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High basal expression of zif268 in cortex is dependent on intact noradrenergic system
I:.'ur,qwatt Jourmd ~#"l'harma~'oh~,ay -- ~fi*h'cuh(r Pharmacoh~gv Se('tion. 227(1~2!.147-44S i~102 Elscvicl Scic.cc Publishers B V, All n,~:hts icscrvcd II~J22--llOfi/(;2/$05.1111
,!47
ILII'MOI, !H21tR Rapid commtmicafion
High basal expression of zif268 in cortex is dependent on intact ~ noradrenergic system R a t a n V. 13hat a n d .lay M. I-~ar;|ba|| Dep, uotu'nf~ ,d' N~'ut~cieme. I'sv,,tmttt3, a,!.l Ih'hat ioral Sl'iem'e~, hJlm~ Ih;l~kuh Unlit r(ity S<'h~.d ol Meth~'me, Baltimore, M D 21205+2185, {]>~;q
Rt:~ tired 23 Scptembci I~1~t2, acccpl,e,I h Octl(bcr It;q2
The Inmscription faclor Zi!268 displays high ba:;,tl levels ~,4'expression in ¢orlc× ihat appear 1o bc dcpcmlcli! (m I~llysiologicat synaplic aclivity. We rcporl that selective Icsion,~of the Itoratlrcllcrgic syslcln illduccd by DSP4 tllarkcdly SUl:~l)rcssbasal .,:ij208 mRNA levels in corlcx. A~:cordirigly.Ihc i~oradl'CllC|gi¢ '~yM¢ln which projects extensively fo the ¢orlcx arid is Iollically aclj,.v may '~!av a key IO1¢ ill mailltaillillg ii(lllllal |lill|Cl'llS t) ~' g,rP~.' ¢xprcssiOll ill [al'gCl llt~tlrOllS,
Transcription ['aclols; Locus cocrulcus; DSP4 (N-(2-chloroclhyl)-N-cthyl-2-bromobcnzylaminc)
!1Neuronal stimulation can elicit rapid increases in the cxprcssion of several transcription factors. By bindiilg to rcgulatory domains of largcl gencs, these faclors, .such as c-Fos or Zif268, are thought to mediate changes ' i n ncuronal gone expression underlying stimulus-induced neuronal plasticity (Shcng and Grcenberg. lt/91)). h~ addition re; Ihc transient increase in expression typically exhibited by these rapidly inducible transcril> lion factors, Zif268 also displays a promincnl basal level of expression in several braln areas, ivcluding tile cortex (Worlcy ct al., 1991). Pr,i-vious s t t u ~ s indicate tha~ this basal expression of Zlf26 ~' ::-,'cor lcal neurons is drivcn by ongoing, physiological activation of synaptic inputs (Worley et al., 1991). As the noradrcnm'gic neurons of the locus coerulcus project extensively to lhe Ik~rcbrain, including tile cortex, we wondered whetLcr this Jrput, which is tonically active and responds to a broad range of environmental stimuli (Jacobs, l'Og7), may contribute to maintaining Ihc basal cxprc,,sion of Zif268. To examine this possibility, wc asses~;ed the effccts of treating animals with N-(2-chlorocthyl)-N-ethyi-2-bronlobcnzylamine (DSP4), a selective noradrcnergic neurotoxm, Ihat ix i:mrticularly effective al Icsioning tile projections emanating from thc locus coertJlcus (Jonsson et al., 1981). I~A::Ic ,~]i::',:gue-I)~tV,'[CV~':9_~;(200-250 g/were [,iven a single injection of I)SP4 hydrochloride (5(I ntg/kg, i.p.) ('Ol'fCspol(dt~llct~ t(1: l)r. Rajah Bhat, DeDartlnt~nl of Ncuroscicnc¢, WBSB 9[}8, Johns I!opkins University SCllOOl of Medicine. 725 North W~II'c ,qtlccl, Bahimolc. MD 2121}5-2185. USA. Tel. (,111)/(}55-25[}{}; Fax (~ II}) t)55-1}383.
