tbac is 8 pmt d d of evidc~lcc indi* r P b - M A interaction, the data amdy

aviilrbk w m h b g the & d o n of Pb with the MK-801 syaem tbat Pb induces an

hcrme in the nrmbcr of MK-801 b ' i dg. kit mt thcir muMty kred on behaviod

ObSttMtionS.

ÇPP

Anotha m n i s t wbich piqa a mk in tbe rhantiotl of the NMDA receptor cornplat

CO NMDA sites, thercby nducin~ d e p o h i d o r ~ ~ pmducd by the application of NMDA

b P b npourotba tbit oftk6w(JII(-*ak, C S ' Gtdme& 1998). Pb

capoaire in dcwlopmeat has kca obscmd to alter aamt flow through NMDA -or

cham& (Guilarte, 1997.; lrbihn a al., 1995; Muobioro et al., 1996) as wdl u l l tahg the

expression of subuni! mRNAVs (Guhrte & McGiothan, 1998; N i & Gyilrite, 1999;

O m e l ~ o et al., 19%; Chnelcbko, NoLon & Aîlea, 1997). The mgnitude and d i d o n of

the changes in NMDA ruxptor levd, in Pb-exposed rata rppear to be r f f i e d ôy the Pb do-

thc pcMd of Pb e x p o s w tad the bnia region uiilyzcd (Guilute & Mdjbthq 1998). NMDA

tcccpton in the immmire rat brain mccüa!e longer duration excitatory postsynaptic p o t e

ad am more sensitive to glycine thui mihus NMDA receptom. This d o m not only for an

enhrncsd capacity of the devalop& bnin for 1- d plastiaty, but also an hcrease in the

vuhmôility of the yauie bmh to edotoxic injuqr witb diaoront aibtypea of NMDA '

receptom ôe@ c x p d at ditfirent tmicr of dweiopmmt ( W i n , Kinrmin & J o ~ o q

1998).

Plilirmroologicd and physiologicaf chrvrcteristics of NMDA receptors ue dependent on

the type of NR aibunit e x p d . Omdcbailro et J.. (1996) have demonsttated tha! Xenopus

Lead, the Hippoumpua, and Other Bmh Regiona

of non rprtlli rdations ( E i c h e n ~ 1996). Rif, npidly bore md 6 infodon dur@

soci.ll~~ddbynolrspitiilrtimuli.mo~pmnsnsly~oiyai~~rud

Hoiioway, 1982; GalefB W~gmore, 1983). In ioàrl t m m i d o g rats use olhctoy cuca to

commUmcatt anmngst aoh o k , infbrmafion about indmduility, the piescnt -te of the inmiJ

anâ its environrncnt (Stem, 1970; Popk & Via Ree, 1993).

n of Food

Ritrrapiyacquireudranaaba~onsbawannonspatUlstimuiiuexpresscd

in the sociai tmnsmisaion of food p r c f h m a Tbc interaction of an ob- nt with a ~ibctntly

fed coacpcoific danonstrator ubduitirlly dame^ the ob#rva ratd subsbquent pretèmm fw

whatevcr diet its demonstrator hr eatcn (Gai&& Stein, 1985; Gd&& W~gmore, 1983;

Posadas-Aadrews & Roper, 1983). D H i mdunisms h r tbe d transmission of dkt

pnférrnos in rat pups aOst with pps older than 21 &y ippeariq more d t i v e to the sochi

conta in whicb dia id- olfactory aier am uqmid. Gd&& Kennett, (1987) niggest

that whüe sochdiy Uduad diet pisibcncc in 21 &y old pup cm be a r p W ôy of

simple -sue, olda pups @peu more adtiw to the d contcxt in whicb dia identitjiiae

olfâctofy nies an arpa id .

G d ~ ~ P n t i & B ~ ( 1 9 8 8 ) b n i a b w 1 1 d i i t h o b w m r n t f w m r r a

~ o n k t w s c a t n i o o ~ r y i t i m u l i o n d i o ~ o f ~ ~ o r n t t b r t b u t i t a s t b c

fbod.~Twddorrndarboa~pbi&wacbiraormillgpiasaththc~tbnrth.Obeava

ntrcinba~ondKirdiadecti011~~rvithrd~n~batorntforulittlt

w W e n r i n u t - ( W & St* 198s; R o e + a t ~ ~ W m d ~ ( 2 0 0 0 j n h n d r

p d o u r demonsirations of socid influence on the R t i &ai@ beâavior by provi* evidcnce

tbat rodrl intetaction CM dfbt fbod insrlre, u Won u fbod cboioc. Social influence on htake

wu~rffcctedbydntfUrmiuity,witbobraivsndb~rocidyerifianCCdin~eomly

of rdativay llnfbdiar f d s .

Selectivt nauotoxic lesions of the enth tippooimpil d o n d t s in n o d acquisition

anâ briefrctention of th food odor uuria;on u d c m o ~ by intact mcmory immadiatdy

ifta rocirl training. Ho-, long tam memory in theae RU WU 9cvcrcly impaind in contmst

to stroq 24 hour retention by non-lesioneû uiimrlr, miggeain~ that the hippocimpd region is

requitad for long tami retention of a nonrprtiai hm of nminl maaory (Bunsey & Eichaibuun.

1995). Tba bippocampd region is not criticai to 4 foormr of nrncnl leamine, but may be criticai

Sel&* to those tht require the flexiible e%pd011 ofllstmory as ui inhwnt part of memory

pdorrrrm~t. m e the âippocanipus iuafii wt ewntid to mammy for single odon it is

csitial for the formiton of the mpresentrtiona of tdrtions raong odor mcmoiier anâ fw the

expdon of dor rnmiory represenbtjons in nord ~ o n s (Eichenbaum, 1998). The# vim

ramEii controversial howcver. In an rtampt to repmt the Bunsey rnd Eichcnbaum (1995)

hchgq contradictory resulta wae obtained by Burton, Murphy, Qurrrly Sutton & O'Kde

(2000) aippo* tk idea t k tk hippaampulsubiculu region U aot tdquireû for this

m m - * *

mawry. Further -on Qtrnlaine the enbct of chronic

developamaî Pb arposure may hdp ducidate the mk of the hippoomipis in mnrprtiil

Tbt Mowiqg p t o c t d ~ ~ ~ outlinal for raimrb and dimmc Pb eaposuro wefe ooinmoa to

cach of the six e q e h m t s described bdow.

Anima

prcgnmt f d e t o n g E v w Hooded mswefe o#Msd ~mChnrlcsRiwr, canada.

The diy of b i i of the lina was mrdca u postnatal dry 1Q1). Sincc Pb is administed not

toiadividualraimilr. but tocatireüttarinitwiyviithcdam'rmik, Uiimal~inPbrswarcbm

typidy -sa fostatd at b ' i in order to ducc any &ectd due to îitta. Thb hdps hiavs that

any obrarved cffêcts of &hictain8 Pb to r litta arc due to the Pb riaatmait nthar thui rom

otha iaherited biobgiul or behaviod rttriôuîm WC to tbe litter. Thdorc , aU ütters were

d o d y cross fastetcd with other dams tbit M givan b i i within a 24 lu period. In ordà to

redu~tWCi~ditr~&etodiff~in~wdp,~ü#ar~rlroculledto I o d e

pupr. Ifliaa containad lus than 10 d e pqs, fcmre pups wac d d d ru necuwy to

mUntUntheüttadzdat l O p ~ p ~ U w a t m t L a b r ~ ~ ~ ~ p a i w n t ~ ~ o t h w h

the roQll transmisdon of f d p r c f h m tas& (me bdow). AU Uters were providecl with d hi

f d a d anter, rnd h o u d h Ndgcne cuges on 8 12 hour i~luminaiion scbedde. ûn P26 rats

wae &@y boused.

