-,
.
!,
.
~
r
.
A Comp.ua(lve S t ud y on, th0!fecc B of
1'l~ ectl q'UI
U n l1 a t~ ra l
Lnt t-a nrg r a I
of SUb.lIt a nce P .e nd ,Su bBt a nc e K
o n Cl rc l1 ng
Behav l ~r
: .J .
©
,
\
Enri co uus eo , B.A .
.
A Thel:lh 'sublllitted I n parcial. fu lfi llment
of th e req \llrelllents fo r the deg ree o f
,~J ,1 9 t e r of sete nc e
~
.' Department o f P' ;Ch Ol"Ogy"\
Memoria l Uni ve rs i t y of · Newf ound la nd
'March 1986
St . John's
.
Newfo u ~~land
...
Permissio n b~S been 9r~nted
.. to t he . .Nat ional Lib r ary of
"
.
'--:/ ~~;:~s~ a~~ ~oicf::di l~~;~i~
. copieS-Of t he f ilm. .
.
;}
"
1&
~~tt;a~~:sae ~ ~; d:"iCp~~~~;~~~ ;"
Th$ : autho~ ( copyrigh t owne r)
has
r e s e r ved
othe r
p u b lica t i o n , r i 9 h t s iCn nd
neither the
thes is n o r
e xtensive extracts ' f m it
ma y be printed or othe rwise
~ ~e!f~~~e: .W~ ~h~~\ i~i;~h~ ~
~B~
.
-ee vend re d.e s \ e xe mpl a i r e s du
· f ilm.
\
~tA ecco re ae
B iblioth~que
national e
L'a utorisatio n a
,
- -
,
L' aut eu t' ( titu la i re du 'dr o i t
d'au teu r)
se ' r As e r v e
les
autre s dro its de pu b Li c e t Lcn r
1 a t hDs e ' n1 d e l o ng s
ext ra its de ce 11e -ci ne
doive nt aeee l mp ri mAs O U '
au trement r eprodu its sans so n
autor i . aqon f!c~ e .
n1
1J-315 -3HJJ2 _4 .
/
••
; ~.
) .
The
e~feci: s
of unilat e ral
l ntr,ln lJ:::r"I · j..r1j~c: tlo,,~
\
MUb", ~ "IIlc:e'll
of
nnd
the n ewl y d is c:o"ete ~ · t ~ c: h y k l n l n . s ubs t lln ce K, Io/~ re C:O~~ ~~ C:d u 8 1"1:"..., r ot D llll!t ~r
.. , t o mea sure
c:lrc:l1 n~
.
. "d i r e c t l y Into
hehe vt cr
rl Rht
c:h rori l~lI i l y Impl ant ed
. 'nnd
in
V~l't0';ls.
r at s ,
solu t1 0.lIs we re
"
th e
" u bsta nt l.a
nl~~Il ' pa rs
S~bstilnc:e
ll:u lde cannu l ae ,
fo't
viA
s~b!l tanc:e K; ~poMr l'hl ne "
1',
sal1.n ~' ~' re a<lll ;nister~d5eqUentta~lY
",~uuru d';"",i~n_ ';,Ho wed
I nj e c t e d
r'!t l~ul."ta . ( ~ N R ) ;
"1n: k':C:h~ ,n tr' Thl~ ~repeated '
~onipll. ris on s t~ b~ lJ.ad~ ~lt h 'rc ll p~c t to. t h~-:;r;ec u ,
of l e a c h so l ut t cn on c·l rcl l ng . S, p il~ ac e groups were fo rmed~ o , tha t three
"d'if f e r u t e e ncene e ac'r c os of. S U bs t~ n.c e P and eubs r .. ~ce K could ' be t ell ~ e d '
.. '
.
(Gr oups A, B, C .r ec e ilr e 4 8 . 12. ' r e
ug I
. 5 Ill . In th lH orde r } .
.Grollp s >0. II"" IInll
.
C. w.ere pre treated w.lt li d-~mp het.amlne . whll e Cr ou p'O was not • • AI 1R ro ups. lIl s o
rec ei ved
Intr:8:n~gr.ll.l.
i nje c t lo ns of
apollH>rP~l ~e_:UL~_L •.5.JJ.ll-and _aa ll n-C-.--_ _
At a O::~nl:: e n t r R tl on of ~2 , ug . s~bs tan ce
.c o n t r a la t e r a ~
c1rcllng- w~e n
admini st ra ti on s .
,
elic i t
.
II;
si ltn'l f l o::an t ly' tn~ re Il8 ed the alllo unt o f
co ep e r ed
wtt h
"'?"
' o f ," conr r ct
,
0::0nt ra~e t8 1 ve
ce ne e n e ee e ren e o f
'c l ro:: 11 ng when
~ l ltht a~d
adlll'ln lMe~e'd'unli a tcr~ llY ~ nt'o the
16 u{: of s u bsta nc e
in c rea se cen e eate eeea t ci rcl ing .
None of
Increasi ng c i rclin g" In
c!rc li nli;
th .ree . ~rpups .
1~
one ,l(r o up .
'I(
-d t d not
SNR:
' s'l g n 1J l ca nt l~
the thre e 'd oae s n f SP, e llc1t~d
sign lfi cl nt l y m~~e c1 ~.cliJlIt .than dt d saltne.
c o n t r~ e n l ve
th e
The se Ire the ,flr st da t il to i nil1 c ltt e t ha t subs t e nc e K e lln
,!,h ti e
Apomoql l.l1ne W8S. Jneffectlve a t
It ~' !R.n l f l can t 1y .i ncre8ll~~
In _': 1I...... ln1111( ,t he r eault ll o f
expe rI11Ient • . th e effects o f eeen so l u t Lon a re 'dhc us ile d.
th e
' ~: lI p la n 8 li ionll t )'la t .• .
may serve to c ~,lIrHy in consist encies are .fl r o p o llc~ . ,.nd lin ·e ft or.t I II ala o 11I~J e '
to reco ncile these rellult s ""lth thole r e:p o t' ~ e~d I n th e ret evenr 'I ( t er a tu re .
....,. _
.;
11
ACKNOWLEDGi:MENTS
( I w"i;;'h, t o than\!. vsr.lDua
•.
, i ncl ud e
1"
Hrg~'K:
'fi ria nc i al
.
McKay.
"'~si8tance
Dr. : G.
l~dlvldull.b Uo
'.'
Har tln .a~d
'IllS rr ovld ed by
th~
:
prov!ded 8ss1st'll'lcej "c he se'
'
.
Dr • • B.T .L• . ~yu8ky.
Depa rtment of
.
Pet;sonal
Gl'Ilduat~ St~d lC8 ~
I I(
, ,:-/--(
>. .
~
.-: -
add ition, -l would U ke to thank. Du . D. Corbe tt and O. Biege r .rer .rhe1r
.
.
. help ful a u'!Jgestlo ns ,a nd COIlln~ nt8 durinR t he co urse of thh work .
nna l ly , I
,
~
woul d like .to ltha nk Or . Charles 'Halsbury for his kin d help and e n co u rag ~me n t : '
.'
.'
.
.
-'----~ n ~ r-provf.-d-fn~ · lIIan y_- o-f--t h e · hl e a lJ · -elllb o d i ed - L n___t_his_work .__---:---. :.~
,
.r" \
' . '~
~" "
.
- - ~- . . -
.
.
I..
~
~
.
/
ill
.AlJat r~ct . -- ---- --- ----- ~- - --- :.:---- -- ; ..
.
:-----.-I".--.--- ------- .
.,~ . ;[~~:i~±:~~~32S :
.
'
\
~"
Tac hykl'; ln '· ·---,:'- ~-:'_· --- - - ----- -.---_"::'·"·--;,-7 - --- --- ....,.--
I
J
. 6
. Re ceptorLand I lIIlllU no r e a c t l ve II.ratll Si tu --- - - .,.- - - - Beh a v.1orill Et h cte ,o f SP a nd SK ...- - - - - --- - - - - - - - -.- -
T~~ su~1~r~:::~~~E:;~i~:;;~:=::::':::::;::.::::::~:::::~::::~_ ~
~~~~:; ::~~:~~;~::;~:;:-:::::::::::::~:;:;:::::::::. .
! .
:;
The Neur a l '..! a o f Cir e llnl': - --- --..,-- - - - - - - ----------------16
-:- SfU(ITi"s-aiiii d- on Des t r uc t l o n o f Tilsu e ......:.- - - - - - - - ....
17
Stud ies laud o n Di re c t St ll11U!-4l tlo n --:. -----~ --- " . 2.3
~~~: ~~~~~~~~~~
Perf usion an'" lU ato lo RY - - ---- - -,,- -.---•• ....;.- - ----~-:. --.... '
."
.
'
-
Hl."'0.~:~;~:~~:::::::~:=::=:~::~::::::::::~::::..
------------=.:------:.----------:.------------.-----------General Ob • • r v llt l on l .:- - - - .,.-::- - - - - - - - --- :.- - - - - ---- - - - - - - - --"':'- General Coru:lu slon l ---:---1'------:---:--:----r-- - :..-- -.:--- --- - - -
Di s c~l l lon
~fer~nce8 ..,------.:.---- .---- -------- --- .----------~- 2--,,_-.,;, 7"-- --.----
u ·
".
,."
29 "
l2
))
"
ii
104
_ 52 '
53
ss
. .'.~
" '- .
Fig ure 1 - .Appa u t u ll Ulle.d !O a ea eur e
/
'
Ci rcl~ng
- ------------:------
31
Figur e 3 - CIItego rl:r.atlo n of SNR I n jec tion Sites
with respect t o Rolltr~-ca uda l Plane ..------------ -;- ...-
39
Fig ure 4 -
"
He a~
Ci rc ling Rate Totals of Groups Teated
-----~------
42
Tabl"e I
-
•
•
I
Type s of Tis'll ue Frolll Which Sollie.
•
Tachykfntns W~r~ Fi rs t" Isolated ---- ------- ------- -\
"
\\
~~e
v:: ~::;,
.
Tabl e 3
Ta ble 5
.
,Tab le 6
,I
, Pl'oposed\Tac~ykin i n Recep~~rs an d
, Table 2
-
-
V;a ~~;~~:~n:O :!~:~~_~
i
"
,
'
.,
~
.,
.
_
I
Cyto logica l Character t:a t:lon of SN ,Ce f l Ty.pes ' --- ----::
10 •
ae cr eee wr Nigt'al Afferents and
Relevant Neut'o ttll. ns1ll1t te ,rs .- -- - ---- ---- - ~ - - - -- - ~ - - -
1]
Di rectio n o{ ,Ci~cltng Ro~ro wing Un llll.t et' 1l1
Intr ll.nl g r a l AdUlints t rsqon of Various
Substances
---------:----;----..1-----------..;----":'------
"";"h 0.. 1,0
~---,-~t-----:--:----·-------·--·-
. ' , I
Dia t rib utiQn of SNk' Inje ~tiOri
S i~~rtn- Ani mals Tested l --- - - - - -- - - - - - - - -- - ~- ~ -- - - - -
Ta ble 8
Ci r c ling following t.n.trs ni gr a l M.min ia tt' s tio n
~o f SP . SK, Apo . a nd Sal ~ ----------- -- - - ----...- - - - - - - -
"
J4
4D
43 ,
{.- , '; !I ,.
,\
. Tac:.hyki ntns
Dutln~
th :
last
de.cade
there
has
grOwln~ : f n t e.r ~8 t
been
neurcoee t tdca and t he role they lIoay p l a y 1n the neural e e nr ec t <if ;~e ha v (o r .
•
recent esttlllllt es uggesu th a t over 40 b:raln
'
.
In II number
ofl~or tllnt
"
1 ' (
and/~ p:eptldes;ruy
. .
..
behaviors (Krieger , -1983) .
In
A
•
play 'roles
.. .j .
Little is -known about
~ny o f t~e'lle' n~'uroPep
tld~8. .a'lt"hOugh: II ' nu~ber
~'f ['~~'"M h~~~• b~~~(l~'itC:llted
in
.
"
', ',
'w'; :·
th~'controJ
of specific: behIlVi. 0 r
f
\ (980» .
\
(;g. a ng i o te ns i n"s nd
..
.
Rec ently lnter"est hll; bee:
,
\
1e uropep t l des . [ .h E! ta c hy k i n l ns.
_~enera~ed .by
Member!!
d~t~~l~ ( Flt~sllIlons .
,.
one pa 'ttlcular hmily of
"
family. _ ~ha re -.
of ,t his
C:Ollllllon
. lI!1\lno-ac1d sequence 'a t their .c a r boxy l - t e r m nu l (C- t e rn.l nu8. ),'<Phe-X:;-Gly-L e u-
/
Met*NH2 , where It is a hYdr~hobl c o r e reee'cr.c r est due} ; , ' Su bs t anc e P (SP ) ,
\
.
.
. , .',
'
t h'e !lOS t studied of the t a chyk lni ns , was discovered by lion Euler and Gaddulll
( -' (l!n-i')
,
1rI al coho U c extract!! of equ ine brain and .inte'st·ihe.
, .
'
'.
,
''-
1· ", :
' Ita sructurd
'
'
chirae-te rtut i on ' followed l a t e r , i n 197 1 (Chang, Leeman/ and Niall, 1971).
Ot her " members of _t he tac'hykin in famUy include eled~i:~ in, physae1elllln ,
kas'i inin .
8Ubetanc~ i.(SK ,
neu romedin
L~
neu\ ep tidea "was ',f1rs t iso lated.
SP and
-eeeeu eeee
'SK ee n, i~
c e r t v n caBe"
o.f
A) :a'~~,
ne ur omedtn K (N",
.
tta,~e" each o~ the latte ..
'
b~ pa,t ~
.
,
()'f
t he B8~e p o l ypep tide
llo1e c:ule . Nawa, Hiros e , Tak aah . a , I n 8 y~.II,~, and ,Naka~i9~i ( 1 9 ,~ ) )
we f e ' a bl e t o cjcne eDNA
en.~od lng
neurokinin
Tab l e 1 ahows from ~wh.ich tyoe
neUrokinin B).
f or Sf .,
,:quenc:es th~re c:o~l ~men t ll ty
to Ill~A e eque ncee • '
Following th e analysh of :t he nucleotide 'sequences of th e
i
JI ..
.:.t,;'
...
· ~ .!.:. So IllO! ~llI bO!rll o f thO! tachyk1nifl faml "lY an d t he co rre epo nd ln Mt ype, of\
t:.1.aJwa,..
fr olll whic h t hey were f it et " 110 ta ted
El edo l s i n:
Phyu e l ell\l n
•
It,u slnin
Mp hi b ia n . k i n . .
Su bs~ a n c e l
Pl g .p i nAl co rd
Neurollledi n It
P1s: spinal cor d
eDNA,i t lola . d h eo v~l:'e d t ha t bov ine br lll1n51' pre c ursou a re ~neode d by at le a at .
It is known th l_~ t t\e' pr e cu-u or ,Alp hl -pl:'e pr o t l ehyk1.nin
tWO di ffe r.ent mRNAa .
,(r-t"A- pPT: 119 I lli no Icide.) 1Ia precur Bor to
B se c ond preeursor, Beu -
lo t h pre pro tlc hykL;"in l have; 111 a llllirio' acidl In co~o n; and ..,it hl n ~he~e ~ l l
, : i~
con~a~~
, '
: ' r:
Bj,' ,~PT are /nd i da ~ea for .r~lea~e ra
te ~ida ~ th e' S1' pa ptide. The I:'ellla i ni i\g 19 I mi no I d da prese nt in B-P!T alone
. " '.'.
'. , :
Sp" wh i~e
prep rot ,chYk;ini n ( B-p1'1: 130 I mino adda) c,?n U ins co pies of bO,th S~ an d SK.
,
;
. ~
t hOle
10. whi cb chara~·ter1ze. SK.