that was dissolved in water immediately prior to injecion. These rata were pre-treatcd with the selective scmlonin (5-HT) nptakc inhibitor flnoxctine (10 mg/kg, i.p.) 311 min prior to the DSP4 il;jeclion to prcvcnt possible effects of DSP4 on 5-HT projcctions. Animals were sacrificed 3 days aftcr the DSP4 in!eel!on. Brains from conlro[ and trcat~,'d rats were embedded ~ogcthcr and processed for in she Ilybritlizalion, In preliminary studies, we checked lh:;t trcatment with flnoxctinc alone did m~t affect z!1208 mRNA levels. Ill some animals, norcpincphrinc (NE) levels in cortex were mcast~red using standard HPLC techniques (Kubos and Robinson, !984) to confirm that NE lcvels wcrc rcducod to less than 5% of control levels by the DSP4 injection. 3SS-cRNA was synthesized from a lincarizcd lcn'platc contaiqil~g a full ienglh ral zti/268 , D N A (kindly provided by J, Milbrandl), Cryostat sections (12 ~m) were incubated with approximately 10(' cpm rd~oprobc overnight at 56°C and then washed at 35"C with l0 ,ttg/ml RNAsc A in 2 × SSC as described (Bhat ct al., 1992). DSP4 admini~;trat:on produced a marked supprcssi,m ip basal lev,~ls of ziJ268 mRNA in the neocoriex and si:riatum (i:p. I, top two panels). In contrast, hybridization in hi!~pocampns was lmaffccted, while tile pyriloml c:~rtcx displayed smallcr decreases. To assess !lie seleclivHy of this iicatmcilL wc al:;o examined ~,l~e response to Icsioning the 5-I-I'1" system. To this end, rats wcre injected witll the specific 5-HT neurotoxin p-chloroamphctamli;c ( P C A 10 mg/kg, i.p.) which lesions 5-HT projections, cspecially those ocnved fi~,,~" the dorsal raphc (Mamot, nas and Moll!vet, 1988), in
4,is st:. ]tl l~icviotts shidic~,
~ P ,i
CCN
v,c have d e n l t i n S l l a l c d I h i l l lUflilt~al fit Mfol'~"nl r ¢ l h l a l inpul SLIpl]rCss¢$ ;,([~}(ji~ in lh¢ p r i l l l a l y via;tiM t't)rlc':< (W~irley cl ill., l~t~ll ). A ¢ ¢ o r d itll/!y, thc~c basal levels ;.ipllcar It) be d r i v e l l by o l l g o i r i g l~lly~d~lol,,.icM ~.)n~pii¢ a ¢ l i v i i y . T h e finding.s o f l h i s s l u d y mdic~ti¢ lh;il ih¢ NI:] Sysl¢ili w h i c h i~ I o n i ¢ a l l y a ¢ l i v e ~il~t~ ¢onli+ibtil¢~ hi i l l i t h l l a i l l i n g basal e x p r e s s i o n o f zi/2(~7, In l-CCelll SltldJc's. we IlIIVC f o u n d l h a l chronic
t.'OCLIillL'lre;dlnlelll prilduces il reversihle s u p p r e s s i o n of haslil levels of :(/268 in the cortex a n d s t r i a t u m , but not h i p p o c a n i p u s (13h:il cl al,, 1992). C o n c e i v a b l y , ¢ocaill¢'s e f f c c l rilav be m c d i a l c d viii a l u n c l i t m a l d i s r u p li, in o f ih;" N[,] syMcni. O u r f i n d i n g s suggt;sl I h l i l the N l i s)'Melll etiIl c x c t t l o n g - l c i l n el'feels Oll ¢ortic'al liC|lrllliS hy a t l e r i n g eXplCssion o f Zif2t~X. T h u s , f',lis n l t l n i l i l l l l i n e syMelll, w l l i ¢ h is ¢ X t l u i s i l c l y s c n s i l i v e l o C i l v i r o i i n l c ' l l l a l s l i n i u l i , m a y p r o v i d e ~iil live||tie I])r changc~, ill the CllVirOllllleill to citie¢l the p a l l e r n o f geric" e x p r e s s i o l l ill ¢orlic:.li IICUrolis.