Cbnnk Lcid Esporuc

Nu* ciam were nndomly assignai to 8 I d (Pb) or control diet on P2. The pipr

~ ~ ~ l p o i e d t 0 ~ ~ ~ h m i t d ~ 0 f d u a , ~ 8 g m u n d c b o ~ f o o d

prrprntion contain@ 0.4% N O , by wdght. At tbk thte, thaia has bœn no & to

iadicrttwhcthaW~uiy~onthcqurlityorquuitity0f~mitanilaiültPrevi~

rsrcuchhairhbhurbomtbit~moftbUdorsofPb~ddVdopmens hduca

23

A discussion of the rcsults of pup body weights is prcsmted in the Oeaarl D i d o n

d o n at the end ofthis pepa. Each khivioral atpaiment is prcscnted bdow and hciudes the

methOd~resuhsrnd~ap&iact~thearpamia* .

Diet Condition r

L

Conîrol r

Pb a= MM litter weight in gmms + SEM

n

4

4

Postnatal Agc

PS

9.82.4'

8.82.2

Pl0

21.32.8

18.8i 1.4

Pl5

32.52.8

30.1+ 1.4

P20

44.12 1.4

39.1+2

P2S

63.94.9

50.e 5.5

and w a t administd 30 min prior to a single dose of NMDA (20 rsen<g in physiological saline,

--- - M d ~ b e î o w . TI# p ~ a m p b y d b be)ra~dobservations anci aatiœ~caI

uulysiswaehsimfordwiPusactivitya<pamients.

AU animais wcm o b d in a aarll dgem cage fiir 40 min foIIowin8 y&on of

NMDA by an observer blinâ to the traitmait group. Behavioral rathm were ltcordd awy 5

min wi,q a rQPira rathg suk h m 1 to 3 (modified v d o n doptd h m Racine, 1972) for a

total of 8 time in teds . Animais wac nttd on the foilowing d e : (O) typicai exploratory

bsbmor. (1) taü twitching (2) ruMing ad body shdces; md (3) samrre ramty.

Sbtiatid An8Jysi8

Seizure activity &a wrr anaiyd usine a w e d measuru ANOVA on the Statistid

P a d q e Tw Socid Sciaces for W d o w 95 (SPSS). SMm mtiw wu the dependent within

subject mcasuft and diet condition anâ dnq group were the bctween subject hdon. Subsequent

pst-hoc analysis was conâuctd usine Tukq's HSD when the ANOVA rctwhed ovedl

sicpiific~ct @<.OS).

Rcrulb

A significant miin of dia p(1.79) = 27.6, pe0.000] on scizure activity wu

obsendwithPb-expo#cl Wmrlsdispîayuiehi~ovenllmanseiarrrlevdrthancoatrol

rnimrl.A .inii(t.nir&cffcaof-F(4,79)= 1Ib,g.0.000] ~ l ~ ~ e d T h

dietldnig interaction approiched. ôut did not mach sipifiance (F(4,79) -2.3, p10.0681. The

control raimils pretreated with saline (see Fig. 1A). ûver the 40 minutes of bebivic+rai

Contd-CPP groups or between the PMPP and Pb-saiinc groups u a d of tbe p r e

- Pb Control

AMPA CPP MK-801 NBQX Salim

Time (Mirin)

Figure 1. A. Overail soiaire activity (aisui + SEM) for oantrol and Pb- expoatd ioimrls adrninistered vuious dnigs foiîowed by NMDA (2ûmfig). *

- -

indicite sisaific~t differcnces wO.05) between the contrd and respective Pb lpwp and indicatm dgnificant tiübmms ktwan Pbani~ and Pb-saline group.

B. Tbe sQzun activity (mean rathg + SEM) ova timc for contra1 and Pô- exposecl animais administtrcd N i pnor to NMDA (2Omsn<g).

-*-*. - EXPERMENT 2: -OF G L U T A A U " DRDG DOSES

Th previws Cxpanient fw-d oii the geamliEsd dufamafergic ystcm. H o w w , the

d t s su~ested that the doacger admihtcrcd for the vrriou phnnicologîcni agam w a e mt

mxsmdiy optirml for produ* the dgind behavionl Ogectr TWore, the nimiit

a<pauncat was conducid to hutbss aimioc the rok of the glutamatergic sys&ern in erily Pb

apoauq ushg the same dmgs as usecl in Bcpahnt 1, kit witb aiterations in the domgm uccd.

The MK-801 dosage wu d u d Bwn 1 m m in arpaimcnt 1 to 0.5 mgkg in Expaimeiit 2 in

an attempt to duce the sîumbJir@disofientiag type of bdiaviot obmd widi the b i g k MK-

801 dose. The dosages of tbe reraainder of the dnyp wac kcpt the same fat comparison

purposes and to increase the numbct of Mimals in cach group.

MtthQd3

On P25, cuiimals îkom both diet tnihaenis wa-e rdmllristcred randomly r si@e

aibaituicau dose of one of: AMPA (10 me/ks); NBQX (20 mgkg); MK-BOl(0.5 mgkg);

CPP (20 mgkg); or 0.W physiologid saline. M riiimJI were injecteci with NMDA (20 m&g,

s.c.) 30 min foUow@ the yection. For ali pups n=7 cxcept WAMPA ad Wsrünc n=6;

conmI-Salim IF%. The behavioral ObSCNations ud amisticai rnrlyPJ wac the same as in

Eirperiment 1.

h u l b

A signifiant mUa &dct of diet F(1.59) = 49.7, p0.0001 on #iaue ramty wu

obsctvedwithPbQlposed rnimrlr~hyinebi~oVagmernKiaucldsthui~~mrd

mimais. A min drug dikt (F(4,59) = 27.7, p¶.000] wu o b d . Iii dditioa, r sipifiant

diet/dnrg i a t d o n [F(4,59) = 3.27. p i . O l f l wu Jlo obsuvai. The spcclfic resuîts of arch

pharmacologicaî qpt are d t ~ c n i bdow.

orposeû gmup than the wntro1 group (set! Fis 2). The Pbsriline gmup wu si@iady higk

w . 0 5 ) tban the oontrol-srline gmup rt 5 of the 8 îime intervals.

llPE

Animais in the Pb-CPP gmup dUplayed signüidy hi@r rQnin acâivity across JI time

intuvals a d in the mcan o v d sQaue activity ratings rn.05) than the both control-CPP and

the Pb-& gmups (me Fig. 2).

NmC

The Pb-NBQX animais displaycd significantiy hi* w . 0 5 ) sQave acfivity nthp

than the control-NBQX &a the nrst 5 min obsavation pcriod. No siflcant ditferencc was

round between the Pb-NBQX and W h gmups (sm Fig. 2).

AMPA

thatbamntrol-AMPAullmalsb*wtan lOand3Saim. n i t o d r e i n m d v i t y w ~

si@cantly hi* @<O.OS) for the Pb-AMPA gmup in cornpiruon to the contro1-AMPA

group. Tbae waa no diffetence in o v a l l seizure activity,rathgs bctween the Pb-AMPA ad Pb

saiine groups (see Fig. 2).

maL

witb MK-801 h bot , Pb .Id d yimiib yiddd a denifiant iaaacC

in thc behavioral mhgs for dl thne intemûs ud in o d s e h m raniity m.05) in

oompoiioii to dine treated mimais. The W-MKgOl tnd mmoî-MK-801 mimais did not

diaarbomachotbciincQnirarctjVay~(~Fîg.2) .