.
l: ,
,
rn c e , ce rtain neu ro n'l tha t conta in
.
ot SP .an d 'S K•
.' , '
Tac hykl ni n Rec eptors and b llD.uno reacUve Brain Sites
A nUlRber
j ""
of
r e por ts ha ve dellc 'r l be d ' t he , bi ndi ng' pl:'o pertlea of
t~chyk1n lna ,a nd t he one o r more rec e pt or s
:; ,;
'I ',,'
:
t ha t med ia t e th e i r ~ffec t9"
..
'r' .· ' ,Va r i oul plth..,aY9 containi ng tac hyki ni n9 ha ve alao qeen i de nti fie d.
11k' :!'t r1om these Btud~es 101'1 11 be d ucr'i bed iinc e
I'
•
I
\ pr e ae nt ed la te r.
,
~:
l
l'l
pig
L
to
~
,
• ,
ta c hykin i n re ce pt ors' and pr ob,able sub types . , •Th'e
bl add e r, and r at cere br al
co rte~
• .
Bi n d on e'ltperi untal work u sing a
,
.
n~lllber 'of
,
t he SP-P
;'i. "i pbY"~lemlJ» ,
a~d
Sp- E
rece Pto~s . ,
8Ui:e~
a re eXamp lea of- a uch
.
bioaoaay.and
;,o t he r ph s r maclog lc a1 ayltelllB tlol'O, -t;actiykln l n rece ptors wer e
~ : I : propo~ed :
,:
I
Id~~t!.fY
ll e UIlt~ ~Urinar y
,:,: ~r.parat~l~'i .
t
Re 9u1u
eJtperi~ent to ' b~
Bot h perlphenl a nd br a i n tluue preP!lrations ha ve bee n stud Ied .I n
~ ' Cn at t emP t B
' ~. ~
t he y bear on t he
The 5P-P rece ptor ( '1";
~hYSaelelll~~/S1' , ' ka,8a1~in.
or 181ft~ lly
d~algnatln8
e~edoisiD
it " .. ,s hown, bound '
an d
.
.,
' ---' .
.
'
.
th O,lIt p refeTenc.~ f or an y ,o ~e ?t t heae ta c~Ykl n lD s ' . the SP-E . rec ep,~or ('~: ' ,
I
,:
,!.! t1
1}
u i ana,t1 ng e le do ia i n), o ~ t he ~the r hand , "'.. f ound
'ka~t1nin
pn folre nt,1a ll'y ( iversen , Hanley,
wau\n . 198-i):- ,
ec
b ln~ eledois i n .and '
Sand~.rg, ~-e.
Pinnock , ' . : d·
,' .
'i. : '
-..... .
i\
Rec.e~~, \lor k on tbe re c e pt o r bi nding cnllra.c teri~~i.CI of ra dio"lllbe ll'!: d
~llchy'ki n ins J1a&f'fiO_ve r, s uggested b,lnd i ng pau; rn s i . ic:at~ve of a t hi rd
tac:hykln ln
.
'~ ec:e p,tor
(Buc:k, Bur ch er , Shults, Lov~~b~rg , imd.O 'Dol\Oh~·e) 198 3;
'
, '
'lI' . ,
: • .
_
MantYh ~ ~ Hag8lo, and Hunt, ,19B4) -, Buck .e e a l .( 19.83) ulC!d the proc:e ....o f . \
. compe t i t i ve inl11~itioh 88 a . tool i n bindi ng n~die8 an:d re ported, blndi nj :
p••u~rna ,s hown In . table 2; it: there~o~e .apr eau th at Sf -P'4 '5.1'-1:, and .oSP.; K:
NK: an d SKi . r ea ; lIc t.lv e l y) .
--. _... "(1985) 'h"a nl?te
...d.that
" 'a IIIO re l ogi
_ c al cla8EI<l.f1.cat.lon
"
~ 'r '
woul d havlI
re'ce pt o u ' e~(i1t ( t.he endcgenc c e Uganda being SP,
Qu~ r ion
aC~lI!lIlII!,
tli'e SP-E 'tem rep kaced wi t h 'a ' mor e
SP.-E r e c ep t or
\'.
ge n~ral
term.
the~reaaonln8
is t hat t he
b~naa ~"numb~t of ta'ChY'k'~n~nl ' .a~{~hOWS t~e hi.8~eilt' afPl nity
'
,
f or NX.; suggestlng t hat it 18 eere likely., to be a NK r e ~ ept or . · Henc:e, t he
\
t hr e e r e c e pt o rs
. the poss ibil l ty
wo~ ~e
SP, SK,
t~at ,onl Y one
'~~d
NICrec:e pto r'•• •~.hou ld be noted t hat '
eeeeeee e typ e e XiI"t ,!l }wi th 1JU1 tl"pl e
~in~lng
lite~? ) .has: .~een r a 1s~d ( cr ~~co t t , ' 1983) : .,
In the tat braln a uto radlogu phy
ta~hykini~
s~tes j
bi ndi ng
.
.tla~
whereas ' cell '
be e n use d , to l Oc:a t e speci fls:
bOdle8:,-~tu)~rs a~'d' te~lIina1. " " •
c:o nt ai n in g th ea t'! pept1:des hav e Me n l.oca ted u'B1,;g il1llllunocy"toch~:lI try .
.'
bi nd i ng ,Si t es are
f't'e ",Wldll! ;P' re_~d . t~;n
SIC
bindin~
si tes (S hul t·a:
SP
Buck ; ' .:
l.
, . Burc her ; Chase , a,nd O' Donoh~e , l~85) . · ~reas s howi ng a hlgh'density of ·SP
bi ndi ng Ii,tea i nc lude t he
s t ri~ tulll ,
de nta Le gyr us , ce rtain
r~~on.
ct
t~ e
alllygda la sna se'pt'al area , locus coeruleus,' 8uper(or , colUculbs 'a nd do ns 1
parll:brachlal
nui::leu~
(Qui rion, Shults ,
.~O~dY ·'P~("t ,
I
198~ : Hant yh e e ai . , 1984 : ~hult. et a!', 1985")'1,
5K
-
bi n d~n8
,
altes
.i nclude
interpe dunc ular nucleus,
.
,,,tAi. ere.. of \
", : '
v
th~ . s ubatant is
l u p r ac h 1a S lll a t i ~
.
Chase. and Q'D; nohue,
.
Are as vl t h a hi gh de~ a1ty .o f . '
I\ l ~ ra • ~ pars
cOIlPSctS), I
'
nuc l e us:, , upra o ptlc nucleul , Ind
;
,
",,,.<5hUlt. ,, .~ . • 19~" ; .H••tyh " . ' . , i",). Th~
~
,
J'
.CLE'
1=..Th,
~ct
bi.'lo,
;"'00'"
W
it:
" Lot i"
of • • uerber of ",hYk!. nins
to t hree p.ropos ed t ac'hyk Lnfn r ec ep t or s ( ba s e d o n work by Buck e t
<11 . , 1983 ; a nd Qui r io n , 19.~)
.
•
-:-
-
-
r
'.
,.'\
.
··
'
SubsCan ceP
~ . S u.b s t a n c e Ie
Neuroll\edt~ Ie • \
,6 '
SP
> Pi
s > SK
SIC > Kass ) El e
tiJC
> Kass ' )
Ele
~
Ele
> Kass
> NK > SP >
) NK
PhYSt
> Ph ys > 51< ) , SF
.
.,
e xt ernal layer
~f
t he
Olfa c~'ory
bu 'l b , a nd the dor u l horn of
.t ~e
s l'Il rll\! co rd
hut h shoW' 1I l a rg e numbe r o f S P a nd SK btnd lny, s ites .
Al thouRh 9 1 te~ t hat bind-SF I1fe mo r e vf de apr ead than 't holle th u
SK, th~ d 1 9tr ~~tron 'i o f bqt h peptide'" c ve r l.an t o" Inrge exten t .
b1.n d
~'tl~ lt ' .
Yajima . Gu l l ne r , . Ch>1Fle, a~ d O'Dono hue ( 1965.lhave , hown th....e eo nc e ne en et c ne
o f sl> ,and 5K wefe lIla t n Uln ed at a flK .. d rar t c thr ouR hout the _ j u r i ey of - 20
bra i n areas df ae ee t ed ( SP.:SK, 2"1 1 ) .
SOllle ~ ~ ~ ~ ~ g ·
wo_~k
on ·mamllla h . mor e ll(lec:l ftl c lllly '{"d CS.
three t ach yk:1nl ns - - SP, SK and .N'K.
. be'havto n,
For
hall
t ended
[~ .
roc us on
SP ha s be en IlJIDllc ated t n a n.imhei o f
~iarrO le, . de!len~ln~ ~n
th e dc-se and the
pai'~tcular p:}n
thresh old of an animal- an Int,r athecal injection o f SP ca n brlnK about e t r nc r
an analgesic ?r, hypoa Ig ea f c. r eanons e (f'r.edt! rl CIr.9 0n, 8urkes, 'Ha""fi'Cl I, lind
Ed w~ r d s , (9 78) ,
whe n
.i nj e ~t ed
In a~i,U t i on . SP ha s ala o been f Otlnd, t o f a cllltlltt.' lordoalll
I nt o
aub ml tted' , for
t h~
midb rain
pu blica t io n);
c~~tr&l llray (Do rlla~ , 'Ha l Rhllry
e i r e r e . cl rc U nll: whe n
~ ub!l tan t 1a nig r ll ( Olpe and kcet te ,
p~nneY ;I '
" a nd
Inj eeted
l.nt"n
1977; Jallles and Starr, 1979 ) ; 40 d
th e
In crt!"~"e
t occect cr. Ilct1V i t y when ' ad1I1iniste r ed Into the Yl!nt u l te.w;'IlIl!nt.'ll are a ';{VTA) •
.
.
I
Admln19tratl"n of 51( I nto the VTA \"11 a Is o ~een
( St i n'ua ,a nd Kelly , (978) .
rep or~ed t o Inc reas e Io ece urc r aet i vitr , and a co,llt)lI.rla on with SP h~s " no;"n 51(,
to
~
10 t i mes eu r e
and Ro th, 1985) .
. tha ~
I} o~ent
.I n thla res pect ( Ka ll v'as, ' oeu .
Thill l at t e r fo rm o f
s ugg eat that llIany types
o~
con~"lrhon .
ta chykln ln
1,
Ma~ltio,
I n c onj u n c t 1o/,
w l~ 1l
lnformati~n
r ep or t 8
rect!l,tora exil t , . mllde It O.f
i nt er e s t ' t n cc ee e r e t he e ff e c ts of 5P and 51< on c l r cHng behav i or,
del cribl,:,g t his eKPerlment,
Hantyh:--
r e tevant; to
Pr ior t o
t h e IInllco llY of
the
sub5~anti s nij( ra, and Its fu nc ti on in c i rcllnll; beh avio r, will be p r e se n t ed .
The SN is a bi iate ral ve n tnllll!dbrd nstructu re th a t ' lie s dors al t o
h~"
t he ee r e? ra l n edu nc Lea , It
ba llal j(a nl(lta, a l on,ll: wi t h tbe.
c ommonl y been in cluded i n d i c r ip t l ons of t h e
c au~a te!,ucl eu8 ,
pu tamen a nd g lobu8 pa lliduB .of
thef or ebraln .
'. tn orde r t ol.\l.l! y unde rs ta nd the r o l e of t h e Rubs.tantia nigra ( SN)
"' i~ h r.espec: t to be havior, e!lpeciaUy_£.! rc l1 n~ beh.av~or, knowle d g e p e r t ai ni ng'
.
t o I ts 'st r uc turo l and
chela~c 'a'l al1ll to ~y
. ,
is ess e nt la l. - The vari ou" "af f e r ent
an d e ffe re nt co nne ct l oflt, t ha t i nvolve the Sr. and e Lec t rophya fo I cg Lca I d atI!
a lso Ri ve clues with r e gar d to its func t io n .
Cytoa rc hitecture
Cytoa rchi tecturaHy the 'SN has t rlldi tiona l ly been sep arated I n t o
t h re; ~eR io",, ;
pi!.rA.
co~scta
(SNL) ( GU llal'l, 194) .
three't o f t ve c e l ls
t hf
(SNC) ,
p~r8
r etl cu lBta (SNR) and · I?ars 'l a t e ra li s
The SNe. lie!! d o r sa lly and i s made up of ,a thin la ye r
ek,
Th1!l l a yer COl'ltal ns mal nly dop ami ne ( OA) ce U-
~Il d ies. lind h so meti mes r ef erred t o as A9 La cc o r df ng t o t he nome ncl a t 'ure of
Dah lstrom a nd Fuxe (1 964 » .
The SNR., o n the othe r
~n~ ,
makes up the vent ra l
pqrtl on of the Sf{ a nd cQntd'ns a lowe r d e ns it y of ce lls in
.
co~a r i Bon
t o t he
SHC• . AlthouRht he SNR is th e !a rRest reg ion of th e SN, I t co n ta i ns re lati vely '
-
few DA ce ll bod ies , · t ke bulk o f it be i ng ne u rop il.
ph yl oj(enetiea lly th e
o lde~ t
Las t ly , th e SNL 18
feR ion of th e: SN and c:ont a t"" a r ela tive l y s mall
_ nUlIl b&r of neuro"~ ( Dra y , 1 9~O ) :
/
I
o\l though
c ha rac te r ist ics
d lllen5 1~ .of
t he r e ha ve' been "lU1ll! r Otl8 .. t udle ll t)f the. laOrpho loll le a l
·~·f-S~
lIe ur o lls , a
cont rove r~y ~xlil ts
neu r OIlS found 111 the thr ee
reglon~
r e l(lIr dl nll' the eoc t
of the SN.
For ex •• l o!' ,
Culley an d Wood ( 19 71) I d entified th ree types o f neu ron . In th e SlI': ._L I ( I L-
ee d l ull -sbed lIeu ro", "'ere f oUnd t o be p res e n t I n al l eh eee r e l(l o ns o f th e -SH;
~he r ea. large ' neu rons
wer e
McConne l , and Net s k y ( 1970)
f ound ~ lnly
in , t he
~OUld ~ri ly ' lde nt lfY
SNlland SNt ~
" ,," s ..a y,
t wo t ypes of netl r <Jns In th e
SN: .• small-sb ed type . (8~ 1I UIII) p r e se nt ,I n t he SNR a nd ~ NL , and II llelUUlIIthe SN~
s i ze d t )'lle (12 -17 um) p re s ; nt I n al l th re e relClons of
,
'
J U1'll"I U1,
... . Wil son, 'alld Gr~ve9 (19 7 ~ ) Id entified th ree type. ' o f neu r.o ns:·lI mal l ....h. ed
neu rons ( 11-20
1I1l1)
p resent I n all th ree a r eas of t he SNi l'IledlulI-s 1zed neu r on a
,
( 19- 46 ull)p r e aen t 1n the SNe and
~N R ;
a nd (lna U "
IUlte-s tz ed neu r on s (4 ) -74
._ '
UIlI) c reaent. I n the SMR and SNt..
\
Re ce n tly , Po lrle r , C1suere , and Ha rchantlo(l98J) have sultlle" te it"to~
p oss i b l e f " c t o1'l t hat IIIl ght e e l d A IDany o f t he dt "c tepll nc:lea 1n t he
eee or r e d a bcive .
rellul t~\
To beg in "'lt h, th e f.ct t h at t 9 0 f ew nell r?na ",et e "''''.led
. fro.. e Ach o f t he S~ ~e~ lons llay ne v e l ed t o t nac cu rat.e ll:e nera l b afluns with '
reKa td~
to
t he i r
s be a nd dist ri but i on .