Aekmlt~ledt~enlcnls
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l,lt'l.' lh;llll~ | ) Rodgel~ hit t"4cclleIll ~c't'!¢laliitI ;l~:,i$1:llll;C' ~il,d "l' ~ll)hilt alld .1. I~ayloI1 [~ll iIkMI){flg HI- k'vcl~. "l'hi~ t~.'ltrk v.'a~, ~llppilr!cd by USI'I tS g!alll~ I)AI)l)211fl d.M.B.), MI tl}llit2(i (J.ll.~ |].}, alld MI11533ti IR.VB.t.
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ix'..,A Reti:renees
! Ig
I
|)3P-I
If~!ccll~tt ~llpplt-,,~c~ b,i~,il Ic~ ~. l~l <'l[efl,k' IIIRNA
l!lhal, R.V.. AJ. ('olc and J,M. I~maban, t~t~i2, ('hronic c~¢aim.' IT~'LIIIIIL,'Iil MIprt'+~t.'~,I~II~LII~'XI~ri2"~iOllel 21~.~(h~ill liI|I~rchram: ill ~ilU h~hiidb'alilm "urdi¢',, J. Phammcol. I x p TlWl. ill pfi<',,,,. I)'Am,ilt~. I,~J., B.I, I.algt.'lII,A.M. 51u~mall and S.I I, Sir~d~:r, I0;.17. ~cI~2ii~i., J;lill
cRNA Ill hr;fin xcc'ti~m,. ]]rliill~ holll corltlt+l ;ilid !rt:+llCt| 1;11~%~t+'rl~" CLIi <,agltlCtlly +ill lilt" llllctlttl~.+ ('llmillCflit'l!lai') hem! t~r.iill~ t~t'lC' tht_qi align,sd ,tlltl cl-tlbcddc-d Ii!~c,l]lt, F h~p l ~ i);lllt'=~ di~pla) c~titmal ~,.,~'lio~l,~ l~l~.~:ll IFlilll II~LII- bl~lt'k~ tOlll~ it~llil " I+~ kdcrlht:? {ll~.'hl~ tll tt~lihiiii p,lll< ], h'h hcllt !)f~llll I~ tlltln ,i l't~lltfi~| ~al arid llt~hl ht.'tlli-ltl~tlII h II~itl ~lllt' ~;IVlilitll]d I d~l}~ ' tt,lltl¢~lll!~ Ltll Illj,u+llltll 4>1IJ( ill/tt} lllj~ i l ~ . 111 I.
,l,lc~d~,. I l l . I ~ 7 .
c;~p:ra:>~ ~<; tile mai kcd suppress|or, p r o d u c e d by DSP4. zi)~2f~X m R N A imvcts wcrc unal'fc~ ted iii arihnals sacrificed 3 days M t c r l h e P L ' A ini~:clhm (fig. 1, b o t i o m
toI~l l~r cemnll and peripheral noIadlc|lalhl¢ llCtirOl~, |{ILL J Pharm~col. 72. 173 Kuh~,,. Ki.. and R G , Rohhe, lm, I~JS4, ('o!liCM ulldelctII~ in lh, ,a! l'if~dL:c~,,l~'~IlllltL'IrIcill l~cJlavinral ic%pOll%L"~ V,ilh~lli ,l]llt,i~l~ , ,2Llli~'12hilJ;iIllilIc~ii11ct[lli,lllilll ~,, I ~,I~.Ncurol. ~3. 154n.