34

Discussion

T b PBMK-801(0.5 and PbCPP Mmrlr demonstrateci r ign i i jdy h i g h

kvdr tbin the Pb-Slünc raimPlr. Altbwgh ths ~OSC of MK-801 wrt ~ U C A tû 0.5

m@kg MK-ûOI hom 1 .O mg/b in the prrviwr exphen& this lowa dose of=-801

continucd to naih in signifiant incmsm in scizure d v i t y as cornpucd to Pb-sdine gmups. A

possible explanation for this U MK-8û1 rdministd at tlns dose miy have triggd a

. compeasatory mechanism in the bippoumprr. E x d v e blocking of tha NMDA receptor

compkx prior to the Odmiiostration of NMDA m y have causuj an increase in d t i v i t y at the

tCCCI)tor Isvd. The subsequent administration of NMDA 30 min later may incms #Uun

activity to a kvd higher than tht Wllüns group. Si@amt devations in NMDA naptor

binding in the hippocampus of Pbcxposeû rmmils hw bem dsmonstratd by Brooks et al.,

(1993). An innare in the nmbcr of fidccptom may exp& the compensatory up-mgdadon of

mepton which WY strongly suggested in this eqehmt hum .ccoUntmg for the

upanenPtivity to NMDA demonstmted by the Pb-exposed uiimilr. It b codvrble tbit the

MK-801 dom donc may have kca d u e n t to indua an upmgubion of the NMDA rroeptors

since the W-MK801 rnd oontrol-MK-801 groups showcd Banlu devated l d s of seinire

activitiia. Howmr, tbU U a vcry short thne paiod for a ubstantki upmgdation of receptom

rid it t coaoQvable tht otha Wors may be imroIvaî.

Tbe resuits of the pdouc studies niggcrtcd &a! the NMDA systun was the prlliipy

receptor chaad cornpiex riffected by Pb. Thereforq tba nvrant acpaiment was undedaken to

examine the NMDA system in more detaii. To aocomplish this goal, chanBa in the dosaga of

NMDA anâ MK-801 were made In an attcmpt to d n i w t e the floor effbcta obwved in

Experiment 1, the dose dNMDA wu inaeued hm 20 mgkg to 30 mgkg in tbis replication.

Two additionai MK-801 doses wae admhktttdd (O. 1 m&~ rnd 0.05 m@g) to WCT

examine the intaaion of MK-801 and Pb. F o i y s in an attempt to understand the d i i k i q

CPP results in Expaimat 1 and trpaimait 2, and obtria consistent d t s with this antagonist,

the do- wu i n c m d Born 20 m@g to 30 W.

Mtthoda

On PZ5 animais h m both diet tmûmmts w w rdmiriistd d o m l y a single

aibaitu#our do= of O ~ C of MK-801(0.1 w; MK-801(0.05 rqg/Lg); CPP (30 *);

or 0.9% physiological d n e . AU animals wac injcctd with NMDA (30 mgtks, s.c) 30 min

foüo* the &st injection. For aU gmips ap6 uccept Pb-MKo8û1 (O. lrnghg) n=5; ad Pb

srüna ad cmtro1-salinc n=4. The behavionl o b ~ o n s and Stisistial uulyss wcm the Mme

rciaExpaimait 1.

h u m

A signifiant miin dl'ibct of dia [F(1.35) = 11.07, p10.002) and dnq F(3.35) = 3.32

@.O3 11 w a o b ~ e d . The diet/dnig intctlction wu not si@cant F(3.35) = 1.32. e.2831.

The re8ul!8 of each phrmtcologîoJ a@at 8m wed baow.

uios

The ovarll wm rctmtym&swere Pgnifiouitlyhigher(p4.05) in thePb

the rcSuitafiotMIL401 (0.l.mglLs)8œ-~llloPb-M#1801 ~ p ~ u p ( O * O s

r b o a r a l W i n t r a . d i v i t y r i m i l r r t ~ ~ ~ . r l i n c ( g a t p ~ t h t t l P I l o w d o s o o f M K ~ l

wu inadcquate in bl* the ieaiitivi(y to NMDk

The proposeâ atiwnM1(sant pmpatics of NBQX werc aot apparent in this arpaiment

with the Pb-NBQX riiimib dunons tdq reinirc d t y rimürr to the Pb-sdine mids. Thir

aiggests that b k k i q the AMPA fdCCPtOm d m not duce scizurc activity in WIIIposeâ

rnimilrndththnurlwiaiitn&edin#inirsrotmtywasunderthein&i~tl~tofthe

NMDA rcceptot and d e c t e d ôy lctivity at the non-NMDA recepton. Also8 0, the

AMPA receptom did not alter reiPue lctivity in ths Pb-AMPA dm& in cornpuriion to the Pb-

SalintaniinalS.

A h h o u g h t h c t C S U l t s & o m ~ 1 su~esttbatpraadmuustnh ka of CPP (20 .

mgllrg) in pb.cxpo#d uumals miy atmuate the I d of bdirvioral activation towucb w m l

l eda (see Fig. 1). fimdonin,g to tanponrily mase the danage to the g î u ~ ~ ~ c r g i c systun

iaduocdbyPb,tbcra~waenottcpli~adinEirpaimcatZmrwitbBP(30msnte)h

Expabn t 3. ûther pnüniinuy resauch in our iaboratory (unpubfished &ta) apniiniae the

cffads of CPP at a lowa dose of 10 on Pbexp~sed animais at a dighlly olda age (P32)

hw yidded an enSt of CPP at 10- the scizure ntiqe, in tbese animals. Unfortunately,

because of the b w n changes in NMDA with devdopmental age. it U not possii to compare

the# &ta direcuy ka fiirtba ra#uch is warrantai to dctaniiae if a biphPc dose relationship

p a h p s ~ ~ w i t h P b 8 n d C P P .

M e t h o â ~ Coaaidttrüona

~ d i e b c a t ~ o f N M D A ( 2 O ~ o r 3 0 ~ ~ r l m o r t i d c a t i d I « d r

0f#inmictRiayuithePb-~grou~HgrL~1~(1~3)hwsbo~11tht~~m

39

- Pb Control

MK-8û1(.1) MKBO1(.05) CPP Saline

Drug

Figure 3. Overall seizure activity (mean rating 2 SEM) for control and Pb-expod animais adrninistaed various dnigs followed by NMDA (30mgkg). indicates signîficant differences (@.OS) h e e n control and respective Pb group.

bipbuio dose relationship &sts with Pô rnd tbc wmpdih NMDA antqonist CPP. The

Time (Min)

- Pb - Control

Dnig Figure 4 A. The seinire activity (mean rating 2 SEM) over time for control and Pb-exposed animals ad-stered MK-801 prior to NMDA (30mglkg). The Pb-saline group demonstrated sigaificantly higher seizure activity than the control-saline group across ail time intervals. * indicates significant differences @<O.OS) between Pb-MK-80 1 and Control-MK-80 1 ; - indicates si@cant differences between Pb-MK-80 1 and Pb-saüne.