SeCOndly ,
t l ~ s 'l e
p reo u ilit io n
.. eth~d9 vilir te d eonlli de 1'lbly be t wee n stud ies ao th a t varia bliit y In t he
re sults co u l d be
e >tP eet ec;h_~
Accordinll to POl r le r ee AI . ( 198 3 ) , . ene I tze 'o f- a ' neu ron can no t b.
use d 019 a r ; 'i1a bl e p re d i ctor o f Ita l o ca t t o? t il th e
t he
SN
r
In
t
he t r 'o wn IItudy o f'
Pot rie r and hia co Ue ap,u el Id ent ifi ed f ou r t ypes o f neurons be u d on
n~'ll be r uf c yto lo lll clI l cha ra e t e r 19 t ·lc . (she, ah ape
au ba t a nee) ,
and alllolillt
The lIeuro nl ve r e c a t e Ror h e d aa be ing e i t he r
of
Ii
Nl8"1
co~ecU ...t ype
n eur~ ns,
r e t l cu l ata-t ype ne u rons , Internledlary-type neurons, o r g l c bul ar>
The name of eac h type o(neuron l~"l1es lu reeae i c e wl t h" n the
t yp l neu rons.
Tab'~e) sUTllmarh e8 the
SN, exeep r in t he elise o f t he glofrula r - type neur on ,
characte ris tics o f , each type of ne u ron a nd thelr number i n,t he ra t SN.
E ffere n t P ro l ec t10ns '£!.~~ !!l!!!!.!!!.
Becka.tead,
allto~adiOJl:raPhY
uce es t ce ,
t o lila!' 'ou t t h e
and
·Nau t a
ef\~ent
5111011 1 amount s of trltl.a t e d ,amttl o acids
used
(1 979)
co nnections
the
at t~e
method
of '
SN i n 'the ra t .
(leuc1ne~nd p r oline )
were In j e c t e d
· _~n ~ o both the SNC and §NR.
Both the SNe lind SNR we r e found to be t he o r ig ins of . aa cendfrig a nd
des ce nd fng
f~tie r
project ions .
Wit h re gards
to
the SNC
'th~
ascend in g
' Il rOj ec t l o n~ were ~ e rve~ t o terminate in tne s triatum, globus pallidus , and
ven tr.omedla l and eec t c dc r ee t thalamic nuc,le i .
v all
o r~anl"ed
The nigro'lt r iatal o ro j e ce t c n
so that fibers orig in.. t Lng fu m medld regions 4 f t he SN
te rmi nated I;\ medial p a r t s of the st ri atum wh ile fi be rs originat i ng f r om more
late ra l
re ~i o ns
o f th e SN te rmina t ed i n more la te ra l pa rts of the s tr ia tum.
I n t er1Dll of t he ro s t r o- c aud al orll;aniu tion of the l1rojectio ns t he authors
concluded th a t t he l oc a tion of a cell body in t he SNCwa" not a
· o f ttll te flllinal fi e ld i n th e s t r la tul'l .
E!I~8e n t ially ,
~ood
predictor '
all pa r ts of. the SN
JlroJec"t to v ar i~us are as of t he IItria tulD along the rMtro:-cauda l p lane .
Descemling p ro jections of t he SNC wer e a lso fo und t o terlllina te 1n a wi de
· var ie ty o f !lr ea s .
Thes e i nclude d the medi ,all rap he ' nucle us, ' d ors a l r ap he
nuc l e u9,lle dunc ulo non t in e ,nuc le u",c::e ntral g r e y
!Ia ~ te r,
a nd l o cu s cee rute ue,
With resp ec t t o th e SNR bot h Lr a.e s ce nd tng a nd des ce nd mg project ions
....ere f ound t o be "omewhat dif fer ent fr om t hou
of t he . SNC, a l t~ough SOllie
10
.
_
TABLE
~ Cytolo~lelll c:ha rac:terlattca
!1
J
. .4
cor r esp ding to ea ...
the fo u r t ypu
of neu rons i de nt ifie d In th e substantia '.rlf;;av Oby Poirier et
a1: (1 983) , a~d the~r number ion th e r a t
Neul'o n .!l.2!.a rid DUlIber : COMPACTA ( 9 , 92 S: 44 % of t'otal)
'~ .Q.!. Sotlla:t: r l an&u i a ~t"IIo . pyl'a lllld 41, polygonal, ovo id o r ~p l ullp '
Ot h er Cytolosical Chancte ris ticl: 1") r.!lat 1Ye l y l a r ge pale nucleu a t ha t h .
< .
o f ten not .ce n t r a lly .l o ca t ed .. il l large a lllou nta of Nisl l
. 8ubs e.oce dla trlbu1;ed i n patchu a nd i11 ) lIIean b "gu t
dlallletel' o f 17 . 2 UIll
.
Neuron ~ ~ nUlllber' : ,~ 0 ,122 : 14% o f toui)
~
Q! Soma: multipolar . triangular or ovoid
~
Cytolo81cal Characteris tics: 1) large " ",~ u n t 8 of Nlnl luble_nce, but
not as Qluch 18 .t he cOlllpact a-type neuro n , 11) II llIo t'e centrally
located nucleus and Lii ) a i.ea n l arg e s t d l alDe t er of 20 .0 Uri
1
~!l2!.!.!!!~ ~ (3,227: 14% of to ta1
~
Of Soma: elonga ted, t ria ngul a r o r f usiform
Othe r ~to logica l Cha rac teristics: i) t h i nner proceu88 t an e i t he r of the
a bove neuron ty pe_, 11 ) the d.rlt.'t nuc I eu of all typ es and
11 i) a ~ean larges t dismeter of 16 .0 11m .t :
~ ~ ~ numbe r! ~ (6 ,258 : 28% of total)
~ Q!.~round
~
Cytological Characteristici : 1 ) a hi gh nUelear /~)"
a clear nucle us and 111) a lEIean larges t
plasllltc ruto, 11)
llI111ete r of 12 .1 UIIl
11
Fo r e xaec t e , a lthough t he SNRproJ e c::U t o the st rlat~tII ;
pv e r lap wa s ev iden t.
~he
e tae
of
p roje,c t lona
the
{ [t)lIl
p r o j e c ti o n
18 ·re l at iYel y; smalle r.
Ot her
a!lcendlng
t he SNR I nc:lude thoae going [0 .t he paral..8 lllellar z one,
ven c rceedt a t , medio dorsal a nd pa r a f as d c::U'l a r nuc le i o f t he t ha la mus , and
R: l obul p a ll1d"ua.
The de9c'end lnj( p roj ectlollll
hf
the SIffi t e r mi na t e mostly 1n
t he s upe r ior coiUculus , p e dun c:u l op ont l ne nucl eus , pe r laq ued ucta l g ~ey.' an,d
re t icu la r roeeec r on.
To
~re
.
ac curately
.
i den t if y
l OC: ~ltl ? n
th e
of . ni g ra l · neu ron~
, p rojec t ing , t o the supe ro rco1l 1cu lus, thalalllUB and 's t r latu~ (;Ji r~e maj or
re c i pi ents of 011(r81 output) Fa ull a nd ttehle r (I978).·lnj ected horseradish
.
"
.
Since t he e nz :o' rne 111 t ak e n up
pe rox i dase ( HRP) In to the t hr ee le t ter re,q:lonll .
by te rllll naill
"nd 'lIl
subj ect
t o ' re trog rad e axo DlIl 'trall9p c> .' :. 'the cell
d ist r ibu t ion o f -t he th ree sp ecific effe rent s ye rees c ould . be map.ped .
au tho n
r eported
th~t 1)
distinct cell
three prC!j ec tiO ns and 11) th e etee n
f or each egg r e ge t t cn ,
i\l'll'l relta t iorl~
sit;
o f the ce r t dreeeee es was
l ar.lle st lIlesn cell diame te rs
SNR.
Llls tly '.
diffe ren~
Nigrote c ta l ce t is were of medlu. s ile (16 UIlI) and
were f ou.nd mainly t n t he ven t ra I part o f t he SNR.
cen tral
The
cha r e c te r te e d each of th e '
N1l:l ro thal8mtc ce lls had the
(19 um) a nd were loc ated ' i n the la teral and
nig r os'tria t-a!
~e l1; '
lta"d t he
cel~
smallest, mdan.
dl a m'et er ~ 1 4 Ul1I) an d wer e al mos t e xclusively l ocated i n t he SHe.
[~[9 .
un c e r tain whethe r " t hes e ce lh co r r e s p ond in IIny way t o those de sc ribed
ea r lie r, ba s e d o n the work of POirier e e Ill . (198). ' I n ed dtt lon .to all of
t he a bo ve it has been'Yep or t ed by o t he r lIut hon t ha t -t he SN als o pr oj ects t 9
the ce re be ll ulll (Chan -P a lay , 1977 i n Dra y. 1919 ) . amn:da l a ( Fa llon . Rlle y, and
Moo r e . 1978 ) and t o rtex (Ave ndan o , Rei n,oso-Sua re t " and LllI llI49 , .
':r,. .
1 9 76 ~ .
-,
12
Affe rent Pr o Je c t i on. ~ ~!!!.!.!!. ~!!!.
Foll o"ln~
.. t
the .t c ro t o llt ODho re c l c adllll n (, t n t Lon of
~RP
tn to · the SN
Bunn,ey and Aghaj.nhn .( 1976) we r e able t o identify llIou r Cei o f .ff~ r en u co th e
SS.
The
aut hor ,
p r o jections . '
ca t e!to r lz e d
e l~ he r
t he
den,.(t y o f
high a ll' l~~e Mtty a r e a • •
l arg e'r SN "a ff e r e nt oa t hwa YII', "hUe
.
'
. R l o b~ . p•• l lld u~ .
lour ce"
. f f e ren t
of
"ull:~e .. t
lowe~ d.n.~ty .~ • •" . uggellt ...... 1 1.11'
nu.be t o f oroJe c ting tiben are i nvo lve d.
caudate nuc l e us ,
the
KiII:h denll t y a re a .
Hlgn deru l1 t "y .reu i nc l ude d th e
.
.
.
nucleus aeeeeee ee , ce nt ra l ec c t e.., o f t he .
alllygda lo i d coapl~x ~nd do ru l r\i Phe ".nu c l e us ..
LOll den,lty Ilreaa In e I ud ed t he '
co rt ex (la yer ' S) , h a be nu la a nd hyPo t ha l;t mu• •
O~her
a ut hou haVe r epo rt ed th a t 't he cerebe ll um ( Snhler ,
~ l tt,
lind
Snide r , Un6 ) : 1 0~ u lJ coeruleus (Sakal , t c ur e e , ' S. l ve r t , tege r , and .l ou ver ,
111 1 7) and subt ha lamus (ltanau~a. Ma r~hail, an d 1(0)11y , 1976 ) a la o pro J e~[ ' t o .. t he SR.
Table 4 I UllllUr h es 80 lle o f the "tt: u l dff ffr e nt p ro ,lect lon8 3 nJ t he
[ u l\Slli t ters be lie ve d to be of re l evance In e . ch o f th es e.
~
Reuro cr a n. .tt ten
!!!. !l!.!.. !!! .!!!! !!.!!=.!!. -
rollo wl nlt
'm.
A v I~ e v arI et y oLpo~e ne r. l nell ro~ran' ,II1[t en h.... ~' been Id en t lf l ed
i n t he SR.
Thele I nclude SP (P owell , Lee"'", Tre Ke llf , Nia ll, .and Po t u ,
111 13 ) ; SK (S hul e, ee d. , t975} i I;ABA (P er ry ; H.!'un , and Klo'l u r ( 19 7) i DA
(Ande n , r uxe , It. rlIbe r ge r ', an d Hokfe l t ( 196 6) ; ace ty lcho line ( Chen ey , Le f e vre , '
a nd Ra ca Rnl , . 19 7'5 ) ; se r oto n i n a nd Rl ydn o . ( Dra y _an d S t r" lIRhan,
19 7&) ;
e nke p ha U n (I naR:a kl " nd Pare n t , 11I8 4 ); an d d )'no fYIhln (Khac h . eu r! lIfl; Wat l on ,
Lew19 , Coy , Coldstein , . nd AUI (11182).
In ' a r e vi e w, On)' en d St r a uRh. n (1 9 76) l ulftfUr hed t 'he e ffect. o f I O-e
".
-- _
14
followl.nll; t onrccno r e c t c admln ls tredon Lnt o the SN.
--CABA.
noradrenali ne,
produ ced
a n d f':lyclne, ...he n ",dmint&ured
inh ib it ion ;
acetyl choline
whe r eas
acetylc hol1ne
Lnt o t he SN'C. 11 11
el( clteL($..ll", .
In
th e, SNR
a.l~o i n cr e a s ed th e baseline fir i ng r a t e >!of neuton~ W'hile GABA'
I
and glyci ne i nhi bite d ne u r ons ,'
Sero tonin e xci ted a nd i n hi bi t ed" ce ll fi r ing
I .
I n t ile SNR.
Data
c:onu rnlnp; the e ffe:cta o f lori tCll ho re t lcally applied SP on .
.
.
I
It has .been
. reported
', . t ha t .l o n t op ho r e t l ca ll y app lied
. ' SP exc
I ited ec re tha~5 1: of ce lls
~ .,
.
,
,I
.
tested (Wa lke r, Ke~. Yajlm8 . Kl ta ~ awa . and Woodru ff , 1976 ) . ucceve e ,
.
.'
.
single unit 8ctivtty I n tile SN a re more dlf,;l c ult t o r nrem ee c-
Pi nnock.· and Dra y (l982) .c oul d on ly demonstrate :ex ci t a t I o n t n "] 0 to 40 %o f , the
ee l Ls they t es ted .
.
More rec en t r ep or ts ha ve e ith<! r
.
i~l1ed
t hat SP haa no
ef fect on te lls s ituated In th e SN ( I nnia et a1., 19 84) or: a t bea t . ve'ry
inconsistent and weak Ly
C~hase . _and
exc1t~.tory t!f f e c ~ ,
(L, , ' ~horn,
O'Donohue .
Shul~B ,
Walters , 1984 ).
Jcnee and Olp e (198S )" have hypo t heshed that inh i b i tory r es p onee a
f o ll owi ng Lon tcohores ts of SP in va ri ou s area, of t he CNS,
I n d ud ~~{Lt.h e
. may be due to a SP-depend ent re lease of an in hi bi t or y , ubstance .
SN,
It ha s a b o
be en s ug~ e Fi·t ed th a t SP's exci t a t or y ef fec t!4 mi ll;ht ~e media te d by !lome o t he r
exc i tato ry
fOl i'ow~n~
t .ran s mi t t er
(Davies
. ,
and
SP 10nt oph o r e " 18 i n t he SN a re
,
Dray,
p rol ong ed du r a t ion '(tan tho rn ee a l ,.; 1984) .
t ~ those
197&).
ch~ucter h;cd
.
" "!"
r es p onses
by a s lo w ons et a nd
These o b>lervat lo ns , in ad d i tion
r e ,;:~rdi nl:t th e sca rc ity ~Pre c ep t ora
""?" support
Ce llu la r
In
t he SN (Qu i rton e t
t hat spp~ te n t lat e.• t he
ele ne
of o ther eube r eneee th a t in t urn a {fect rec ep to rs I n the SN ( J ane . a
Ol p'! ,
e r . , 1..9,83) , hav e
.
198 5) .
fo r
.
Ot hers ha ve Bug,l(~B te d t ha t --cellular re sp ons es t o 51' a r e
l ower tnan
II
ene ee see;; wi th o the r substa nces po s e1 pi y bec ause SP h a la r ger 1lD1e cul e. an d
t he re fo re e xhi bi u a a lo wer ra te
of' dH f uaio n (Guyene r
I
xe c e , ARhajanlan , a nd
te e ee n , 1979) •
. The eff ec ts o f lon topho r e tically applied SK 01'l"'SN neurons- also s ee m
va ria ble, a lt hou gh v~ r y li t tle r e s ear c h has' been done with r e gar d cQ. SK.