panel), In par;dl¢i siudics, I~1tl , : i l M o p r a n l a ~ i l o r a t l i o g raph7 { D ' A n l a h ~ el al.. 19N7) ~.ls cmpi~)ycd I,~ COlll~rnl l h a l P ( ' A . bill i]ol D S P 4 trt'cltlltCrll~ ~<~,~i~c f f ¢ c l i v c ill lcsioiiilig. 5 - 1 I f Icrnlin:.its t d a l i n~ll ~ t l o ~ l ) . "l'tlc a b i [ i l y el DSP-1 1o stii~prl.,~s basal e x p r e s s i o n o f 2([76+~' indicatc:~ l h a l Llnder !)hy,;ioltlgicat c o r l d i t i o n s lh¢ HI},. sy~lt~lfl plays a key role m mairiiaininl.,, ,qesc Ievcl~. T h e rcgionat s e l e c t i v i t y in Ih¢ Stlpprt:sSiOl/StlggCsls ih~il l h c olI~cr~,'¢ct (tcc'rca~,¢ i'~ IlOI rncre!y dLIg I?, ~I iitJil-
,q;ecific of feel t~,f DStM t,n h)'l;ricti/ali~m to n l l t N A i)~2i-
( ' c n i n l l III(lliiiilnlilIL'Q, ic IICIIi~:~-" ~,illgle lllliI Mudiv ~, ill 11~.'Jl;l~ill~ ;#llillI;ll~., ill[ l)'~rchol'~hill'lllilCOJog~.: The Third (;l~'IIL'IJllt)ll Ill Phi!?.f~L~.'%cd. II.Y ML'hzcl (J'~il'~L'll I)I'L'S~. NL'w Y~tk) p 159 ,hm,~m. (;.. I I. l lalhnan. F P~mzio and S. l~,{~s~, ivX!, I)SP4 (N-2chlorcihyl }.N-~.'|hy]-~-IWOIl!;~ilClll>%nlIlIi?) a Ils~'liJl (.IL'llCl%aiit)li
M.llllOlill;l~. I..A ~llld ~ . l . Molliv¢;. 1~}SS. I'vidcm',' liar dual ~cm(oi!~.'ll~ic 131oj~.'clil~ll~. hi IIL'OCOI'(~>~: [IXOll~, t'f{llll Iht2 dOIMll ~Illd IIll.'dlilnraph~: lIUi2]clilrl?.liIIercnilalIy ~uin,:rahl,: Io lhc ncuI(~Ira.in p-chh~roami~h¢lamm¢ { P C A L Exp. Ncunil, II~2.23 36,
Shdng, M. and M.I! r ;rcunbcrg. I~,ff). l llc rcgulaliiln and filllClioll i)I c-J(1~ Lllld l)lIl, , lllllllL'di;~It , ~' ~rJ! ~:&ql~'~III lh~.' IIL'I~'O[I~, %y%li~Ill, Nciil~lll ,l, 't77. 7,'~llluy< ILl'., ILA. ('IlliCit, Y, Nal~ illul)pU, R . V lJlilil, A,J, {'lill" iliill I.M. tlaiahatl, ItYJl. ('l~llMiillli~c c>Mirc.~ioll lit 'l[2fl,~' in neocof Ic,~. i~ I~.'gtli~llc'd hy '~}llitl)lig ,It'li~ily. Prll~. Nml. Acad. ,Sci. USA ~ , 5 Illl).
,!47
ILII'MOI, !H21tR Rapid commtmicafion
High basal expression of zif268 in cortex is dependent on intact ~ noradrenergic system R a t a n V. 13hat a n d .lay M. I-~ar;|ba|| Dep, uotu'nf~ ,d' N~'ut~cieme. I'sv,,tmttt3, a,!.l Ih'hat ioral Sl'iem'e~, hJlm~ Ih;l~kuh Unlit r(ity S<'h~.d ol Meth~'me, Baltimore, M D 21205+2185, {]>~;q
Rt:~ tired 23 Scptembci I~1~t2, acccpl,e,I h Octl(bcr It;q2
The Inmscription faclor Zi!268 displays high ba:;,tl levels ~,4'expression in ¢orlc× ihat appear 1o bc dcpcmlcli! (m I~llysiologicat synaplic aclivity. We rcporl that selective Icsion,~of the Itoratlrcllcrgic syslcln illduccd by DSP4 tllarkcdly SUl:~l)rcssbasal .,:ij208 mRNA levels in corlcx. A~:cordirigly.Ihc i~oradl'CllC|gi¢ '~yM¢ln which projects extensively fo the ¢orlcx arid is Iollically aclj,.v may '~!av a key IO1¢ ill mailltaillillg ii(lllllal |lill|Cl'llS t) ~' g,rP~.' ¢xprcssiOll ill [al'gCl llt~tlrOllS,
Transcription ['aclols; Locus cocrulcus; DSP4 (N-(2-chloroclhyl)-N-cthyl-2-bromobcnzylaminc)