B. Overd sehure activity (mean ratine f SEM) for control and Pb groups above. indicates significant differences (p<O.05) between control and respective Pb group;

** indicates significant differences @<O.OS) between Pb group.

--A EXPERMENT !k THE MORRIS WATER MAZE

Thc Morris w ~ a nirzq a bvioral task thiit aliows the qdCILt ion of the stm@

a n d ~ o f r p i t i r l I t a p i a a ~ u t Ü i E C d t o ~ t b e ~ o f N M D A u d V U i ~ ~ d o # s o f

MK-801 on Pbcxposed animais. Past d hu d c l i l o ~ t t d tht chmnic ddopmental Pb

a<posurr d t s in impaireci aquhition of rprtial lauaiiig on t h tasle. This Qcpaimait wu

undertaken to racesc the effdcts of NMDA and MK-801 on Young PaarpOseâ rats on this tade.

Mttbads

On P?8* uEmils ann t u t d in r modificd M o d wita mane with a diameta of 80.5

an. andadepthof22.Oun. Thcmazcwasfllldwithwatcrto 1.5 anaboveadcar, Qrnilu

plexiglas goal pl&orm 16.5 cm high ad 5.5 cm in diameta. Four cardinal loca!ions of entry

were markad on the outside of the mazq north O, south (SIs eut (E) and w a (W) diviâhg the

maze into fw q w h t s , one of wbich oonrriaad the phtbm. Exttr-maze rprtirl a#r incldecl

a v i d w r o o o r d a m o u a t e d r b 0 w h ~ 1 t W U d ~ ~ ~ ~ b d d n d t h e m r t c . t

E. Onh~dryoft~rllrnimilrwatrdrptedto~~dplrtfomibyplrcanaitontbe

goal platform in the mioc for tai seconds.

Aaimrls h m both diet trsitmaits wac aâministcreâ d o r d y a singît dose of NMDA

(lû@kg); MK-80 1 (0.01 nie/ke); MK-801 (0.05 a; MK-801 (0.1 m g ) ; or 0.PA

p h y s i o l o g i a l r r ü a q 3 0 m h p n o r t o ~ ~ d i y . Aiirnimalswactcstdfwhwtrirkpsr

diy. on Iwr co~lsdcutive days with a d o m order of initiai amy point on adi diy.

Pdormanco of the riimul wu recordad rad prajectd to an djacat m m via M

ovaberd c l o a t d Q r c u i t o r m a r E i o b ~ ~ ~ l o ~ b y b i r t r ü t o a M d a m f y d ~

urdiarl~~nwhichwumtrtdtor~pooitionfaarchubsepudllittrirl.~tims

t d r e i i t o d t k g d p l r t f b r m r a d h W ~ ~ e d t h a p . t h ( t h s ~ e k a w r e n b

4s

~ h m i i q p d t h c d k c t p P l h h o m t k ~ c r Y v A U u r r t o t h c ~ ) w c r e m .

EachWwas2 a i i i i i n l ~ w i t h m i n t a r r L l i n t d o f 3 0 ~ . ûnccthegd plitfonnor

o Q l i P e b ~ ~ ~ t h e u d m J w u r c m ~ v s d n O m ~ ~ t o w d d n r d andrranisdtoits

home~whichwrrdbyibsrt i i \g lunp.

Oatbefddiyoft~duiimJc~uptsdintwoatntriils,rproktrirluida

visual discrimuiati a *on triai. Duhg the probe triai the platfonn was rsmovcd fiom the maze Md

the amount of time spait in the goal quadrant d* the 2 niin üiaJ wu m r d e d . For the visuai

diSctirnination triai, an orange d e r waa attackd u a vinul nie to the g d platform and the

thne taka to reach the platfonn wu tacordai. The rmximum tirne dowed to cornpletc the task

w s s 2 h

Sutbtieil Andysb

A US. 4 4 split-plot tictond ANOVA wu ut i l id to adyam the q u b 4 &y trirl dru

T b atmai rubject variables wara diet ind dru8 d the within aibjcct vMab1c was day. Two

dspcidmt variables were ussd, meui aapo IrtCIICies to the hidden pkâonn and initial hcadings.

Subsequent pst-hoc analysis was cunducted usiog Duncan tuu whcai the ANûVA reachd

o v d !Ii@crnoe (p<.OS).

The probe rad v i d y - c u d triais wem riulylsd witb r two way ANOVA to examine the

&actr of the hueen abject wiiblea of dia d drug. For thc prok triais the depadcnt

vuiible~tlmecpanh11#wmçtpurdnatindtort&virurlly~~~drridstbedepend~

~lewmbmeanacrpelata ioytothecuedp~rm. Initttheadingwasalso~rdadrad

milyzsd u r dependent masun. Subsequaü post-boc d y a b wu conductecl Iniacrn

tests wbea the ovarll ANOVA reachaâ sigdance *.OS).

Rcrolb

ErgiLr T W

A main &ad of drug wrr obsuwd for both the dcpadeat msannes of mean escape

l a t d c s F(4.59) = 12.54, pc0.000] rnd iriitiil herdings [p(4,54) = 6.81,@.000]. No

sienificant main of dKt was observeâ for mean uap ia tdes IF(1.59) = .04, pE0.850],

(me Table 2) or iniw p(4.54) = 1.4 1, w.24 1 b (sec Table 3). Then wu no diet/d.8

interaction for man etcape latendes m . 3 8 5 ) or initial hdhgs F94.54) = 1.21, p=O.316].

&di, then wrr a signifiant &y e t k t (gQ.0000) ad dmg/day i n t d o n

(p30.042) for the meui escape la tdes . Each &y m l t d in a dgnüicant dccmse in meyi

escape latcncy across groups @=û.ûûû). T h w was no sigdflcant effkct of day on initial

hcdings.

The MK-801 (O. 1 mflg) gmup h w e d an inamse in mean o v d escape latendu '

(plo.Oûû) wbai cdlrpscd iaor diet comparai to rll otba dm8 groups (ree Fig. SA).

SprcieuUy, a Cgnüïcant d i f f h m was hd betwœn MK-û01(0.1 m*) and the NMDA

p p on &y 1, Ath thc MK-801 group d e m ~ w 10- kmc# to Bnd th0 biddai

platform (sœ Fig SB). On days 5 3, and 4 tbe MK-801 group took si@@ longer to nnd

the platforrn compareci to di 0 t h group. The MK-801(0.05 mgkg) group dso hd a

signifiant incrercc (p4.000) in marn o d escape latdcs , kit ody in comprison to the

NMDA group, spe&aUy rt &y 4 (roc Fie. SA and B).

The MK-801(0.1 m) rpatp ibowed a igniûcant (pe0.000) inonue in mam imttl

CiSiificmtmainsgSd o f d i s t F ( 1 $ 2 ~ = . O L & ~ ~ b r t b o ~ b i r l o a t h 6 ~

mcra~e of t h rpait in the CO- qurdnnt. l'hem wu a b no dietldrug i n t d o n p(4.52) =

1.3, p10.2911.

Wbüe the Pb-cxposcd group Jid show d W m in the initial hcrdings as wmpd to

controi uiUnrlq this diâ not mach sigm8cance F(1,55) = 3.3, p==û.O7S]. No main dnd ofdnig

F(4.55) = .9 1, p=0.464] or diddrug i n t d o n [F(4,55) = .43, W. 7891 was observeci.

ThCMK-801 (O*lmgllrg)~prpsatà@~~1liyl~~(p<0.01)in~oonact

quadmt whcn compad to the otha group~ (me Fg* 74 . No other gmps warc signifjcra<iy

différent h m tach otha and no sà@&ant d i f f bms wa f d acrosa goups in the initiai

headings takm to n u h the platform (see Table 4).