I nn is' e t 41. ( 1 9 8 ~) r e por t e d tha t SK prod uced e xc It atIon I n a pproX llllate ly 50%
o f DAer gt c a nd
I
no n -O~ rglc S~
ce.l1l1 s8 a1pled ;whe reaa inhi bi to ry r es pons e s
Both SNR. an~ SHe n e~ro n8 r es ponded in
were r ecorded in on ly J% of cet re ,
d m.ll ar way s [ 0 SK. ".Th1l l at t er o bse rva tio n do e s " no t agree ~l t k r es u lt s
.
.
.
,
whi cl'l' lIu8Kest t ha t a cell'i a na-COldes l l oca t i on wi t hi n t he Sit cor r e la t e s ·wi t h"
ttl reaponse t o SK (l.antho rn
et al. , 1984).
r e por ee d to be excited by SK; al though
DAer,l(ic.
Wit hi n
th e
SNR Lanthorn
The ref or e' , although
r e apc nae s ,
t
et
Cella i n an ~ 'l!I rou nd the SHC wer ~ '
he-se ce ll s were not belie ve d to be
~ 1 .( 1 98 4)
it ca n be
r e port e d
au~~eated that
excita tory a nd i n hi bitor y- e ff e c t s o n SN ne uro ns .
in h i bit or y'
SK
ha s both
co ncl u8 ion ~d i ng
bo t h
--.!.!:!e neuro!,! t ype s af f ec ee d and th eir loca tio n i n t he SN ca n onl y be te n tati ve .
-r-te-ne s be e n r e por t e d t ha t DAne ur on s i n the SNCa re de pressed when DA
Is i ont o phor e tic all y appf Led (Ruff leux a nd se nu re e , 1980); whereas neu rons
,
.
in th e SNRare bo t h i n hi bite d and ex c ite d by llA ( Dray and'S traugha n , 1976 ) .
DAha a bee n r e ge eded 81 ·ha v i ng a cr u cial r o l e i n th e SN.
I t has been
anown t o re lea s e [ ) H) -GABA fro m ni gr lll sl ices (Re ubi, t ve r een , and J e aa e ll ,
1977) ,
1983) .
"II
well e e 1llOdub te GAllA 'a ac t ivi ty i n th e SH (U,!I8Z"cack a nd Wal ters ,
Pe r h~ps
1llOst, i lllpor t ant l y i t hu
. de ndri tes i n t he
.
h ~lXl th88 1zed
SN.
bee n .sh own t ha t DA 18 r eleased by .
Thi a r ele a se fr OID n o n -ter min a l eerucecree has bee n
I
to have 8 number
~f
pos s i ble f unctio ns , t he IjIOs t i n tr i gui ng ..of
whi ch ar e a ut o -inhl h1t {on and l a t era l inhi bi tion o f SNC l:e lla tha t pr oject to
j ,
re
the
striatum
( Che r a my.
r
Leviet, and Glo wi n a k t ,
198 1) .
Gef fen,
Je aee t t ,
Cue llo , a nd ~ ver8e'" (1 9 76l have aho sug gested th at dendr[[ t.c:re lease of DAIn
t he SN may' tlaVe a rOl e:~:_lIY in the co ntrol c.f r e ge ne r a e tv e spr ouC,ln/{ and th~
es tab l ishme n t of
new .~ses.
- -.---
,
.
Tur ning produ ced .by the stlnwllltion or Lee ton to g o f vnrlOll s "braln
ette e has beerr-e-eper ued over the c?urse o f
1llOre
than SO year s ,
I ngr a m,
Ranso n . a nd Hannett (193,2) r.e l;>Ot't e d 't he Ipsiversi ve turnhlg o f head lind t r un k
In t he ca t ' fo l l o wlr lg the e l e c tric.."l s ti mula t io n o f t he t egmentum d or sal a nd
r ae eee r t o th e re d nu c!eus .
I ~Sl ve ra fve-turnlng ha s at s o' be en
r e ported
follo wing 'el t he r th e removal of t he "head of th e ,caudat e nucle ua or the gl obut'l
pallldu8 ( Met t l e r 81ld ·Me tth-.: . 1942 ).
A large number o f other stru cture s
have be en i mplica t e d , a t o ne er se or o th er , ' in t urning o r circling behs vior:
t hes e i nclude th e subs tantia nig ra (Anden ,
"-
Dal ~9t:rom,
FUll!,
and ter e s on ,
1966) ; velltra l te gmental area ( Holm'e,' and Wise ,
1985 ) ; nuc le u e s ccumbens
197~);
Patino , W"ight,
(Kelly 'a nd
Hoar e ,
thalamu.
( Garc i a - Muno z ,
and
Arbuthnott , 198 3): pee re qc ed uc t e l gre y ( Re a v i ll, Muacstt , t.ei Rh, Jenner, and
Marsden , 1984) ; eup ert'or eoj.Lt ec l u s , re ti cu lar f ormation (DiCh illrll , Morelli ,
t epec a ee , and Por c eddu, 1982 ): red nucle us ( Hus ae r'l. 19)4); and zon a incertll
( Heas , 1956 ) ,
Bas e d e n t he 'tesearch tools used, s[udi u concerned with circling o~
t urning behavior can -be divi ded int~ two ce tego r t .ee ,
includes
thO:~
electrolytic
studies 'bu s d on' methods which
lesions , or
The fi rat c,fego r y
de~tr\lY tl~lue (exttrp,t'lon ,
~ hem i c a l le~ionl ) ; ' wh ite the
8el:ond
category
11
.
.
in c lude' thol e ttud le. "hl e h Inv olve
(e1 e c tr tc d
. cu d l e·i
-
.
the d ire ct
o r i::h e"'i c .l tt l .. llt lo n) .
"l ~ l fOl"'l~.
. t l lal la t l on of br a i n [ b lue
A brief l oo k
.lit
the re lutu o f
.o-e
'l
.
It I bauld be nj)te d ' .t eMs p oi nt ch at I d ist l nct,l on 1, u s uol1ol. y IUde
'
bet veen t urni ng 4n.d
-
drc Ung
.
beh,v lon.
( roUt i ng )
"
Turni ng
Invo lves
p08 t ura l de vh t"lon a ll' bb. , wbe re:aRi' cl rcUn.lj: t )? l c a U .y ,I nvolv e ; full ) 60-.
del(~e:e ~o tatl ~n • •
~ !!.!!.!!.~Th e De .t ru C[I!~~~
Th~ fl n t . t~d; t o t "" l i ca t e a IIl1ec1f ic .p athw,~ I n t ur ninK behav i or
. w.. tha t o f And ll!nte. 81 . ( 1966) .
' oJ""
UslnR
e lec t ro ~')' t IC
l elJ10ns a t the l e ve l "of'
t he 1U1lIl1!l1r)' bod t eR t h e ln y:e stlg.ton wer e ab le t o p roduce un ilateral d. nage
to ' DA p . th "I)"
tf8vell~ng in t he e r u. ee re~rl.
of dU fe re nt drug.
! f o t1 ow t~
Ih1f Sy, i:lI!lll1c ~d lll1n t~ tra tlon
th e la tte r elCPerl _enta l IlllIni!" ulatlo n wa, fou nd
t o affec t t he d i re c ti on of t!J rn l~K '
For. e xa~ le . in J ~ eclo n, of I -DOPA. a ', ...
p recurs or , In· co~blnat lon ..,l th 4 lI.~noa .. rn e oxida5e inhibito r p r oduce d ' a
t UE"nlnp: of the he ad
The
.~d t a U
a utbo n · cO"-o;l u de d
ellPe E"l-ent a l _nlpu la t lons
. of OA ln th e
.
III t E" t.tu llI.
towa ;d9 the les ioned ', l d e
that
(tp' l~e~l;e tun, l nJl;).
r be • .,y~ t rte . , ? b, e E"ved
we fe ,P t"I!!I~b ly
fo llowing
t'he
d ue . t o an effect on the f unc t 19n
.
'
a nd t hl t lel .1on" o f th e nlg ro. t E"laul p a t hwly , ve ee
u 9P onel bl e ' f o E" th Ol e aI~ t de • •
. '.
Sl nce ttl, nlg E"oa tE"l a u l pattl".y w. . p E"e'u l1led to play a r ete 'I n\
.
,
'
.c1reUn~ behavloE" . · l u buqu e nt s t ud ! e!i
~y,
'
o t,heE" lnve"lt lg At'oE"S
co nf1 r Ol.nd add to t h e data p r evf ded bY,Anden e t 'I'I1:C 1966).
"t~e"" t'ed
The dOPll~l,;!rgle
n. t u r e o L t h e nlp: r ollttl u al ". thway ( Dl1hl t ro l1l . nd Fuu , 1964) .4110"',d fOE"
t he
oae of
OIon
1!,,,"'c I U e
'
to
l edonl ng teehn l~ lIU ". " n. ..e l )' the
use
of
6-
.:
h yd roxyd op.8mlne
(6 ':OHOA).
6-0HDA
h&9
c atec:bo lam ine rJl:il:\ neuro ns .lihen I nje cted
been
a h ovn
I nt o . t he br a tn.
destroy
Therefore.
it 9
adlll ni~'it rat to n tn cc -rh e pa;~ ~o"" "ct .. ·o f t~~ .~ ,:! b" t·lJ n't l l1l 'ligr.. . lihe re 'DA ~e l l
bodi es a re located , en ab le d ~ h e.. apec t f Le dee t r u ccton of na -e e t te •
Thto ugh t he
UI~e
o f 6-0HDA ~esl o~9 Un¢ers te dt a nd Arbu thn ot t ( 1970)
, s howed t ha t ce t r e e e eat d'allla Ke
niS t" ( plirA
when d,h
t
c:~",,~c(8)
t O DA-c:tln ta lnl~g ce l1
~ub9 t ant la
bod i es o f th e
~ea1oned
ca u'ied 'a n illlals t o"'c irel e towards th e i r
u rbed Ify ha nd .l i n" · or whe n inj~ cted with d-a~ het~lIIin'e :
, i d'!
The aU~ ho t9
h Yllo t llesh: e'd t hat , s uc h lus lve rstve c:t t' C11~ ml J(lit be du e to aDA t,llI.h;tlanc:e
.
,' ,
\
•
be t lleen , t ne l e f t
.
and rl ll:ht ,s t r ta ta.
Thill explanation sUJJge!lt ed that t~e
..
, I n[ a,ct .. nc n-Ies t cn e d a i de c ont ain; d mor a DAth ah t,h~' i o n~d s i de 90 .t ha t the
. i nfl ue n c e of t he I nne rvated s t r·lac:u"". "cve rp cve r ed " that o f t he de netv; te' d
s lde , th u ~ resul ting 1n
•
However ,
anillla~ wi ll Cic1eto~~rdS
~t
clrcl1ng b ias .
It
a l thou l{h.
th l~
.
,
"
trad lt 10nal
vl'!w
h aa ma lnt a i.ned th at . lin
th e 6-0H.DA-le SI 0Iled " tde : t t
w~ ~eported~~ A.nd. en
d . (1 966) , nd llnge r s c ed t (,.197Ll th a t th e dir e c t i on o f cl r c llnll; wall a 18 0 a
f unet1 00 o f
~ ~ all10unt
o f ti me t h at had e la paed between the da y of tHe , 1\!lIi on
.-
'- .
and th e l;es t s es Lcn,
FoS' e xa nc Ie , Andl' n and his t olle al!:uea
OOPAsc)llIetlllles elic l t ad ' tu r nl nK ecnt revere t ve t o
~he
r ep o rte~
thRt 1-
l e ; l on...a.J..Le ( a'way fr olll..
8uperiens i~lvlty .
we'll-document e d i n
th e Ie e t cn ed '::ide) . Th e cc nc ep t 'of
0 .
.
·
·
.
_ _ ~ t u dl e s of the p e r Ie he r a L ne r v oue 8~ te ra WIUI us e d t o . eX'lll atn Iiuch c:t r cllnli:
b~havtot' •
.It wa 9 r euone d 't1'la t t he lac k of 00\a o t 101\0 n s trta t l'.l recep t o r.' on
t he le e Lc ned e Ide c e ue e d " t r hi t .. I t Ias ue .t o ee coee eeee
"
'
sh own that the n umber of OA r e ee tors und tr
(C re e8 e ~
'lurt,
8 n.l
Sny de r , '
8 ~ n ' ~ t lve
.
woul d o o r lll811y be t he c II" e wer e t he s t r la ' 1lI1nne rv a ted .
77).
It
uc~
wOul,t
to DA t han
I
It was lIub'lI;e qu e nt l y
clrcu~tances
f ollow
the n
1n c ru tel
th a t . ,lIn y
..... '.
't "
19
adllll nh'tutlon of DA or DAn rec cre c r s wou ld have a Hronge r()ef fect on t he
(,
, der.e rva ted ~ trlat uill .
{/nll;er.sted t (197 1) ~ ound ~ 1iat 01\ tet' mlnlll& lost ene rr co n t e nt s 24 ee"
. ·48· hou n foll.ow in~ t he~m i n i !l t,ra t ion of 6-0HDA.
A period o f w.:eks fo llowed
durln~ · ....hi ch the s ens l~ ivlt y of lIt ria u l e t eece t o DA' and OA agonists
·l nc r ea s e d .
Unge rst~dt
' r epo r t e d ,
admilli s t ratl:~n . of , spomorp-hine
.
.
~ont ravers ~v~ c1rcl1n~
l
f Ol low lng
the
a nd , [-DOPA. Addltional e vt dence .. that
' ,
."
co ~tt~l'atersl clrcUng Willi due t o supe rsensitlve ."D~ecepto rs ln t he
.
,
Lps'i ~a t e nl '~~~ ulll
,
-'.
7118
,
'.
. -
cllme 'fr olll th 'e'
'
.
..
fll~t
, ,
"
st'r~um
t ha t when th e ipsJ lateral
'
.
' \:
.
~ la,c~ ~o lytiCl' lly cosguL:.c ed f<JlloWi nlt. the ' 6- 0HDA 1.ea..iO~OW " " .Of
.
apo1flor;phine had . no e{fect on' ci rcling .
,
"
,
e cne ee e ne t e r ve
'
s' t ~ ~ a u.l {e ceP to r
e t te s
Once t he r o l e o f t he SN in cl
.r ese a r ch. e ff or t s
~
basts o f
c ~ r c li, nll:
beh a vior
wer e direc ted t o.,;4. tds II Lurt'her
behav i o r .
i~
pathways an d areas .
the
the-poRliibility tha t t h e y
oo9t~'yn~Ptic
r c l1 ~ '
otentially ,
.
eU mi na~ed
Dli,:r:ht , be st imulated bf : in th i s case ; a
.
The de struction o f
DA
wa~
all;oni~t ..
fi rm.ly established
e l~boration
n~u ~al
of t he
Efforts were ma de to ldent ify othe r
i~ ortan t
br~ai'~~~'hat are i nvo lv e d ln ci rcling behav io r .
('~9H) blo~ked the r'o tation ~hich fo'llowed
Harshal l -and Ungerstedt
u nilater~i'6-0HDA l e s i ons
of 'the ni gros tr i atal e ys tea by using s eleCt ; ve i"y
p la~knl,fe-cuu. " They ,r epo r t ed th,,!t cutting "triatal eff~rents t o the
s~blt.nH. n.1R: ~,a ~h'ieh tr!'l "el
:- -: p a r t ' of the
••
' . . The ,:r ole "tif
•
i
i n the inte rnal
c.p~le ,
:s tr htu_~ . bl,ocke~ c,i,r ciinR .
.
or
dest r~ying
•
a ma j or
"
ttie ·' ,it t'l~to~~ gral p ro jection discussed a bove 19 no t ·.