!1Neuronal stimulation can elicit rapid increases in the cxprcssion of several transcription factors. By bindiilg to rcgulatory domains of largcl gencs, these faclors, .such as c-Fos or Zif268, are thought to mediate changes ' i n ncuronal gone expression underlying stimulus-induced neuronal plasticity (Shcng and Grcenberg. lt/91)). h~ addition re; Ihc transient increase in expression typically exhibited by these rapidly inducible transcril> lion factors, Zif268 also displays a promincnl basal level of expression in several braln areas, ivcluding tile cortex (Worlcy ct al., 1991). Pr,i-vious s t t u ~ s indicate tha~ this basal expression of Zlf26 ~' ::-,'cor lcal neurons is drivcn by ongoing, physiological activation of synaptic inputs (Worley et al., 1991). As the noradrcnm'gic neurons of the locus coerulcus project extensively to lhe Ik~rcbrain, including tile cortex, we wondered whetLcr this Jrput, which is tonically active and responds to a broad range of environmental stimuli (Jacobs, l'Og7), may contribute to maintaining Ihc basal cxprc,,sion of Zif268. To examine this possibility, wc asses~;ed the effccts of treating animals with N-(2-chlorocthyl)-N-ethyi-2-bronlobcnzylamine (DSP4), a selective noradrcnergic neurotoxm, Ihat ix i:mrticularly effective al Icsioning tile projections emanating from thc locus coertJlcus (Jonsson et al., 1981). I~A::Ic ,~]i::',:gue-I)~tV,'[CV~':9_~;(200-250 g/were [,iven a single injection of I)SP4 hydrochloride (5(I ntg/kg, i.p.) ('Ol'fCspol(dt~llct~ t(1: l)r. Rajah Bhat, DeDartlnt~nl of Ncuroscicnc¢, WBSB 9[}8, Johns I!opkins University SCllOOl of Medicine. 725 North W~II'c ,qtlccl, Bahimolc. MD 2121}5-2185. USA. Tel. (,111)/(}55-25[}{}; Fax (~ II}) t)55-1}383.
that was dissolved in water immediately prior to injecion. These rata were pre-treatcd with the selective scmlonin (5-HT) nptakc inhibitor flnoxctine (10 mg/kg, i.p.) 311 min prior to the DSP4 il;jeclion to prcvcnt possible effects of DSP4 on 5-HT projcctions. Animals were sacrificed 3 days aftcr the DSP4 in!eel!on. Brains from conlro[ and trcat~,'d rats were embedded ~ogcthcr and processed for in she Ilybritlizalion, In preliminary studies, we checked lh:;t trcatment with flnoxctinc alone did m~t affect z!1208 mRNA levels. Ill some animals, norcpincphrinc (NE) levels in cortex were mcast~red using standard HPLC techniques (Kubos and Robinson, !984) to confirm that NE lcvels wcrc rcducod to less than 5% of control levels by the DSP4 injection. 3SS-cRNA was synthesized from a lincarizcd lcn'platc contaiqil~g a full ienglh ral zti/268 , D N A (kindly provided by J, Milbrandl), Cryostat sections (12 ~m) were incubated with approximately 10(' cpm rd~oprobc overnight at 56°C and then washed at 35"C with l0 ,ttg/ml RNAsc A in 2 × SSC as described (Bhat ct al., 1992). DSP4 admini~;trat:on produced a marked supprcssi,m ip basal lev,~ls of ziJ268 mRNA in the neocoriex and si:riatum (i:p. I, top two panels). In contrast, hybridization in hi!~pocampns was lmaffccted, while tile pyriloml c:~rtcx displayed smallcr decreases. To assess !lie seleclivHy of this iicatmcilL wc al:;o examined ~,l~e response to Icsioning the 5-I-I'1" system. To this end, rats wcre injected witll the specific 5-HT neurotoxin p-chloroamphctamli;c ( P C A 10 mg/kg, i.p.) which lesions 5-HT projections, cspecially those ocnved fi~,,~" the dorsal raphc (Mamot, nas and Moll!vet, 1988), in