VuuiUg-cued Triil

A sienifiunt min dbt of dru8 F(4.59) = 20.9, p0.0001 wu o b d but th- was

no miin &kt of diet F(l,S9) = 0.25, p0.6161 or diddiug i n t d o n F(4.59) = 0.67,

fl.6151 on maia escape liteacy.

Tbae was a ignificant hcrcase (p4I.0000) in the vidy-cued laîaioy for the MK-801

(0.1 wbca CO@ to dl othw dmg groups, witb the MK-801 lpoup takine longer to

rcaci~ the plrtform (tee Fig. 7B). b

The initlll bdhgs fbr the vi~-aad trUl showal no mrin &a of diet, F(1.56) =

0.06, p30.3721, drug F(4,56) = 1.09, p = 0.3721, or dieth* i n t d o n rF(4.56) * .48,

p4.7521. Tabla 5 show the initirl îmâhgs taka

Diseurrion

A ~ d c i l d b w l s d g e b u b ~ a i i h n a u o o b c a i ~ ~ o m i i c i l . r a d

a e u r o p h y l d ~ W i w t h e ~ ~ ~ b ~ w i t h î b e M o r r i r w i t a ~ p M d i g m

48

biw Pb levds (1000 ppm) yiddeb no hLP intk h@pomn@ CA1 mgkm wich

respect to gder or dia (aser & Müetic, 2000).

The lack of signifiant diet &td in thb study muid poocily ôe explaincû by rereuch

finditigs suaesting that the NMDA receptor~ NMDA receptor-madiated LTP, ud eva~ the

hippoampu itaelfam not rcquired for the leu ni^ of rp.ttl tab Jthough they may contnie

in a non es- way to spatial lami@ (Cain, 1998). Atta prrtnimn8 rats dministd

NMDA reccptor antagonistr !O a visuiUyaed pWonn, Cain, (1998) showai that these nt8

wae subsequently able to successfUy leam the location of a Yddcn pluforni in the Morrir mer

meamhm suggest that hippocampal dunyle dom mt to pravart the f d o n of rp.tia

rmps but instd i n t d i 4 t h îhc use of the UlformafiOu to @de locomotion thtough the

eflvir0NIIcnf.

Furtbamore,Huortactrl.. (19%)~vedK,wntbatfya~knockait mice, inwbich

h i p p o c m i p i l L T P L b ~ o r r b a a i t o u i ~ ~ M a r U ~ a ~ ~ ~ t h s y n d f a m

inipaiimaatthtcompro~dieirrbüitytoswimnana9y. ~ m a y b e U i t i d m P b -

@uiimrlrkit~~ykuwwdiruptioadtbcrrtrianl~m&thitl~

rrspoiua cumot k rpplicd flucii to novû Mons This b a h aupportaâ by the hdhgs of

P e t i t e r l , ( 1 9 8 3 ) , h w b i c h ~ ~ t r ~ n i o r r ~ ~ ~ ~

rewards on DRL-20 tasks.

Dny Effbda

AsBiiifimdnigcffccta~obmdULWsbchGdtidcAW@Pbhukan

h w n to d u c e the biding of MK-801 to NMDA m o r s (Omdchenko et al.. 1996,1991;

Cory-SIechtr et d., 1997; Shgh & rang, 1997; GutowrlO et al., 1998; Rurn et ai., 1998; Gübert

st ai., 1999) no MW801 interaction was observecl. The I.cL of diet efftct sumests that any Pb-

induccd rcâuciion of binding ifpresent wu not @&ive. Possily this mhiiiition of binding could

explain why the lowa dosa of MK-801 in the p m m t 3tudy (with the acept of the 0.05 m m

dose of MK-801 a u h g a süght, but signifiant, inaerso in îatcncy as oompMd to saiine on the

fourth &y of test in^), causecl paifonnuums rimüu to dine ad NMDk whi* the O. 1 m&

doae of MK-801 causeâ seriais d m in the mer m z q impairin8 acquisition of spatiaî

learning on ail trials.

The sensitivity of NMDA mcqtors to Pb inhibition is dependait on the rcceptor subunit

composition (ûmelcbeako et ai., 1996). The# rtsc~vchers hve danonstrated tht Xenopus

oocytu with NMDA tcotptors constructed with oniy NRI/NR2A or NRI/NR2B aibunit

i n l o e s , ~ w t o c h o a e s c a i i m ~ n t ~ ~ r f e x , a ' m o n ~ t o r m i i b i t i o n ~ r a n ~ b

thn those wnsüucted h m 1 tliree aubunits i.e. NRl/NR2NNR2B. Tnis mcarch n i ~ c s t s t h t

rats with NMDA mcptor subunit cumposition simiiar to those displayed at maturity w d d k

leas subject to Pb &a. The phrmroiogical spdiaty for the NMDA reccptor in the tnature

nt waild be 10- sincc fcwa îmmame NMDA m o n would k prrsait.

NRI mRNAQ<prcsrionhthebippoormpuofpb.arpod~perlrrrt21 -and

-A - then h l L t o ~ ~ ~ 0 m p u i b 1 ~ t o ~ . T h s N R U m R N A ~ J l o p a l t l c t ~ t o 2 1

days of age whilc NR2B mRNA a p d o n fLUr with age (Guilartc & McGIdm, 1998). nicre

dui~~~estthittbeeffectsofPbonbduviorwül~liLdy~fld~to21 dayain

rrsponsc to th large expression of N'RI mRNA S h e the NMûA mcqtor nimba wodd k at

a perL, it h potsible this comIates with the Jett et 11.. (19978) findine rrporting a pdc in

behavioral d d a t s meacwed by the Moms wita mue at P21. The nimnt mdy wm

udcrtakcn at a lrta stage of d d o p m a i t (P28) anâ hippocunpû NMDA receptor

coaformation w d d k closer to tha! of the rduh. Leaâ d d h m lm of an d i on lemming

involviq NMDA receptor activation in thU arq a bypoth& rotlec&d in the d t r of thir

study. The î d î q that bnia Pb lcvds peak neu P(l4) ad dccmmc thraigh (P28) (NIIIIU &

~ t , 1 9 Q 9 ) U ~ 0 n s i s t ~ w i t b t h i a v i m ~ t l i U m o d d w o u l d p ~ ~ a d ~ h P b .

b ~ ~ o m r n d t h u s a d ~ i a ~ ~ a i n t o f P b ~ i n ~ b r i i q a l t h o u ~ ~

&kt m y rlsa reflect muuntion of the blood brin.

Racentiy N i et al.. 2000, bve demonsbated in Pb-axpoasd ud control &termates a

siflcant dose dependent reduction of NRl subunit gene rnd pmtein expression in the

hippocampia Wts of tbe# rcscadm m m dut rata ckonically exposai to Pb may have

f m or d t d NMDA rcœpton comprrrd to controb and tbrt this reûuction in NR1 subunits

may UllCIeriic the dc6ats of spatial Ieaming and LTP. Unfbrtunrteiy, the tcsting pdod of P28 to

P32 in the nimat study ir correiatd with a iate point in bippooimpal dGYOlopment, and &kt

o l i ~ M o < N w i t a ~ ~ ~ 1 t b U ~ o o u l d b t o o a i b t k t o d a e a .