. ',
"
C~q:J1'et;IY u'l'ld ~ r? t o,Od .
A nua ber of
'
.
.t~ve!ltlg~ to rs have··~ug~ ested
/'
'
that the
, --!!.ria t,onl,IC ral p r~jeci t ion se r ves ' all a fe edback' lOop', .and i n t his wa y provides
" -:;:....
D~ eerte
in t he SNC'
Wl~~,',informatiOI'l
t ha,t ,
.f~eetl
DA
t\lrnt?ver·iar~eiy
in t he '
.
20
ipsilate ral strlat ul'il.
A second IfrOUP of
Inve'tlg&t() fs
bas 9holin
s t r la t o n l gr a l p r'a"Jec tlon wh i c h is "l1I\HAet'!tl c ca r r ies "trlatal
~utPut
o
"
( 1 .e . ~all\mU8 . 9u~er lor
<:0111 c \l I\18
8.
ro the
ds ttl ("'''~.
SNR.• • In t h is ceae the SNR could act 8S a r e l a y at at io n tha t m
eff er ents t o o t h e r ar eas
\
th st
aLld 're~tcu~:r
fo rlllation ) , and , I n t h ls way, may itself af fec t ci re ll i'll/; behavior.
1'\1e f llct
that little change 11'1 DA meta bo l i s JII r e ..u l t s frOID r he unil ate r al trsl'll!ectlol'i
""-",_ th. ".,. ,,,« , ,. '"' Iw,y , whll' et. tho "~me tim, Ip",,,,,I., .'"llm, [,
elicited; SUP'~~8 bru. dew (Garc.ia-Mu~z e t al • • 1911).
-.
•
""
Whl.1~he
n l gr o s t riatal
pathwa~ 18
invo lved 1" , eue .... inK . t he full
cit'cling r~nse 'ln vo l';e ~ o t her ' e eeceeeeee lIS .~ ll ; t heae . ~ n.du de the
mes o limbIc DA system, n';cle ua ","ccu,.bena, vr ntromadial t,h.11al!lus , superior
cct t r cc t c s , and reti cular
:.~' has
conditions ar~
fo r~ tlon .
be e n sugltes.ted
"
pOst ural
while
I118 gnU 'u,de <If
the {e ve' l
·c~ C'l1ng .<
(a fo re brain 's t r uct ure
s e nd s
eHere~ts to
( e u nlnR)
a nd
9 ta~ e o f
a
of
Io cceo co e
s t l lllu l at io n
' bil~ter:a l delltrl.1 ct i?~
will
determ ine
the
?f the nucle us ac cumJens
that e e e e t ve s DA pro)ectlo ns f(' om. the VTA a nd .t hll t
t he 'S N) in unllate ra Uy les ioned 6-0HDA'a nlmalll reduced";;-
' co lD p l e t e t y abolished
Unilateral. l e s i o ns
r e s po n s e s .
:The
a s yrnme t ry
The ~ !l} ur al bia s <l e r lll1ne a the direction of
i ncrea sed t ccoec ec e a c h1t:y.
J:ircllng
th~t c l r c,l.l ng can be elicited whe ll ' t "'"
"
~ a t h f,l e d :
any ' c ir cling, pr eviou s l y e licited
of
the
nec Leus
a cc u~b e n ll did
not
by
8.RO~.1l1 tll .
DA
af f e c t
etrc l1n il:
Kell y and MQore (1976) r ep;s rded this.ils suppo r t ' fo r t he ar gurae n t
that.llct(vlt y in the niRros tTla tjl l DA 's ys t e m dete rmines t he d irec t io n o f
cl rc lt~g wher e~s ac tiv ity
m~.'ln l tude of clrcllng see n .
If.Ollle tll11es. :
"
~r red
"
to sS jthe
i n , t he ' m.esollmb l'c
DA system de t erlll .ln:s
t he,
Thll ltne of r e s so ni n p;
ts
two-c~lDponent
.on e componen t, the SN., \
system ,
\"
embodied j n IIhl. t 11.
.
~
,
'
21
/
ee e rt . an e ff e ct o n c he le t 1. t i l DA bala nce . nd pr o du te ' "t u r nhllh whe r e a s t he
o t he r co. pon e n t 'e xe r t • .lin eff ec t 0 " -t he le ve l of t e eeee t e e ac t i v i ty ( Pycoc k
and Kat ade n . 19 78) .
I y'u"
f uncc!o na ll y dll tin c t
a nd
I n t he Slf th a t was -"llude d t o e a r j.re e ,
h11 co i leaRues h4v e pr o posed
oel ghe re. I n t he
DAer Blc
s ya tem ,
th a l a lllUlI ,
S N~
It ha.
th8 t
".
nl gul
e ff e re n t
DiChia ra
sy llt e..
be.e n de l:JOllstrat ed
t hU . t he npe l' lo t e o l Lt ee l u s ,
grey , an d r e t ic ul a r fo rlU c io n a Ll r e c e i ve i nput
o r i gina te I n the SNR ( 8e; ks tell d e t al . , 19 7?) .
DiCh ia ra e t 11 .(1977) firs t
kat nic .-=l d ( a neu ro to dc
r e port~d
the adlll nl ~tr .t10n
tha t
ra t l were g iven bl h. te ral 6 - 0 HDA
- .
.
Itai ni .c acid
' .
le s t on o f
t he
le~ lonl
\ '"
• no n-DA ' IYl t e ( '.III,.
.
c~rci i ng
SNR•. t he-'tu nt r a ve u h e
I nv o h ed . l i n ce .
'6 -oH~A
ha d
. . int tta lly e lic I te d by?'t ka I n l c acid lu ton .
,.
The 6-oH DA"rh'io n. l o wered n iR r al
Thh
~ eff~ct
.
.
wh1 ch
fi rst
s ug ges ted t ha t ..
on
t he
cirel i ng
,
tYTO l1 ne .hYdrOlYI~le ,c tivlt y (t h e
ra-te - 1111.1 t l ng s te p I n t he bio , 'Yllt he al l of
Cl " <a. ' , - " ld ... ..
When
o f t he SNe fo llo wing a un ila t e r a l
a ppe a r e d fo llow t ng t he Ital n l c.....-cld 1e "1 ;;n pe rl h t ed .
110
of
m al a g of g luullII.u ) I n t o th e SN r,es u lted In
con t r l ve r . l ve c i r c l i ng ( i;:.oHn A l e l l o n l pro d uce t ptlv e ul ve tur n i ng ).
')
t ~ tl
f unc tion . I n a IIl4nlle r oPpol t te to t he nl gro llt r h u l
pe r l a c~ lIe d u c t a l
f ro lll c: e ll~ .
t ha t
DA) by mor e
than 8!1 pe r c en t' :
"'boxj..•,~ I~HY !<a""'t l~C'BA .,"' h..'.). ho~""
va. no t, a ff e c t ed.
The
.
t e .u l t s l ug gea t e d , t-ha t GABA may pla y ,n hlpo r t , n t
t ell e ..! n t hh parti c u l a r SN a ya t e m, which ill fun ct -lon a ll y o p posed t o th e r o l ~
- of 1he DAer gic 'n l g r oat rh ta l
8y~ te·~.
I t ha l ,bee,n ge net a ll y accep t ed t ha t
e xel t. tio n o f the nl gr o_ t r t at a l pat hv a,r pr o du ce •. cOIlt.ra ve rs tv e c lrcli~ p; .
1111l1la r f or" o f co nt u vl n l vl circ li n g c', n bl! e Ucited
..
by t hl
A
d, st r uc t lo n o f ~
22
cr e euced n l gTal GAflAergl c e ff e r e n t
pat hway ( OIChh ra
ee
II " ( 917) .
Th ill
G~Aer 8 lc
pathW6y Is beli ev e d to s tr o nj{l y I n h i b it ac t iv i t y In o t her Ilr~IIB
r~~ 1Ylng
the
~roj~ctlon (e~ • •
ve nt ro med ia l nucleus of the t ba l aeua (V HT» .
O~e h Y ~\~h; sl S t est ed by Carcla-Hu nu z e t a l. ( 198)) wa s t hat , if t he VHT ha ~ nn
e)(C lta tor ~ i nfluence on other a t e a s (co r t e ll: ? ~ . an d wu no rma lly I n hibtted by
th e GABAerg l c project io n I n ques tio n, then des t r ue r ton of t he lps llat.U·lll WIT
J
.
s hou ld dta sti cal l y red uce
the IIlllOun t of
cuntr ala tera l c l r c U n g s e en when- "
an i mals ser e adminis t er e d apo1llO r ph ine systemica l ly fo llo wing u nl l11te r a.L..6- .
OHDA lesions of
t he
n l g r~8 t rta t~ 1
pa thway .
The
hypo [ heS, 1~ . wIl9
cc nf t r ae d ,
Additio nal t est s of t hi s SNll. rmdel hav e been ca rrie d ou t, ",gain the
idea be in g that if o ne remo ~es ' t he i nhibi t ory Un~ -pr e vtde d
"
by t h. SNR
e ff e rent systelll (dlsl nhlb lt 10n), co n eeeve r s tv e c 1rc ling r e e u tt s ; whe r ea s t he
Y d e s t r uct lon of
GABA-T e c lple n t a r eas 1011 11 r educe
res u l tl ng 1n Lpa f ve r a Ive c t r c Lt ng ,
to
spec l f lcally l e s l o n a r e as
for matio n
s 1~n lflc.a n t
In
no rllllli
tend e ncy
r ats o
to
of
'th ese
c:1rc:le
th~lr
exc tt e co r y o u t put ,
DiChiara e t a t , ( 1982) u sed \(aln l~ 'u: l d
t he
s~pe rl .,r co Ll lc:u Lue a nd ret i c uillt
ltro upS
of
~pslve rs lve ly
..adQli n lst ra t lo n o f l QWdo lies of e pc ecr pntne ,
a nifllBh
ell
f o llo wi ng
e l[ pre~ee d
the
a
sy lltelllic
The sl! H ille l es l on s re duc:ed t he
SlIIO u nt of ccnt re vee erve c:l'r c l1 ~ g whe n an lma18 wer e admin lste red apo morph ln e
fo l lowl n.'l u nllat er al
to
6 -~ HDA
l e 810ns of t he r o e rr e l SN ( wl\e r e
t he strl &tu lII conve r ge prio r t o pro jec ting to
n l~ ra l
eff e renu
th e Ilt r l a t ulII) .
On t he ba d!' of all tl) e e ltp e r..lme nt a l res u lt'! dhcu!l!ieda ooYe lt ca n be
co ncl Ud: d tha t, at l.e u s t t wo d lltlnct 8yst elll; ea t s t In t he SN~ and t..ha t bo t h of
th ese ar e l nvo l Yed ln cl rc llng (Starr , Su mmer hayes. and Ktl [latt1c: \(, 198 3) .
1I0wey e r . t he Ill8jor it y o f the et udl es di llcuue d 1I0 fa r have us ed v:",rlo us for flll
of
SN l eli lonll t o a tfe c't c rr c t rng ' ~ e h s Y l o r .
The fo p~...ln g a ub eec t r cn ..,111
23
lnc l ude s t u-d iu de dlnJt wit h d i r e c t e t t .. u h el o n o f SN ne yro ns .
~l!!!!.!.
Arbu t h nott Slid Crn v (1 9 71) repo rte d [ Mt elec t l"lc:a1 atLlIIUla tlo n of
th e _dLa l 8ub u a n t la ni gr a pr Qduc ed ce n ereve ea t ve ci rcl i ng .
Frankl in
( 1982)
llleuured
c ir c l i ng . rel pons e a
va e ea e rec and
fo l lo wlJ\Jt t he , unilate ral
el e c trlc~l 6t 1)l\I18 t l on o f t he SNC and r e por t ed [ t u lu th a t sdgges te d t he
ee t e ee ec e o f. a f unctional ,dif fe r e nce be,tWeen t he l at er a "- and Illedh l _SNCe..__. _ .
Con t rav e n l ve
c1 ~dl nJl;
r esul t e d frolll
8t illlu la ~lng
th e llIed l al SHe, whe r ea!J
Ip d vera1ve c l rc l1ng l".fsulted fr olll s tllll u la tl ng th e ht.e r a l SNe.
wi.. e ( 198 5), ul l ng a
.
I
n'W)~u ble ~e c trode
Gra t to n a nd
t o stillulate, var i ou s r egi on s o f t he 5N
110 ng t he dur.o_t nr r.l pl ane cou l d not r e produc e Vl c e ar ioo ', and Franklin' ,
resu lt. .
One
po • • i bl e
e xplanat i on
f or
t hi _
III ,. · be
tha t
t he
l ate ul
Itll11u la t ion sl te lS r e po7 t e d by Gra tto n a nd Wh e ( 198$) were no t e s l a te r a l . s
thole repor te d
by
Vlccl rino an d
FranltU n
(982)
( Frlnkl1 n ,
pe r lonal
..
co l:llllun l c. tlo n) ,
Al tho ugh th e co n te n t io n t hat bo th i pslvu slve an d c o n t r ave rl iv e
. circli ng -can be e l1 c1 te d , depe nd i ng o n whicb SNC t e g l on_! l1 lIthul a t e d , ltas no t ·
bee n fu l l y con fl r M d , t he e lic i ta t i on of
con tr l ~ e n1ve
clr cllng
f o ll ow ln ~
t he e te c er t cat 8 t l . u18 t l on o f t he SN I n gene ral h.. been widely a cce pte d .
,A l e r ge nUlllbe r
ot o ·ther, stud i es hiv e I n vol ve d t he us..!! of d i'l"ect
che llli cal stimulation . Wher eas e l e c t r i c a l 8tlmu ht~ on e xc r eee all t y pe s o f
. neurona , Chi!!lIIlcal I tllllula t t ;;n technique gi ves t he In ve lt l gl t or . t ~e o.pt lo n ot
s t l lllU l a t l ng a dlltlnct t ype of c e ll within a b rier ne ur onal po pulation .
.
.
.
As dlll cribed el..rllu , a large nUlllbe r o f po t entia l ne ur o t ra ns mi tter.
_
and /or neuro11lOdui a tora are found 1n the SN.
The li st incl udes SP, SK, 'CABA,
DA. no re pi ne p hr i ne , enkepha l in, ,d yno r phi n , a ce t y l cbo Hne , glutalMlte . $nd
serotonin .
Table S sUllItllllrtzes the ef f ee t s some ,?f the se hav e been . reported
t o have on circling b e havi o r vhen adminlstered i n tr an l gr a lly.
The da ta sh own in Table S can
f i nd i n g s dt s cue eed ear li er
be expla ined . if
one
makes uae of
(p o 2 1) , which 8ugge llt t ha t two fu nCl;i'Hlally
opposed s ys t e ms a r e present in the SN ~
One systelll i n ~ lu d e ll those DA ce ~1s
, ' t hs t a~ e pr e se nt 1n t he SHe and that make u p the n 1p;r o str lat al pr oj e ct i on ;
wheteas t he other sys tem i nclude s 't ho s e CABA ce lls t hat are pre se nt i n ·t he SNR
and
that pecjeee to
te t1 cu l ar
( ormation .
t he ventro!ll!dlal tha l amua . superio r colli culu5, a n,
In
t he
ca lle
of
tha
former
Ilyllt e m,
intr anigta
I
-~
admin is tClttions of drugs t ha t unilaterally excite thiS DAsystelll p reaumabl
Incr ee se illlpulae fl ow along the nigrostriatal pa t hwa y. , As s con8equen~e of
this
incr e ased ,neuronal ou t pu t ,
DA l e ve ls
Inc reas e in , t he ipaU a t e ral
str iatu;' and co n travers l.ve c i r c ling results ( J llrnes a nd Starr , 1979).
is Oile hypothe sized IIIOde of aetion
fo~
lllOrphi ne , dYnorphi n , a nd lDe t-en ~ephal1~ .
seen t hat . unUateral
l:hia '
su bstances such ss SP, DA, IImphe t ami ne .