4,is st:. ]tl l~icviotts shidic~,
~ P ,i
CCN
v,c have d e n l t i n S l l a l c d I h i l l lUflilt~al fit Mfol'~"nl r ¢ l h l a l inpul SLIpl]rCss¢$ ;,([~}(ji~ in lh¢ p r i l l l a l y via;tiM t't)rlc':< (W~irley cl ill., l~t~ll ). A ¢ ¢ o r d itll/!y, thc~c basal levels ;.ipllcar It) be d r i v e l l by o l l g o i r i g l~lly~d~lol,,.icM ~.)n~pii¢ a ¢ l i v i i y . T h e finding.s o f l h i s s l u d y mdic~ti¢ lh;il ih¢ NI:] Sysl¢ili w h i c h i~ I o n i ¢ a l l y a ¢ l i v e ~il~t~ ¢onli+ibtil¢~ hi i l l i t h l l a i l l i n g basal e x p r e s s i o n o f zi/2(~7, In l-CCelll SltldJc's. we IlIIVC f o u n d l h a l chronic
t.'OCLIillL'lre;dlnlelll prilduces il reversihle s u p p r e s s i o n of haslil levels of :(/268 in the cortex a n d s t r i a t u m , but not h i p p o c a n i p u s (13h:il cl al,, 1992). C o n c e i v a b l y , ¢ocaill¢'s e f f c c l rilav be m c d i a l c d viii a l u n c l i t m a l d i s r u p li, in o f ih;" N[,] syMcni. O u r f i n d i n g s suggt;sl I h l i l the N l i s)'Melll etiIl c x c t t l o n g - l c i l n el'feels Oll ¢ortic'al liC|lrllliS hy a t l e r i n g eXplCssion o f Zif2t~X. T h u s , f',lis n l t l n i l i l l l l i n e syMelll, w l l i ¢ h is ¢ X t l u i s i l c l y s c n s i l i v e l o C i l v i r o i i n l c ' l l l a l s l i n i u l i , m a y p r o v i d e ~iil live||tie I])r changc~, ill the CllVirOllllleill to citie¢l the p a l l e r n o f geric" e x p r e s s i o l l ill ¢orlic:.li IICUrolis.
Aekmlt~ledt~enlcnls
k,. 7:
i:
;it '
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CON
.+
l,lt'l.' lh;llll~ | ) Rodgel~ hit t"4cclleIll ~c't'!¢laliitI ;l~:,i$1:llll;C' ~il,d "l' ~ll)hilt alld .1. I~ayloI1 [~ll iIkMI){flg HI- k'vcl~. "l'hi~ t~.'ltrk v.'a~, ~llppilr!cd by USI'I tS g!alll~ I)AI)l)211fl d.M.B.), MI tl}llit2(i (J.ll.~ |].}, alld MI11533ti IR.VB.t.
•.:i :
ix'..,A Reti:renees
! Ig
I
|)3P-I
If~!ccll~tt ~llpplt-,,~c~ b,i~,il Ic~ ~. l~l <'l[efl,k' IIIRNA
l!lhal, R.V.. AJ. ('olc and J,M. I~maban, t~t~i2, ('hronic c~¢aim.' IT~'LIIIIIL,'Iil MIprt'+~t.'~,I~II~LII~'XI~ri2"~iOllel 21~.~(h~ill liI|I~rchram: ill ~ilU h~hiidb'alilm "urdi¢',, J. Phammcol. I x p TlWl. ill pfi<',,,,. I)'Am,ilt~. I,~J., B.I, I.algt.'lII,A.M. 51u~mall and S.I I, Sir~d~:r, I0;.17. ~cI~2ii~i., J;lill
cRNA Ill hr;fin xcc'ti~m,. ]]rliill~ holll corltlt+l ;ilid !rt:+llCt| 1;11~%~t+'rl~" CLIi <,agltlCtlly +ill lilt" llllctlttl~.+ ('llmillCflit'l!lai') hem! t~r.iill~ t~t'lC' tht_qi align,sd ,tlltl cl-tlbcddc-d Ii!~c,l]lt, F h~p l ~ i);lllt'=~ di~pla) c~titmal ~,.,~'lio~l,~ l~l~.~:ll IFlilll II~LII- bl~lt'k~ tOlll
,l,lc~d~,. I l l . I ~ 7 .