N M D A ~ ~ d t b o u ~ r i s p i s ~ b e t t e r r t c d v i 4 g t h t M o n U w r t a m a z e

t b u i ~ n r i w i t h ~ ~ l a v a o f M K - 8 0 l arpoaaertillâibdto~lutritauiyPgai6orat

i m p r o ~ o r b p a h m t s w b c n ~ t o ~ ~ ~ i n t h c ~

52

s h i & . A g i i o t b i i , h d h g ~ ~ t n d i c t a p a s & ~ ~ U P t ~ A d i g i p r t n b i o s ~ r

d e c r d rality to leam in a d t i iobsdule of nl#rtod acquisition iad pafwmiacc (Cobn &

Coy-Slscbsr, 19W; Cgr-Slechta et ai., 1997). Althaigâ NMDA rats did have rüshtly Mer

escapeIiteaciesondays 1.2, and 3,die~oftbeNMDA~ptodifiF~~d@untlyfiom

the d m gmp is aot undcmtood.

Several tcsclllchefs have reporteci Uiaslstd escape l a t d e s with MK-801 administration

in the Mords water m i ~ c with the thrtdiold do# qu i& fw Uiip.irrd acquisition m g h g h m

0.05 mgkg to 0.2 m g (Fi- & Blrnchct, 1995; Hale & Hadey, 1990, Kant, Wright,

Win, & D'Angdo, 1991; McLMb et d.,1990, Win, Crooks, Slinihirm & Cirllrghr,

1989; Whirbrw & Auer, 1989; Ylinen et al., 1995). MK-801 dmiaistration resuited in a dose

dependent &kt on lemhg in thir stuây, witb tbe MK-801(0.1 m g ) group derno-

acquiring r Eidr. It ir possiile that tbae sensorimotor âktwbms could e x p h the spatial

lcamiq ddkits that were obsavcd in tbia saidy wah MK-801 rdministdon. If rats are

iatroduccd to tbc ta& throu& utha spittl or nosspatial prs-tmining t h y can jdonn

nonnilly in the Mo* water mam &a bl- NMDALTP induction (Buiaamui et al.,

1995; Saucier & C& 1995; Saucier et J., 1996; CM. 1998). Dirturbaacss aidi rs &cihg

swhdng owr, or dcfiecting off of the plrtlonn w w Ob- but not fdcorded in this study

anci it is not possible to racatrin if the bigha dosage of MK-801 d t e d in i n d

semohotot dhduhwu. It is colKiCivaô1e that the d d & Ob- may mt involve spatial

Icuiiiqg at 4 but in hd, mry only k r netledon of i waioiimotor d i m .

hobe and Vüuai!y-Cueü Triab

Thav isur l l y~d~wzruader takento~thcrb iü ty torp i t i i l l y lmth t

pWom location bom the buio abiüity of the Immil to niim ind perfom viurl disaimlliltions

(McNamam & Skdtoa, 1993). The d t s of thh stuây md othar. sbow dut Mimals rccciving

MK-ûOl(0.1 m m ) wae imprirrd in the aqhition d t h t visurllyaed as wd as in the

biddea pkfônn proôe test ( R o b i n et al, 1989; Ahluide et 1,1999). in the p m t mdy,

the htda of the MK-801(0.1 wara more tbin 10 tirnec h i g k th the dine -p.

Tbe~thrttheMK-ûOl(O.05 ~ ~ p # i p w i o ~ i n b w n i e d t u L s u ~ t h t

thsI~impiimseacecnintbebid~plrtfOnntuLondry4wuputlyrttri~leto

Dmg Condition

. + NMOA 4 MK801 .Olmg/kg + MK-4301 .05mg/kg -4;~- MK-801 .1 -0 + Saline

Figure 5. A. Mean overail escape latency (in sec + SEM) to n c h the hidden platform for each dmg group wffapseâ amas dia. 3 s dgnificantly diffemit Born al1 other groups (p=o.oOo).

B. The day by drug interaction for the mean escape latcncies (in sec + SEM) collapsed across diet gmups *is significantly different QHI.000) Rom ** on Day 1 and fiom al1 otha groups on Days 2,3 and 4. * ** is significantIy different (p=O.ûûû) h m ** on Day 4.

0 57

Drug Condition

Saline

Figure 6. Mean initiai heoding rngle (in degrees + SEM) for each drug group. Diet groups were not signincantly difkent fiom each other is significantly different fiom all otha groups.

NMOA MK-1 M K a 1 M K a 1 Wiiw .Olm@g .05m#kQ .lmQ(kO

Dnig Condltlon

NMDA MK-801 MK-801 MK-801 Saline .OlmQlkO .05mQ(kg .lmOlkg

Dnig Condition

Figure 7. A. The probe trial mean escape latencies (i sec + SEM) for each dnig and diet condition. Diet groups were not sigdicantly d k e n t fiom each other * indicates signiacant difference ftom al1 other groups (pc0.01). B. The visualniecl trial mean escape latencies (in sec + SEM) for each drug and diet condition. Diet conditions were not significantly different fiom each other. * indicates significant dinerence fiom al1 other groups @<0.000).

59

Table 2

Mcra Escape Lattncy by Dkt and Dnyl i c m m the Four Days of Tcrting

MK-801(0.05 mgk@

a = Nurnbcr of pups in group b = Mean labllcy (sec) + SEM

0'

30

6

6

6

6

6

39

7

7

8

9

8

Ltey

Day 1

110.5 + 4.6b 93.3 f 14.2

116.3 2 2.6

119.5 2.1

116.5 4 . 9

107.2 t 7.9

112 2 3.5

106 +, 10.4

114 2 2

104.2210.4

1202 O

u . 6 + 3-5

Day 2

88.6 + 8.2 63.5 & 20

f7.2 f 20.3

103.1 S .

120 2 O

mi19

89.3 f 7.1

72.8 f 18

66.6 2 19.7

79.7f17.3

120 O

98-6 + 14

Day 3

59.7 + 9.3 33.2 f 16.1

38.2 f 18.3

71.4 22.4

1202 O

35.1213.6

69.6 + 8.3

37.6 2 15.4

362 17.1

60.4419.8

113.5 5 5.8

86-7 + lu

Day 4

47.6 2 9.5

28 18.7

27.3 f 18.6

50 2 20.2

120'0

12. y 3.3

47.8 + 7.5

17.5 f 5.3

22 2 8.6

46.1 f 18

108.3 5 10.3

30.7 + 7-5

Robe Initiai Heading: Mmn An* firi the PlrrtCorm per Diet and D r y Condition

b = Mean initial heuhg angle in delpser + SEM

, D W

I

NMDA (10 L

MK-801 r

MK-80 1

MK-801

Saline

Table 5

V b u ~ u e û Hciding: Meaa Angt h m the Plrttorm per Diet u d Dnig Condition

a = Numbaofpupsintmtmat

Controi

D W

r

NMDA (10

MK-80 1

MK-801

MK-801

Saline

na

5

6

6

5

6

Pb-Ex@

Initial H*

54.0 + 20.8

45.0 2 16.1

55.0 2 23.5

64.0 2 23.2

31.67 f 12.5

a

7

6

8

8

8

r = Numki of pupr in îmtmat b = Mean initial kâing in degrees2 SEM

Iilttl Hading

25.0 11.4

33.3 5 12.6

22.5 4.5

52.5 + 12.1

31.3 f 8.3

CoatiPI if 5

6

6

5

6

Pb-Erporcd

InitirlHeaâiq 29.7 + 7.62'

28.0 & 9.15

41.2 f 17.3

34.0 f 9.0

54.7 f 14.4

a

7

6

8

8

8

Initial Hcnding

19.0 7.6

34.3 & 17.7

42.4 & 14.7

44.8 7.9

37.6 7.6

TbradisOmdpbuerfor~rad~waefdtoWdd* IaphreI,the

demonstrat~r wm fd dsprivsd for 20 h Mlowcd by 30 min accacs to a metrl cup

~ontainins 75 g of ground d e n t chow mixed witb one of the four d i M y meci s p h .