L1s i ng similar r.e8 son in ~ . it can be
in tran igral adlllinistra tions of
impulse _flOW slang the nigrostr ia tal
pa~hway
dr ug s tha t
ln h i b.it
e.l t c t t tpsiversive7c ling
( i .e . ap .ororphine) .
W1th r eepect to th e CABAergic syste .. dtURS tha t t ncr ee ee the ou tput
,
of ·C.ABA cells i n t he SNR ( thereby I ner ea e t ng t he inhib itory
ventromed l a l '{ ha lam ua , s uper i or ec Lj Ie uj us , snd reti<:.u la r
ipsi vera1ve d ; t i ng (e .g .
":I
!'
picr~tox1n);
wh ile those
ou t pu~
fo rmat lo ~)
dr':'g~
to the
e licit
t ha t r edu c e t he
out pu t oL~C"'A cell s orig ina t ing ' in the ,SNR elic it cont~av.u ive cit"c ltnlt
( e.g. GADA a nd muacimol) .
\-
/'
'"
"
-4
~
.
- - ! ~ -~
. . ., I= - :
s
,
I
~ i
~
~I
-,
-,
~
j
w
§
'.r
:
~
0
~
;
!-
1! S
:
-:
..
!
~
c
~
~~
; u
~
-~ ~
.
~
u
~
~
~
~ .';;
;!;
,
~
.
~
1!
~
.§
~
~ ~
,= ~
~I ~:
~
~
I
~
~
~ ~~ §
~
8 s 8''§ ! 8
7
-~
~
~
::;
::;
w
~
~
c
~
.\
1
.
.
w
~I
~
§ -=i'-~,l-~ §I ~
8 8 s
S S
~
-
~
~
,
E
~I
~
.
~
~
~&
~
~
I8
i
~ '
:t'
;
1 e-
I
~
r
i.
i
l;
c
f lil
~
.
§ ~
~
~
(").
II
.
Al<~U'h
SNR r e j eec r c ne c
SP ha ve been h;PO<h" '''d
~.
impu lse f low along the nf.groe t r I at a I pa th way , SF' s prec r s e mode of e e t t o n
not
kno wn.
hypc t he sd aed ,
As
ment io ned
a nd
immu,norea ct l v tt y t o
in
e a r li er
addi tion,
both , SP and
var ious
t he
tl\chy klnln
SNR has
bee"
recep to rs
shown
SKI a ntiseu , ( S hUl t s et
con sideration o f t he above , in co nJ~nI~ tlon with ~he tact t h ~t
eo
exh l t,l t
81 . ,1985) .
SJ(
{!'I
ar e
A
hal a l re ady
been shown to be to times mor e pot en t t han SP Ul l!ltd t l nR certain beha vioral
!
.
~
r e ~ ~.n 8 e s ( Ka~ iv llS ,. Deut'ch , Ha ggi o, Han tyh, and Roth, 1985) has l e d
of
i nvea tlii:stors t o .,e xpr ess r e s er v e
previo u'!" repo~ ts on t~e eff ects o f SP ,a d llli nls t r A¥ o n li.
.e ucf re servat ions , r e s t s o n
th e
1\
number
conCerning ' .t he · l n t e r pr e t a t lo n of
po ssibili ty
The rea8 on t.Og beh ind
th at effec ts
ca use d.. by
SP
inje ct ions mig ht be due t o the 8 ctJvat lon of recepto rs whos e aHin ity'migh t
s t Ll l be hig hest for ot her eubet.ance e , t , e , SK or NK. (Innis , Andrade, a nd
AghajaRian, ,1985) .
ae eeer c b s U81lesting tha t dU f erent tachykinin r ecepto rs
ed s t a n d t ha t each may be d ifferen tially se nsi ti ve to a number o f tac hy klnl ns
can help E'ltplain ce r t a i n puz:dtng r e sul t s .
For example, wben cne compa res
publis he d desc,r1~ti~ns of the dht ribut lon
o f ~e c e pto r bindIng slt)S wlth
desCr lp[ i.~ns o f the dist r i butions of cellular i 1Uluno reactivlty to SP a nd SK,
st rik i ng diffe rences ar e noted~ espec ia lly wi lJl respe ct to
n i gr a .
t he "ou b s ta nt i a
Although t he SN r ec e i ve s a dens,e SP inne r vatio n f ro .1ll the s triatum ,
few SP r e ce pt o r s have been loca ted In the SN ( Quirion e t 80 1., 1983) ; whe rell.
SK bi ndin g dtl's have been vi~ullli z:ed i n t hi s 'area ( Kant yh e t a t , , 1984) .
posalbiHty "thet.efore exl,a ts t ha t so me pa thwa ys
Th e
cOJ'ltain lng SP may al s o
contai n SK; a nd t ha t behllvior,epo~ ted r o -be due to SP Illillh t . also,l nvolve S K
{eg , c i rc ling be ha vi o r ).
In n is e t a l.( 198 5) have ope culat e d , fol l olOtlnll:t he
d taceve ry of SK recep to r li te s in th e SN, t hat SP e ffect8 in t h 18 r egi o n lIU1y
27
have bee n due: to SP _e t l a n o n :
1) Ip. ~. e bu t e d . t i ng SP re ces ec e e , or ,
ti ).bund,n t , bu t SK- prefe r r l ng r e c e pt or .
t h,a t . ho ..
SOllie a f ti n l ty
fo r SP.
An e x pe r t_n u l . ,del th3t lIlay be u led t o te at the h ypo t heRb t ha t SK
~.n
dIc it behavior al re spon l es sl.. 11 ar
c {r t H OR or rot a tion .o del.
to' tho a e eU c1 t e d by SP 11 t he
It has bee n aholol'flthat IIl cr o l nj e c t l o ns o f SP I n
the 'SN R eli d e .e1 r c U ng .co ncn ver sive t o the d te o ~ inj ection (Ol pe a nd
Koelll, 1977;
1un
and Sta r r, 1919) .
It
"I • •
t her ef ore of
ln t er e ~ t
I n th e
pr e s ent .st udy to 'f11 1 cr O i n ~ e c t ~K "l n t r a ni llr a lly a nd compar e J.tl eff e cts t o
t ho l e o btai ned wit h SP i n j e c t i o ns .
Suc h a n expe r i me nt a l manlp ulatlo.n 1 8
'de ac r t be d below.
~ ~~~~ng
One hun dred an d twel ve
ea I e
weighi ng betwe e n 2) 0 an d J::i0g were
.
(Que bec) .
"
Upon th eir Arr iv al a t
.
t he
r at l
or
the Spra gu e - Dawle y tt r .. !n
purc ha .ed fro ll. Charles River
l aboutor r
I niu b
were
Inc .
.
randolR1
y
div id ed into-'troup l o f three o r f ou r ,- ~nd hou l ed I n a t ra n sp a; e nt plexlgl••
~'gl!.
(44
~1lI)( 2)
c m ll: 2) CIlI) .
Food a nd wa ter were .. v ~ ll.b le a t .11 tl mea .
.
In
.
. dd i tio n , t he Up;ht cycle In t he an illlBl{te.tlnp; r oo fllwas ee ve e eee (Ugh t a o n
a t 21 : 00 hr. a nd off a t 09 :00 hre) , and t he t emper a tu r e "1'19 mainta i ned a t 20
degreea Cels ! u• •
Anima ls were give n II minimu lIIof f iv e daya to adap t. to the i r ·
ne w llvl1'!'8 qu arte rs.
Thta pe riod e na bled t hlllll t o adjus t t o t he r e ve r . e d
ll ght fd ar k e ycie a nd t o eeeevee f rolll a ny _rru.ea . ..oe l ated wit h thei r
.'
28
tr an .port .
tollo wln g t he a4. pu r lo n pertod so.
of r I ca were t e ' U d f or a
~r o up .
na t ur a l circling btl . , ell:pr ea led .. .. te nden cy t o ele ele prefe'u !TlUI'Uy I n I
par t lC!ula r d irection .
t o the . cr ee n l ng tes t each rat " • •
On t he day prio r
handled .f o r a pe ri od o f fi ve .. I n ur e s a t t he flnd o f which I t wal pla t ed In a
cyl1nde r""130 nl n . } t ha t Wot part of the apparat ul \Iud t o quan tify c1 rc l l.np:
behav io r ( de ec e t be d below).
The t at t e,r was cs r r led eue dudng t he dar k put
g'f th e Hghe / dar k. cyc l e, as wer e a ll o t her
On t -he eceeenteg te st d.y e ac h
te .~-r el~ ted
an~lILI l
proceduru.:.....:...
11'8 ' gt ven a
. ~ b~ut. neoul
Inject'lon of d-alllph e t alli ne ( Illig /kg) ZO 1II1nutn prior t o being t e .te d f o r a
.
.
-etn:llng bia ..
D-a liphe Ul.ln e has lu pe ak e ff ec t 20 mi n u t es follO lll ng ltl
subcutaneou s a dllll nittr a tio n ( Nt \/hi te, pe nona l eo-.. n lc. tlo n ).
fo ll o ~ ln g
th is 20 . l nu te tn tervd t he ' n l lU l va s ·pla ced In the c t r cl l ng . pp. u t .. . . And
"l
t he lllagni tude and dtr e ~t i oo of c1 r ~!!g o ver a
io . t nut!!
period va l r e·co r ded.
Earl i er work . ug gu te d th a t be t .:e en 20 and 25% of a ni_I. v i t h i n an y g r oup
v~l1 s how a lla r ke d t end en c y to cl r c l e "re pe _ t e d ~ y tn ' o ne dl rec:tion v hen
ad lllini. t er ed ..
\
gr~u p o f
10101da l
e o f d -a ll.phe ulI. l ne .
j.n o r der t o I c r een f)u t t htl l a U e r
an t_l_ , and ye t ret a tn a l ar ge e no ugh a,..pl e
t e sti ng", a cr r ce r r en of 15 ·t ur n s vas
ad opted .
C allo v for aubleq ue; t .
That
Is, if an ao 11l>8 1' ,
cUlllU la tl ve numbe r of tu rns was bi as ed I n one d l re cHo n by IQO re t han U t u rn .
thi s a n i ma l was no t in eluded
t n the
ex pe r Ieen e ,
CertaIn s u bgro u p s o (
a nlllla ta wer e no t ecree ne d f or c"lreltng b ls.s e s e t nce I t Val pr e s umed a t t he
the t hat a s ubcut aneous a dllInls t rat lo n of a 10 ,:"dose o f d -alllphetaliine ~ d '
no t by Itself e li ci t c1r cllng . ·
,
.
"
PriO!:,
to
8Urj;:er y e a c h a ni mal wa s ve tg bed a nd anaes thetized us i ng
sodium pe nt o bar bi t al (SOmnoto
1, 60 IlIg/kg).
t he
when r e qui re d .
smielt he tlc
was
give n
s nae n he l la hair o n and aro und the
an elect r ic halr cli pper .
A s u p plemen tal ad min is tr a tio n
Following
pi Atned s f t ec f
The animal was
th e
r:r£...J
ind uction of
10dale n waa
cl1ppe~
u8'lng
th en placed I n II at!!reotax lc.
Inst r ullIent (KOPF) . ' A 1II 1 d l~n e ,i nci s i on sp p.roxim.il tei.y I. S CID long wa s made a~d
underlying lIlembra ne", wer e cut an d pus hed a ~ lde t o e~~8e th e co!o na l s utu r e
a nd breg lll4.
~laa t lc
us ed
8S
Two hol es , l arg e eno ug h to ac c:o modste sta inless . s teel acr e ...s
Pt'od uct s -l . wer e "t he n " " ' " thro ug h t he
ancho r i ng' s i tes fo r ac rylic 'ceee n t
S~~ll.
S~.eel
,
sc ee va.ve r e
. ,
Following the pj e ce ee nt o f scr ew'a a 25 ga uge guide 'cannula (Plas t i c
Products ) v e e lowe re d thr o ugh a t hlJ'd dr il l ho l e. the guide ca nnula wa s placed
u81".lI' coo rd ina tes in itia lly o btai ned frOID Psx Lno s and Watllon (1 982):', a nd
IlIOdifi e d f o l l owi ng a numbe r of test ope ra tions .
su bs ta n tia n i gr a par a r eticu la ta were as
9 .3 .
f ~llows;
t he coo rdinates fo r " t he
s.p. - 5 .4; 11\.1. 2.0 ; d sv ,
Al l coo r d i na te s were liU!as ure d in r elation t-ll-bre glll8 excep t t he dor s o -
ye1)tra l coo rd i nate .
I t wlla .-easure d with r es pe c t t o t he e~r face of the sk ull
o ver ly i ng th e su bstantia n igr a .
The p:u ide
ca nn ula "':'Ile cut
I n add itio n , t he noee ba r wa a ee t a t -3.5 .
so that ita, t i p llOu l d lie a pproximate ly one
mi ll i mete r a bove th e ce nte r o f t he aubstantia
n i~a .
Once the cann ula wa s l owered into pLece a weak stream o f at r ve e
a pplied t o t he e x poaed s kull to o btain a dr y eurfa ce .Th19 fac ili tated the
n,!ltllll1on o f t he ~~! l "ce me n t [Sybron (Ke r r )1 whe n it lola'S finally a pplied
ar ound
t~
base of the cannula. Followi ng t he ha r deni ng of
t~e
a cry lic ce men t
'0
on e ...4 r e aa lr lO
ed I n place unti l tea t day
Anll1la15
s ur g e r y .
During
llhen .. pe rio d of
thll
recove r y · perio d
I.
a t l e au fl Ye da y. t o r e cc vee
the y wef t
hou sed
.?
f.r o .
I n d l v l d ua l l ,
In
Iden tlCflI t o those descr ibed ea r ll. r a nd hand le d .u hu t
p l el(1 g 1as c a gn
'"\
V1!1'1!
once , fo r a peri o d o f f i ve .. 1nu toes .
Fo llo wi ng t he r e co ve r y per iod . a nd o...e
da y pr i o r. t o t he t l rlt t e lt ae .. lo n ,
e~.c h
.....,1 .al "WlI I pla ce d. ( n
the
ctr clhlJll
c ylinder ' f o r' a per io d of 45 1Il.!nY.llJl:
Appar atus
-, The appa r a t u9 us ed t o qua n tif y clr c U n g wa ll' . ,llll ! a r In constructio n
to o ne dev e l o ped b y Vac:cllr tno and Fr a nklin (\ 98 2). an d I s .hoVl\ ac he lll4tl c a lly
In Fi gure 1.
cy l in de r 30 ell
The appa rat us co n.h ud of t hr ee- lIlajo r colllponen u ; 1) . pla n l e
~n
dbntete r . " d 38 ee hig h , I I) a har ne ll a r uc hed to a p1•• e tc -
covered ",I r e tha t se rved t o pr ovide a cOI\2.e.c_t1..on between t he
a n~_l a n~
the
c l rc ll;'g co unt er, a nd 11i) a c1 rc l1~lI: co unte r co n l 1l t l njt of a r o t 4ting t u be , a
a U k thr ea d , an d a c:a ll br a t 'e d eea re,
The harnea. con . h ted o f • velcro
pla lltl c-c.o ve r ed e xte~ slo n v t ee ,
(
a trap a t t ac he d t o a pi ece o f
The e xte nslo; w'ir; ex tend ed ve rt i ca ll y and
.
wa s a t ta c he d to a me t a l c U p , t he l a tter being f a.te ne d t o a l;ut 1111 .yr ln lte
ahe ll vh l c:h fit thr o uJl: h a . ho l e In a a upport l n g woode n
c?_~p l~ ted'
p l.~k .