c;~p:ra:>~ ~<; tile mai kcd suppress|or, p r o d u c e d by DSP4. zi)~2f~X m R N A imvcts wcrc unal'fc~ ted iii arihnals sacrificed 3 days M t c r l h e P L ' A ini~:clhm (fig. 1, b o t i o m
toI~l l~r cemnll and peripheral noIadlc|lalhl¢ llCtirOl~, |{ILL J Pharm~col. 72. 173 Kuh~,,. Ki.. and R G , Rohhe, lm, I~JS4, ('o!liCM ulldelctII~ in lh, ,a! l'if~dL:c~,,l~'~IlllltL'IrIcill l~cJlavinral ic%pOll%L"~ V,ilh~lli ,l]llt,i~l~ , ,2Llli~'12hilJ;iIllilIc~ii11ct[lli,lllilll ~,, I ~,I~.Ncurol. ~3. 154n.
panel), In par;dl¢i siudics, I~1tl , : i l M o p r a n l a ~ i l o r a t l i o g raph7 { D ' A n l a h ~ el al.. 19N7) ~.ls cmpi~)ycd I,~ COlll~rnl l h a l P ( ' A . bill i]ol D S P 4 trt'cltlltCrll~ ~<~,~i~c f f ¢ c l i v c ill lcsioiiilig. 5 - 1 I f Icrnlin:.its t d a l i n~ll ~ t l o ~ l ) . "l'tlc a b i [ i l y el DSP-1 1o stii~prl.,~s basal e x p r e s s i o n o f 2([76+~' indicatc:~ l h a l Llnder !)hy,;ioltlgicat c o r l d i t i o n s lh¢ HI},. sy~lt~lfl plays a key role m mairiiaininl.,, ,qesc Ievcl~. T h e rcgionat s e l e c t i v i t y in Ih¢ Stlpprt:sSiOl/StlggCsls ih~il l h c olI~cr~,'¢ct (tcc'rca~,¢ i'~ IlOI rncre!y dLIg I?, ~I iitJil-
,q;ecific of feel t~,f DStM t,n h)'l;ricti/ali~m to n l l t N A i)~2i-
( ' c n i n l l III(lliiiilnlilIL'Q, ic IICIIi~:~-" ~,illgle lllliI Mudiv ~, ill 11~.'Jl;l~ill~ ;#llillI;ll~., ill[ l)'~rchol'~hill'lllilCOJog~.: The Third (;l~'IIL'IJllt)ll Ill Phi!?.f~L~.'%cd. II.Y ML'hzcl (J'~il'~L'll I)I'L'S~. NL'w Y~tk) p 159 ,hm,~m. (;.. I I. l lalhnan. F P~mzio and S. l~,{~s~, ivX!, I)SP4 (N-2chlorcihyl }.N-~.'|hy]-~-IWOIl!;~ilClll>%nlIlIi?) a Ils~'liJl (.IL'llCl%aiit)li
M.llllOlill;l~. I..A ~llld ~ . l . Molliv¢;. 1~}SS. I'vidcm',' liar dual ~cm(oi!~.'ll~ic 131oj~.'clil~ll~. hi IIL'OCOI'(~>~: [IXOll~, t'f{llll Iht2 dOIMll ~Illd IIll.'dlilnraph~: lIUi2]clilrl?.liIIercnilalIy ~uin,:rahl,: Io lhc ncuI(~Ira.in p-chh~roami~h¢lamm¢ { P C A L Exp. Ncunil, II~2.23 36,
Shdng, M. and M.I! r ;rcunbcrg. I~,ff). l llc rcgulaliiln and filllClioll i)I c-J(1~ Lllld l)lIl, , lllllllL'di;~It , ~' ~rJ! ~:&ql~'~III lh~.' IIL'I~'O[I~, %y%li~Ill, Nciil~lll ,l, 't77. 7,'~llluy< ILl'., ILA. ('IlliCit, Y, Nal~ illul)pU, R . V lJlilil, A,J, {'lill" iliill I.M. tlaiahatl, ItYJl. ('l~llMiillli~c c>Mirc.~ioll lit 'l[2fl,~' in neocof Ic,~. i~ I~.'gtli~llc'd hy '~}llitl)lig ,It'li~ily. Prll~. Nml. Acad. ,Sci. USA ~ , 5 Illl).