If it WU necusary to use the danaartntor nt in wm than 1 obsemi/denronstrator pairin#

pa day, the demonstrator wu exposd for a minimum of 5 min to the spiced ground chow

prior to the pciirllig, with the total time fbr fbod acccss to the targct spicc for the &y

romrlliingrt30ininAtta~~~fbodarpwuWCi~toUiamthtrtl~1gof

food haû ken &m. lmmcdiatdy rAu, in phase Iï, the daaocistntor was piaced in the

home cage of an a<paimental obtava h m which the f d d wata haâ been maoveci.

The two animals wao a l l o d to in- for 20 min, der which the dawnstrator wu .

removedartdretunidtoitshomecage. Immediatelydteror24lhIita, rnemoryt*

c o m m t l I c d d i a P ~ ~ . I k i o W C i ~ f O o d n i p r ~ 7 S g d t c b o f a r o c a t c d l g w a d

cbow dia , one of which waa identicai to t h &et eaten by the danonsüator were mOUIIfcd

dhctly on the home cage floor of the obsmm 1 cm apart. nie obsava was allowd to

CO- f d fiam b t h aips for 2 h with d lib accus to wata, then the cups wac

nmmd ud raweighed ad the totd wount of etîh diet coircumcd h m each wrr

rccorded. ~Rdoofk~dt&foodMtktbc tNRsdodor ( i . * , tbstugetfd

eatea by th d e m a ~ o r ) conaumeâ and the totd d g h t of food eaten was d to

caiculatepacaittrainaîodatprriaaiee. Attbetheofcachdyâwingthet~paiod~

ms wefe M appr0xiIIwdy 10 g of nt &W.

scitWkilAMjy8ir

Bduvion ld i t iwu~ur iqsr twoanyANOV& tu!iagthe-of&

effbcrr of diet, drus rnd the diet/&us intaaction rt the zero iad 24 hour d&y condition.

T h e d c p n d s n r ~ m r t i l c ~ o f p ~ t a r g c t ~ c a a a m # d b y t h e f a t .

Subsequent pst-hoc anaiysis wtr conductcd ushg Tulry tertc wbea the ANOVA niobed

o d sisnifiance (pe.05) on SPSS.

Raulb

A U d c m o ~ o r ~ c o ~ ~ 1.0ud 5.3 gofthetarget fooâwiththe

mean targct f d consumcd being 2.4 g. The ob#rva rats consumeci beniveen 2.0 ind 7.1 g

of food with r meui f d collsumption of 2.9 8.

Atthe~otimscondition~wuari~~~tniunc&ctofdnig~(1.116)=

7.47, p=û.W7]. No main eEcct of diet F(1.116) = .04, p=û.95]. or diet/drug interaction

F(1.116) = 0.589. p4.4441 wu obsuved. nie ihuhr of the ANOVA at the 24 hr dday

condition w a e simiiar to the taro thnu condition. An overaü significant main &kt ofdnig '

F(l,86) = 4.44. piO.038] w u obrwd witb no miin dbct of dia F(1.86) - 0.953, @.a321 or diet/drug intadion [F(1,86) - 2.47. p10.121.

No signifiant krw#n the proportions of ptbcxposed met f d

c o d was obscrvad whcn oompariq uiimrls exposeci to the Pô diet (58.6%; d) ad

contid diet (59.3%; ado) at the pro time conâition or the Pb die! (48.8%; ~ 4 5 ) and

oontrol dia (55.4%; FU) a! the 24 hr thne wadition (m Fi 8).

MK-801 trrrtwnt d td in r O p i f i a n t dccmac w.05) in the unount of pre-

eqmdtarget f b o d ~ 0 d . t b o t b 1 1 # ~ r n d U b r ~ p o i n t ( ~ F ~ 9 ) . ~ M K -

801rnimJlooasumad53.2$4(ip60)rid 45.946(a-44)a!thczsrorad24Irtimepoht

m s p d d y whüe the iranc MmiL amsumai 64.7% (d) d 58% (n 46). However,

thie wu & d a m of i food iveaion (See Fi 10) in the contrd-MK-ûû1 group

dday Fdlaiiwiiqpd intcmch ~.07f).

Dkusaloo

RatshiveanraalavCrSionforDwalfOodrrndp~siraseuchhudemon~bltdtht

this a d o n cm be duccd if the rat is prcwntd with a cunsprQBc prcviously cxpod to

the unhmüiar f d (GdefB W~gmore, 1983; Gai&& Stein, 1985; Gaiefet al., 1988).

Chronic Pb atpom M no &kt on the proportion of target f d c o n s u d in the SOCU

~ o n t u L r t ô o t h ~ ~ a o r a d 2 4 I v t i n # C O 1 I C Ü t i 0 1 ~ ~ SWy,aosignüicant

Pb/MK-801 interaction waa observai utha tlme point. However, a h a b injected with

MK-801 prior to d intaction c o d a sigmhcantîy Iowa proportion of the pr+

c x p o d f d than uiimilr rdministd snline. The Pb-MK-801 group testad at the 24 br

time condition coamnacd i Iowa proportion of the pra-exposeû food than would k

antiapated by chana*

Lmd rnd k i r i l Tnasmiasion

No signiûcua &kence wu obaamd ktwoai the Pb anâ control dia groupr with

regarâs to the proportion of preexpscd food c o d . nie# fmdings rn in ypeaaant

with 0th rewnh dtll~)mtdng no ruiuction in LTP thrcsh01d or magnitude f o U o ~

demonsmtai 0 bpWc doronrpoars rdrtiondrip ôetwecn Pô ~lpoaire ad LTP. The

curmt dndimgr miy k indicative of such 1 rrlrtioaildp ud p d a p s da% the .Ctivation of

~ ~ ~ r y ~ i n r r r p o a w t o t l i U l a v d o f P b ~ ~ p o r u c J I ~ ~ t & r b i l i t y t o

a c q u i f e t h s l ~ f b o d ~ t o r a n 8 i I l i n t i c t .

A s d i i o i . u A i n d e t r j l i n t h e M a r i r ~ ~ ~ p r w i o u s r e s e u o b h r ~

piovidsdm~fiorthso~~toQIphinPb~bauviorrld~cibby

66

~ o n t h N L Q M r c c c p o r ~ ~ b d i t ~ ~ o I r ( C o r g -

Slechta, 1997; Nu d., 1999,Ni et ai.. 2000; G.&rte & McGiothan, 1998). Such a

m c c h . a i ~ w o u l d n o t d u t e ~ p ~ ~ k d n t b a r o ~ ~ ~ t i a t o a p o d e

a<planation for the absence of any obstfvai W dkt foUowing cxpoam limitcd to the eariy

postnatal paiod.