£lIer y t urn
by t he a n i mal e eu ee d a 91ng l e tur n o f the. yr lnRe sh e ll. , -Stl k
thr e ad was con ne c t e d to
t he Iyr I nge a nd wra ppe d a round th e
t et re e in '
ecc o r dence with the numbe r o f t urn s compl eted by t ~e 8nllll8 l . Rot a t l on e ve r e
r e pr e ae nt e d I n ..
c u~ub t 1ve
deplc: t e d a chelllloll tlc.a ll y In
' a \lhlo n o n .. ca l1 bu t e d 10'.11 ; t hh
Figur e I .
The d i rec t ion o f
tu rn lnx
Ia a b o
co u ld
ba
(
1I
4
",,
30
2"
20
'[ "
10
6'
' 2l.
~'
3
0
~l
A achema t ic d iagr am of th e appara t us us e d to meas ure t he 1II'l ntrude
and ..di rec t i on o f etrc U n,ll: f o llowi ng t he i nr ran igrai a drdn1a t ra t ll;ln. o f f our
Itolutlo ha • .The basic aPPa.\.atu l 18 ~olllp r lle d of a pl ex iglas cy li nde r ,
tur nin g 1Il8c hanl'lll, .'!W•.{ cdrbrated wa)l • ..The enla r.ed sec tion a hows (~, ,. 1
ee e yring. ,hell . ervi'l't~.. c han ne l tlttOu gh pl ank ; (2) • 5 -cc sy ringe the ll
l uppof Ung ( 3) •• 1 ee .yri nge s hell a llowed to rot_ te ; a nd (4) • meta l- pin
luppo rting i pap e r cUp whi ch In t urn au.pporu a pl 811tic-c ov ered ~et. l wi,re .
I'
"
Fl y!! d.19~ent ~o l ...t l o ns • .,er e\~' l! d
i nclude d
~!......sX. .
Sub. t.nc~
r was
purc ha u 'd f ro. 'Si gma
lDO le ~u lar "e1g~t
Its peptld,; cont~nt
'.
.,,, .
99%.
t he
Chemlc~ l ~lIlpan:y
was IJ' 48 ( 'bare bo nes':
alll1l'lo -acid residue
J
in
exp er t_ e lltr.- The ~ e
hl"e and a-••p he tall!l:I.e
ac l d l H e d sa U ll; , a.polDO r P
lola !
~UIII ,~ f
.'m14'o
+
$o l~ent u~~d
•
in
G
l YO Phl l1 ~a tl0.n.) .
'
Subat.nce K " •• pu ec ha s e d f ro .aachert
.
A nUlllber o f
Wal
I t~
.
In c . ( ~ t
of.
n e pU'rlt y "
•
485A ) , an d {-til
APO llOf,ph t'!'1! hyd r o ch l or i de ."a a a ~.o pur cha ud .fr OIi
Sigma ' ( Lot 14F-GSSS) a nd ha d
s u l fa t e ( ID t SIDXS)
IZ~F-S9~Op .
.c;~d r es rdu~ we ~ilh t . ~ .
85% hlUIII o f alD1no lIc~d re Bi due weight.' I we ,l ght
Welll:ht~
pe pt ide cont e n t was 851.
(te e
80 1utJ.on~.
.ll
.." le cul~ r .wei ght o f 303.8 .
D-a llp he ~~. he
It1 ndl y do na te d b y SlJ1t h lU i ne . lId ~e n c:h Call.d. Lt d ••
· l.~r t.nt ~.ct5' were kept
i l\
.l~ wh U e .....ki~g 80 1u t ioni
con t d n i ng SP o r S~ ( Ste wa r t . 1981) :
t) both t ac hykt n i na be:h.v e Uke
b181~ PO lypePtlde"~ .
..
.
II ') they are "ery hyd ro pho blc anl! " . .. re llul t "do not dlllllolve well In
,
wa te r, espec i all y whe n hig h concent ra tio ns a re desVed •. Acet i c. a d d
helps t o l nereue th eir sol ubl Uty,
Ill ) low pH pre 8er ves t he i r bl o log l c.l acthlt y , and
h ) ate rl i e t e chn i qu e"8 pr even t ba ct e r i d
th e bi olog i ca l . ·ctiv ity of
't'
deRrad adnn a nd "puae r ve
,
t hes e'"p'!p tl du .
Pep ti de 8o l u t l orl!ll wer e u lluai l y prepa red I rn;r t l y be fo re .t he y were
\ ·adDl n i l t er e d . " : ' the · Ie ", lnn;nce8 whe re this ·,w. s n.o t th e
co n 7
20- l0
~l cro l.lt~rS (~ l) o~
'"
.IO lu t l~"n
wre
~.ae . ~UqUOU'
p"repsr:~ :I n, "dil.~ce
ia
' '';' . ';
.
)J
'lrl~,
a nd vere stor ed ina liqui d n itroge n re ee eee ( -60 de gr e e s Cele1us) .
so l ut io ns were kep t in , r"tfige r a to r whe"-not"""tle lng used (' i.e . duri ng
-,
.
. be~we en- t e!l t inte r val s within one pa rt lc ulaCJ lI"sII10n) ••
"':. no ta d a ,:Y,~' ~e us e of 'a c e t i c ac i d i mpr ove s t he ~ol u b l l1 t~ of SP
.
an d SK., AC:1 dt Pied physio l ogiu l .88l1n e (0 .9 % ~ aline ) was IlLade bY.lIl!.xin g 0. 6
r
'~1 u f glada~ acetJ:~ lIdd i;to OI'Ie litre of di8 t 1l 1ed fia~er and,addin~ 9 g o f
I - .'.
.
. .'
NaCI; A fina h~.pwlJrd a.d j ust men~o f pH to &.22 wa ~ ar rq~d aot by the d r? p~he
add i tion of .
,
'
J .,
aal in e ...u
so~'~~l1'- hYdrOll1d~
f in al 1.Y ,
'(in .0 . 9 % s a iine ) .
I
•
•
,
'
..
.
sl:erilhed usi ng l)'Syb ro n (Na l ge ) f il t e r (pore
th~'
sh~
.
ac ( dlf ied
'
"
<
.. 0.22 om).
the a.pQlII) rphi ne hyd r OChloride wa s f oun d to be IOOst s o l u ble i n wate r-.
When
at~elllPts wel.s.Jd~ '~o--:;:" s~s'll ,a'lllOunt~ i n 0 .9 :e a~idif1e~ 8a llne, or
X phyai.o l ogica l
~a l1~e
ve ry
po~r
so l ub ili ty re sul t e d'. ,
00,9 -
Sin~e' a polI,.:u;p'hi ne
1&
h ig hl y.susce ptible to a uto-ox i ctatJ,on, sol~tlo nll were used qui ckl y ( Wit hin, 10
o r ~5 minute s ) .
O·smp hetam.i ne was mixed i n, 0.9 % phys io logica l sa line in a
con centration o f 1 IIIg/lIll .
~rch~!!!!Testinll:~
.
.
~
Th~ ~es "ar c h :des1gn use d is shown in Ta bl e 6.
~
Anima ls ~n Gro ups A, B,
.
,
,
a nd C received .d -a lllp he t. a ~ i n e <ad); wher e as Iln~ma ls in .Group ' u did not .
Sali ne ( Sal) a nd a po'lD:)rphlne (Apo) were a dllli nta t e r ed intr a nig ra lly t o a ll
gro ups . "t n ad d i t i on Or'ou ps A, B, C, and D re ceU;ljld
,CIlic~ogralllll
... r r e e e ,
(u g)
~ f' both SP and "SK t e sp e c tlvely.
12,
16 , an d I2
' 8dllli n is tere~'
..
All Rroupa ,were furt her di vided into t"" i 8ub gr oups 1n ,an e ffo r t to
.
cou\1hrb, lance
th e order of
adll:1niatrat1on waa
.c enee ,
8,
SC"w8a a l ways
Sal-S~-APO
,
.
intta ni ,IfC al. a dminlatu c'ion8 , ", The orde r '~f
fo r one
s Ub'gro~ an.d SP- SK- SaI - ApO .f,or . th~.
D..le t o th e fa~ t t hat da mage t o n ~ ~ral e r e ece in creIBea wit h the nUfll~er
]4
TABLE 6 : Expe r ll11enu l re.e,l rch de dgn d e pl'Ct l ng d r u g co ncUt l on l • •• oe la te d
;rtii""Croupa A. 8 , C. an d O. Cr o u p, A. 8 ,
C r ee e t ve d d- • • pheta.. ln e ( . e )
pr io r t o .11 (ntra n lgra l injec t ion . C. ·) ; ",he re .. Cr ou p 0 di d not e l )
.na
-»
q-f
lnj ec t l~':'~ 11 ~en·•
SK, Apo
wu
.lind a t nc e o u r I n te r e lt 1.)' lII.lIin ly In
-JrlY en 1.lt .
cOllpll r l ~,lI;
SP ...ltll
AI . . nt l o ne d earlie r " nUlIlber of " nl _ I i eer e llOt
pr u cr e e ned fo r c i rcll ng biases I. ubg r o up of A (n -8) ; B (n - 8 ) ; C ( n - 8 ):
The UUl n,lll pr oc edu re
1)
D
i nclu ded t be fol1o " I "I1:=
a . ubc uta neo .... l nj e ctlo n of d-ulphu. .. l ne (l liS /kg) (Group.
b
A, B,C) followe d by e .20 e t nu ee wai ttng pe r Iod ,
ll ) an tnt ra n tg r .d ln j e c U on o f on e of f our au b,t ance s : a vehicl e
eo I ue te e , SP, SK o r epoeo e phtne , lind '
111 ) 8 I S minute post - i nj ec t lon pe r to d dur ing whi ch c it"cU ng 11''\1
Al l
Tub lnl! ( 0 . 5
I nj e l\.t i o n s 'l e u
mill ·
i.d . , 0 . 9
DIll ·
mad e us i ng a 2 11.1 g l .. "
sy r inge (Dy na te ch) •
t?
the i njec to r ca nn u le at
Q. d.) wa s at tac hed
o ne e nd , llnd , /I.e the~ o the r e';d . t o
)
c:onnecth.g t he 'g la l l
lnj ectlonll . ~
.dc r o l yr i ngrt
t he gias l IIte ra.yr i nge .
t he
t ubin"
clel ned
Pri or
., tt h a
to
fe w
95% alcoho l ; foi lo wed by ·lnject io n o f air; and. fl nllly , t he
t ub i ng " 11. fH.l e d ~l th . t e r U e dts ti1.1ed ~aur .
p' ' 'e d t hr oug h t he t u bing,.unU I t h
vi s ual i ns pe c t i on . t h.tt lir b
tu b in ' :
,
" II I
The t iP ' of
t.h~
The d.l lt llled w. u .r .,..
i n vu t i gl t or .... con fi den t . f ollowi ng
b l e , were no t pr e se nt a l on g t he lengt h of t he
2 ul I yr ln p;e ., a l then i n,-er ted in to t h e en d
..
tub i ng jUllt a s t he . yr i nge co n t . i n!ng d h t Ule d wol te r Wei
Ag.in, plIrU c'u lar c. r e ... s t.k e n to e n s ure th.t no . i r - bu bb l ei
• lll n ~ the l e n s t ~ o f th e tub ing.
The p ~ ung ..
of
:f
t he
be i ng r e move d .
.we~
pr esen t
th e 2 u l syr i ns e ... . , t hen '
. . . . iOll.1y pu ll ed bac k 10 II to s llo w 0.5 u l of air into the
l ~jecto r c.n: u l a .
Fo llo";i ng th18 , 1. 5 ul o f t he 'olutlo n t o be . dmlnls ter ed I nt ra nill ully .. ~s ·
" :~ ".'",0.., 10j."~:. , , ."'~' t o .0',f ollov 'o, .0<'
-.
~( ..
,",,,,,,,,,,
.
~
I n j e c tl 0." II c he c k loIas ca rr ied o u t to lIla ke su re t he CAnnul a "',,"8 no t bl o ek ed~J\._~..'~
• All inje c tions wer e made manua lly .
A vol ume of O.!l ul wu i nj ected ov e r II
pe r i od of 60 seconds , a nd the i nje cto r ca n nula
ad d ition al
60
s eco nds
. a d!d n 18 te re d s u bs tance .
In
o rde r
to
,ty o i d
Anl nalll ver e
du ri ng t h is 2 1Il1nute pe riod .
fln
WIIS
l ef t In
1111pro p,er d lff,udoll o f
r estrained as
~_ ...
p lace f or ' /In
the
littl e . 85 po ltil ib l e .
Fo llo wi n g t he r emova l of t he inje c tor can nula
the ob t u ra to r wa s r e pl a c ed a nd t he ' flnlllla l was plac ed In t he a p1JW'C,lIt\l8 80 thll t
d rc l1 n g' d ur l ~ t he f ollololtng 15 minuteR co u l d be meaAlIfed .
API't"o,..tn uHely
48 hours el aps ed be t wee n I n tranl Rral injection s.
Animal s were fi r st deepl y ana e s t hetiz ed u s i n g 80<l1ulII pen t o b a rb i t a l
( Somno t ol
10 0
1D~ /kll:) '
Imme ~1ate ly prior
t o perfus i on ea ch a n i mal ~~8
in je c t ed with a cresy l violet dye ( .5 ul ) •• This
.
.1
I l owe d
ae8 s me n t of th e in jec to r C.1rlllu lll ·0 :C .) t ip' l o ca t io n.
perfus ed i ntr ac ar d ially ut t h 0 . 9
Jar
it
IIJ)re accvea t e
Ea c h .an ima l wa s
t sa line (f or a ppr o xi mate ly
t
he n
10 eec o n ds ) and
10 % pho ;phate -buf fered . f oqll4l1n ( f o r approximately 10 Illi nu te a).
",. r . : .
se r te ....ing
. de capt~ation brains e er e eeeovea and k ept in s ' 10 % f o r maU n so lu t to n f or o t
I,.. e 0"'
~
UaLnR a cryo s ta t~ se~tlona 46
slLde s.
"
U III
t l c k were
to
.
collected o n Rhsa
Every third or fo ur t h s e er I on o f t he br a t n a rea of I n t erest was tll ke n
.
.
and ,4bn ave r ag e, t en s ec e t cn s pe r brain wer e co llec t e d.
.
dry f or 5
leas t o ne da y,
Secttuns were left
f ollow-tn K IIhtch they were sta ined
ual ng a
meta ch r omat i c Nls s l ota in pec ced ur ev . Cannula tip l ocattons eer e identif ted
''>It.1ft a e tercproj e ceor ,
'"
\
)
-
31
Hilltologr
A to ta l' of
94 a'nilllllls
were
shortly afte r su rge ry , while anot her
~ d ur l n g
~_
ce e ttng ,
tnj e eeo r
implanted \itch c ann ulae.
Three d i ed
4 a ntmalB had c annul a e t ha t d i s l od ged
Of t he rema.lnlnll: 88
anlraa.1s~
cannula ( l .c.) t i p I n t he SNR.
56 wer e fo und to ha ve t he
Two main
criter ia wer e uaed In
d e ci din g whether or not an animal was included In sub sequen t data analyses:
'1.)
. the lo ca t i on uf t he i.e . :t i p ( ba s e d on stein d 1f f ulli o n) ,and 11 ) ttie extent of
n i gul damaRe.
l'\Ienty-eiKht aniraals were
rej ected on the bas is o f t he
locatio n of the t , c , ti p s : 13 were f o und to have t he t . e . tip l o <:: a ted. ou t ald e
and dor aal t o the StiRi 11 had the t ,e , tip ven t ral t o t h e StiR ; 'a n d 4 h a d the
i .e. t ip
in
t he regIon
c r iterion, 3 a n imals
to
t ..... fact
The
ca uda I to
t he
SNR.