The role of the hippocampus in wctl traiumission has bem disputed anâ radns to

dite c o n t r o v d (Bunsy & Eichmbam, 1995, Burton c! al., 2000). The prerait hcbgs

are in agreement witb the d of Burton et al.. (2000) refuting the rote of tht

hippocimpus in acquisition of t b sooirl tramnision pudigm. Tbe nirrsnt finâinm nimest

that this l a d of chronic Pb axpoairc dom not akct the ability of the nt to acquirc d

ucploit non spatial iafonnation aquired in a socid tnnavsaon purdigm. If tbe

hippocrmpis is not involveû in noircpotLI rctivitics ud in particular the sochi tiIuwnission

of a food preference, then Pb w d d mt be expacteci to afféct the Icarnina of tbis paradigm

siace the primuy effécts of Pb expaua are essentiaüy iimited to hippocampai cons. Howeva, according to Bwsy rnd Eicheribawn (1995), oniy the conipletc rtmoval of

bippoumppl formation (hippocampus proper, dmutc gynis and ubiculum), mdted in

si@- dSncits in the lesioacd rats' ability to I#rform.thh task whai tagiae was

~ d u a t ü 2 4 ~ r & r i o Q J i n t d o n . A h h o U ~ ~ o r y I ~ m r y k r

reliibbi~ WCIJO~ ~fhippoclmp~l mteenty m tba nt. it rtül romiiar to k dacrmitldd at t~

social mnrmiaron of f d p r t f è m ~ ~ tuL ir d t i v e amgh to detsd any d k b of low

kvd PbQIpoam in rats ad m m speci6ally W'c &CU on hippooMprl NMDA

rOCCPf0m.

MK-ûûl rad Socirl Truumbrioo

- - ~ ~ d a i b r q i l e n t ~ c t ~ ~ r t d d ~ ~ l a w a c h n t b o a a u r t d i n t h l r r a u d y

(Myhd & F1aniSg 1990). Thme h&gs w supported by Jaclwn and Sanger (1989) wbo

reporteci tbat at high concentrations of MK-ûOl a conditiod aversion resuhed w&n the

dmg was administard af€a a mvd sacchsrin drink. Howevcr, at lower doses of MK-801

(ag. 0.W and 0.06 mg/îcg) admals that receivd pfb~tposutc did not MW h m the

i ae rcpa id animais in thsir intakt patterns rad did w t d b i t a d u & food

conaumption, i ükdy indication that thy wac not a<peri* d v induad malaise

(Myhaldk Hem&, 1990). M o u s metuch would hence ream to imply that NMDA

antagonists are able to preveat d laming of diet pd'i if admllllstersd in low

concmtmtions, but ifrdmiiiirtasd in hi* conwntmtions produce a strong conditional

aversions to the new f d . Although these f h h g s may k indicative of r wre locaüzsd

machanim of action, dm* conciusions fimm otfhctory ind gustatory raub ir

Control

O Houn 24 H o u s

Tlme

Figure 8. The mean percentage of targct food consumed by the control and Pb-exposed groups immediateiy following socid interaction (O hr) or atter a 24 hr delay.

Saline MK-801

O Hours 24 Hours

Time

Figure 9. The mcan percentage of target food mnsumed collapsed across diet condition for each dnig group immediately following social interaction (O hr or after a 24 hr delay) . indicates signifiant difference (p<O.OS).

Figure 10.

- Satine MK-80 1

Cont rol

Diet

Pb

Condition

Diet Condition

Saline m M.K-801

The percentage of target food consumed by the control and Pb-exposed group for each dnag treatment (MK-801 or saline) at A. the zero time condition or; B. the 24 hr time condition.

GENERAL DISCUSSION

Consistent with past nsaidi in our hb. txposucc of nt pups to 0.4% Pb &nate

in thar diet did mt àgniîicantiy thair devdopmcntJ wci@ gain as compareci to

control pups fed a sodium carbonate diet. lbir I d of Pb wu obosm .&cc previous

research in our labotatory has sbown thtt it U assodatecl with deficicnt launing anci mmory

capacitics without concomitant demases in body wci8ht or otha ovatly observable

differences (sec Petit, Aifbo & LeBoutillia, 1983).

Tac Pb dose used in thi8 chrdy (0.4%) iCSUlts in b l d Pb levds of 3 17 @dl ud bu

becn labelied as a low to mtdium Pb exposure I d by Petit et al., (1983,1992). It is

important to note that biomarkers such as b l d ud b h Pb lmls arc only Uidirrct

surrogates of the dose ud do not ncccssuüy corcespond to levds of Pb at the ultimite .

targa site. The Pb lcvels dso do not ~lpiain âow .easl to those sitea dinkm by parameters

such as developwntai period of expoaue or o h cbaracteristics aicb u conCsmition and

dmtion of exposurc. A d m of the iitcmtm ülustratm a large range of Pb concentrations

and cxposurc protocols are in aimnt use by meadus. It is codvable that the dose

levd of Pb chosen, as w d as the method of enposurc @ostweiaing protocols vs continuai

arposure initiateci during gestation or a! K i ) m y k r#ponsible for the fiquently

c o n t l i ~ mdts reporteci in the limatum.

E K t d w r o s o u c h b r s ~ ~ d d s t ~ ~ o f P b W h i c h s e o i a s t o ~ ~

its pUUniy c f k ! at the NMDA mccptor. Uahrhmatciy, the aitun of the ~ ~ c c d

changes in NMDA rsaptor b i i rsmiia, umesdvtd. Hownnr, d t s h m th currsat

i a r e u o b i n d i c a t e t h t t h e b e h v i o ~ r r b v i n t r h ~ h ~ @ u t ~ ~ ~ t a g i c ~ c m

involve the NMDA tcceptor *an, not the AMPA receptor qatan.

~ ~ c h ~ ~ ~ t l i i s , c U a i p k a i a a i i E t i o a c S s i t ~ ~ P b r a d

MK-801, prrt of which is count&Wve and aiggests hirthar n#uob diould fQau on

u i d ~ tbir intudon, Attempts to ucpad our aurart undcntadq of this

interaction arc c o n f d e d by sevail hcton making t h resauch more dificult including

1. diffctcnt levds of Pb expoairr produce a wmplcx CUIVC, Bcquentiy observed to be

biphuic in main. 2. a iinear rdatioiwhip with MK-801 d o a aot al- Qcirt as &dent in

the &dataand, 3. changes atthcNMDAmeptorandinPb d t i v i t y o c a a

thtou@out ddopmmt. Ahhough the d t s of thir rareueb appear to oontrsdict maal

otha nseivch fin* there arc many inconsistaicts in the litcmtm. AU of these studies by

otha resecvchen diffiér mothodologidy h m the p m m t study, and &quaitly h m each

other* in tams of the d d o n of Pb enposurc, the animai age rt the connnarement of Pb '

aposuis. radlor the coaoaitntion of Pô in the diet.

Results h m br airraat mearch indicate a potential neuroprotective mle of MK-

mearch into b potmtid ddopmait of a thenpeutic dose for hmwm is warrantad. As a

consequeace of the Ldc of diet Mcci ObSCNCd in both the Morris watcr mrte task and the

socid transmission of food pr&mnce ta& îùture ruuuch M d ôe cürectd at detaaiiiinig

a Pb-sensitive khvioral WC at tbis I d of Pb arpasure or r c t d q to bdiaviod ta&s

pariauiyutüizadinourldondoyhwntodanonstnteW~.~tubdd~

b c d c i û in the rurrnmant of MK401IPb intcndiom ud uiy d o r a t i v e dfkb of MK-

801 (0.1 m m ) . Fuftherstudies*rillaâvanceaitund~of themeduniSmofPb

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