With eespe et;
to
t he
s econd
...
w~ rejected due to lIlIIssiv e de struction of the 5N, d~e
that; small number of guide cannulae were cu t I mm too long .
i.e. pla ce Ole n tll of
the 56 animals cons id e red In subsequent data
anal yses were c a t e gori ze d on the bas is of the ir medio - Iatera l and ro stro ca udal l o c a t i o n .i n the SNR.
t ip vas cona tde r ed to be
de pi ct ed tn !'iRure 2.
Wi th re epeet; t o the
elt~ d 'l
llIe~io -lateral
plane t he t s c ,
th e medial , cen tr al or l a t er a l SNR as
In sd dltGn , i . e . tips we re jUdl\ed to lie 1IlOstly i n one
, c-;.
.
of threl; .p lsnes along t he ro s ~ r o -c ...uda l :~1s" as ahown in Figure ) .
....
~a bl e ' 7
sho ws the di s t ri butio n of placenlenta; an d includes all ajlillls is voose data wall
us e d i n
t he' s ta tis tical analyses.
dls t rl bu tlo na,
.
All Rroups ·showed aimlla r
placemen t
wit h t he majo r ity o f t he s I te s oc cupying t he cen tral and
.
med! al portions of the SN at a level 5.8 lDlII ca uda l t o bregma (based o n Paxino ll
and Watson, 1982).
...
l8
0. ,
,
F I GURE 2 Corona l ..e t Lo n of th e SNR de p l cHng t he llrbl trary C'1.... lItflcatlo n
Iy ste" ti Red t o de l c:rlbe t he lo ca tion of in j e ct ion d ee. alo n ~ t he .c!dt o l a t er-al p l a n e. "
.:
FICURE )
Thre e' c o r onal sect io ns upon whi ch t he c la id fica tio n of i njec tion
~aTo nli the ec e eee- ce ca er pl a ne we r e ba s ed ( t he to p se c tion 19 the moat .
rOl t ral) . Abbr evh t i onll- cp , c e r e br a l pedunc le ; in , i nte rped unc ul ar
nuc leUi1'lll'l , Qled lal l emnl a cull; mn , lI'Ialllllll 11a ry nucleus; pal , pe r l a qued uc tal
g re y; , p , pons ; en, red nuc leus; s ne , SH para cOlllpac t a ; an r' , SH pa ra
retlc'!..la ta ; vt a , ven t ral te!Clllental a rea (baled o n Paxinos an V at ,on , .198 2) .
_.
5.3 ap
~/ ~ !..
Dlltl'lbution o f SHit i n j e c t i on , i t '"
i n anima.is tested
)
.J
.
~
.
5. 3 a p
. 0
~
~
5.8 ap
~
"
"
~
6.3 a p
'YENTRAL
4.
41
\
"
" Res u l ts
~an al y s l s :
Fi gur e 4 s URllI\8. rh es the mea n c t rc ll nK t ot a l " f o r Gro up a
A, B,C , and D d uring;) 15 lIIinute period follo lo/ing lntr a n l jl;ra!
eit he r saline, SP , 51( or
"po.
Ln j ect Iu ns of
rtie Friedma n two-w a y ANOV A Willi us ed to test for
wit hin -g ro u p d i ff er e nce s : fou r Jmp urattons . . .e re ca rr ie d ou t , one f o r cnch uf
the 4 groups: . . A signlflca r\t d lf f e r ence between solu tIo n e ff ect s loIa s f ou nd
with r espec t to Gr o u p. B (p< . 02l; ho wever , an alys 18 o f the data frolll Grou l's
A,e, a nd D s ho wed t hat wi th in
e~ch
of t heae gro u pssn lmah re spo nded to a ll
I ntr a nl gr a lly admi niste red ' so l ut i o ns i n a r.e lat I ve l y s imilar fll sh l on .
Slnc ~he Fr iedman two-way AtlOVA s ugges ted that an i mals litchin Group
S. sho wed
cir cl1 ng
rates
t ha t
varled
d e pe nd i ng on
IoIh l ~ h '101utlon
was
admin hte r""d I ntran i gra lly , f ur t be r test s we r e cer r-r ed o ut to compare the
ve r t ou s sol ut ion effects within Group lB.
Fo r s uc h tests Invo l vf ng r e l a t e d
eae p fe e , th e Wi lcoxon matc hed -pai rs signe d - ra nks test
W9 S
u sed .
Statis t ic·al
differ,ence, wer e fo und between the c i r c li ng rates o f ani mals i nje cted ....i t h SK
a nd Sal ( p( .OOS ) , Apo and Sal (p(.O OS) . SK an d 51' (p( .I)OS) . and f i nal l y wit"h
~
Apo a nd SP (p( .OOS).
Differences bet....
5.11 and SP , an d between' SK lind Apo
....ere not sign if ican t.
Tabl e 8 shows ,the nu~ber of
\_ ~ ,
ipslve rslve ly , o r
t ha t
did no t
animals t hat tu rned ecnt r ave r s t ve I y ,
tur n a t
1111 follo ....i ng
the
I
tntr lln l ,l(r al
ad min ist ra tion o f t he .te.s t ed ao l u t t c e s ,
An exam i na t i on o f t he mes n c t r c t tn g to t al s s hown i n
s ug ~ est ed
ri~ur e
2.
in
add it10n to
th e distr l bu t io .n of t urn ing tend en cies .
r e ce i v i ng
d -alQphe talll lne preh'ea tlllen t ( Gro u ps A.,B, C) all ave r ag e , c te c tee
.II
IIDre ths n Grou p D whl ch-fl-id not rec e i ve a
.
pr e ~ a tlllen t .
t hat 8nl IMb .
SInce the se ,l(ro up s
to.~ _ ··
represented un r elat ed samples t he Krus ka l-W allill One- Way ANOVA ....a s us ed
/
....- --.
cootraversive
10
20
turns
30
"
40
sp 8 ug ::::::::;::;:::::;::.:.:.:.:.:.:.:
sk 'llU9
GROUP A
Apo 1~~9''''''''>''~+~l..l...J
GROUP B
GROUP C
• sp 16 ug :;::::::::::::;:::::::::
, sk 16ug
n=14
AP~~5a~gl-l-.l....:U~..l..:u,
"
GROUP 0
.
n =8
.
"
. -.
FIGURE 4 Hean c:l rc:l1nfl t oull 'f or Gro up. It . B. 't o lind D f ollowin g II U minut e
"ti"iiTiig-per i od . "lIt. Uut ed dlffeunee vae fo und l n Grou p I (F r1e~".n t wo·
WI ' AHOV" . p( .OZ) .
\
. . . ..
TULE 8 Direct io n of c:1rc: lInR: follo",tnll the I nt ra n l ll.u l "dslnh t ut lo n o f
~K:- Apo, a n d Sal.
Ctrc:l1 nl te ndenc: ln of anlaa ls not pretreat e d wUh dallPhe t • • rne a re .lso. .hown ( ,U ) .
I'
12
. .!!
.ll ~
( n- 8)
SK
**
12.!!!. ....
( . -8)
SK
16u,e
(n-1'4')-
,.
APO
I S~ ""
(ii- a)
' SAL
\
:Tii' - 4 8 )
SAL fI"
"""Tn-tl )
,
... ,
44
.
'
·de t e r mi ne whether Anl ma 18' tur ni ng ra r e e we re af f e c:tedoby d-ae phe t .aef ne ,
The di ff e r e nc e wa s no t
t1 1j:nil lca n t.
nuebe r I'If anlull 1n Group 0
!bweve r, i n th is r e s pe ct , the 8mall
IlIar M Y!! pr ev ented
a ny s tatis t i ca lly d e t e c t a bl e
dif f e re nce .
Wlthln-gr o up' co mpa risons
.
oh oted
t hat
in
Group
.B
ccn erev er e.rv e
cl rd l ng In erea a ed ' s l gn 1fle a nt l y f ollowi ng-t he ad lllU\l s tr a tlon of a
.
12uil dose
mayic c wit hi n
the S~R t o
of SIC.
These ar e t he fil"llt da ta to i ndi ca te t hat SIC
pro du ce
contr a ver al v e
co ntra ve u lv l! ~l r cl1 nR:'
c l rcl1 ng .
lIith i n
Group
8'" Ape
also
e lici t e d '
Animals te s t e d with 8, 12 , a nd 16 ug of SP; or 8 a;d
16 Ulj: o f SICd~ld M e sho w s i gn ifi ca nt d if f er en ce s In t he IlIlIgnltude o r direction
~f C l r.e l1n~ ; th r es pe c t to sa Une i n j e c t i o ns .
Apo 's eff e e u, l Ike t h08~ o f
SK, ver e i nco n s l s ten t ac ro ss grou pa ,
l nt ren in g th e do se e of SP a nd SK ( 8, 12 , 16 ug) d i d not br i n? abOut
pr oportlon81 I nc ree s es in
~~e ,
d rcUng .
never t he l eu, . be en repo r ted
Inj ect ed i ntr a nl Brall y (2 . 5, 5, and 10
~,
Dose -related increa ses in ci rc ling
us in~
u~
dlfferent concentrat ion s of
SP
I 2 ul : Olp e and Kl::I e lla, 19 17; L, 2 ,
LO ug I . 1 ul : Ja mes an d Sta r r, 1979) .
In 4exa ml n i ng Sp ' s a ppare nt
la ck of effect o n c lJr c:l1ng beha vi or , a
nUlil be r o f hc:toc,s wil l be . t a ken In t o cc e etdee a e tc n,
,T.h e se will Includ e
quut i ons rega rd ing the bI ologi cal acti vity of th e pe p,t l de aolu t i ons and '
theL r enlymatlc degr~dlliiOn , inj e ction Siu.a , the in j ectio n pcc ceduee , \ n d
_ l n t l y t he
d-alllPhe ta~~
I nt r a n i gr aI
r .'
pr e t rea t llle n t .
~ide
i nj ec:t.1ona pro duced vi sibie
~
l.
rlus~O f
.
the ears
'\
\
"
and 'eeve In the vnt majo r ity of a n imals e e er eu .
b~e n
'.
\
Thill pe r ip he ra l act !.on h'"
dCltume nte d t o o the r s tudies for bo th Sf a nd Sl( (Per nuw . 1 9 6 3; IIo Il: er -
Pe t iche, Schlllleck, Amann, a n d Lembe ck , 1985) al'ld ~ uRgea tg ' th8t the pf/'p clcle
501 ut lon ,' wer e l>101og~tpally po tent .
'.
Procedures ;l?S ur "tnR I c e r l1 it y ve t e a lao
adopted t o.. mi n imize t he poss i b ili ty of ba c t e ri a l de g r a d a ti on .
"?" ob~erva don8 ~d pr e ceu t Ic n e , 8,1'1 argument- b~:e~ on
the peptlrue eo I ut Io n s lIse d we re nut
. ~~e.
In
a ddl 'f.on.
~lo1ogi~allY.a Ct l ve
a l t hou p;h pe ptldases
t he,
I n Itloth r of
as:~llIP(I<ln . ;
:;.
)
J
cannot b e ro r[e f\-l 11y
have beep .,r e por t e d" [,,' ra p id ly
deg ra de fn t tan lgrally tn j e c rez- pepc t de s , da t a r e por t e d ' \)}'. Ol p e and KfleU.n
..... ;:1
•
( 1971) an d James and S tar r ( 1971; 19 79) s ugge a t that t h.19 t yp e o f inacti vatio n
f o~
was not I t'k e l y to have cc cur r ed wlthln t he t ime . pe r l o d used
./.'
lIIl!'lllut in~
circl1ngrates .
Th e anatollli;:a.l l o c a t i on of Injection s1te~ ...a s~l. s o un l ikely to have
been a co n t ributing" f a c to r
.Al t hough
inje.ttlona
in
SP ', appar ent. bc k. ·o f effec. t
~he
Of , SP.. i n
co n travet's ive drc l1ng r e g a r d l e s s of
,
ros er c - caud a;
In j ect Io n
and
here
have> be en
on
.J
e tr c Lr ug ,
repor~ e '1 ~; ' ;e l ict t
th<!i r location wit h res pect t o
.
ned fo e-La t.er e I
s t ees r e-por t ed
SNR
pla ne s
(Ja mes
( t he majority o f
and
t he '-
S tar r,
1979 ), ' t he
whi c h .Jer e
dlat rl bu t ed
throulI:hout the ca ud al ha lf o f the SUR) did not e lid t c i rc li n g .
,
.
Cer ta in da t a s ugges ted , howeve r, th'lt t he peoc ed cee u s ed may have
." , ':Y i nf l uence d t he r e s u l ts o f th e ex periment .
i n j e ct ed
c l rcl1ng:
." "
Ta bl e 8 (p ; 43) SOO""' 11 t hlt
i n t ra nip; r a ll y ....l e h sa l1 ~e d is p la yed
a
di s t i nU
bi u
~n lmah
\ 11
thelr
7 an ima ls t urn e d i ps i ve r d vel y , 8 d i d no t t urn , lind 31. t ur ne d
ec n er ever a rv e l y,
Th e se dtt' a re
~,k,d l, d lf f",ot " 0'
tho ee "po , l . d b,·
Ol pe and Koel1a. 7 7) an d J4 .m1l81nd- i t a rr ( 1979 ) , whi Ch 8 u~ges t.d tha t , " . 11 •
'gro u p, an imals
~~9~~e,!1 ver~ . 1ttt,le
C.
; .
I
blll B.
A nf
'
.
r eee or s
.
u,
0'1, to
.~
I
,. .
'- .
explaIn t ile" clr cl1ng eeeee n se to saline s e en he r e: 1) the
il~
a~t.lIIal
natu ral
46
sa U~e
I nje ctlon ,
biase s . !i1'-nill:r al d a mage o r lv) a nlCo lllb tn a tlOn
CJl
t he
above .
The d f ee:t pr odu ced by con t ro~ i nje ct ion's 1s unlikel y t o hav e bee n
due IIolely to 98111\9 "e a ctio n on the neural ctrcutt r y in volved i n circling,
1I\.81 ~l y because,. uUn e has b een r o ut1 il.el. ~ used a~ II con t r ol sub stance an d ha s
been s ho wn t o have no e~ f e c t o n d:, ~1ing (Jame s and SCUI: . 1977 ).'
CIIlIle
t ~ er.r c t rng
of
tha t
fo l-lo wtd
co n t ro l
,bl a8~s : Po8~UralUeVb~ lnn '~ nd c1r~l1ng
'
.
. • .• •
6lOPhetara.lne (.Jer uSSl ilnd G:
J
can be -eU c1 c! d in' 'i nt,ac t
~nilftlils
adllli.nia te red ' , DA agonl~ts sUb~u traneou s lY I eg.Apo o r 'd- ,
• '_when ' they lire
•
One likel y
inje ction!! i n ~ l ve s an i lll41
.
.
'
\
.
"
c. · . .
.k , .YJ76,. Pl ~a~ and .S ~e c h'tma.n. 1985) " - I t has ~een '
.;.'·suglj:es t e d tna t ,this I!llly· be · due to a natura l .henl1apherlc ·a~ ~etrY of DA
.
re cepto rs
or
.
te rmina ls.
Ther e
.
is
"a.
pos sibil1ty ,
d -amP'net4nli~~ ma.., hav e a ccent~-h~~d I SJJ,C9
pre treatment with
l\YP\J th eS!S i s co r r ec t,
t he r e f or e ,
t hat
If th i s
bia s e s.
~he~ ti s~~ld fO~lo., thtf(Ld-alllPhetam1~e ls effect ' on
c:lr cl~llll: ~ho u l d · nq,t have dif fered Big n l fica n t l y from ' the e f f ec t of d-
, ,
.
...
'II
111lphetamine when tl).e"l atter waa couPlled ~ ~ t h al! lntran ill:r al sal.ine i nje ctio n _
U.inK t he Neuman-'I!:euta t,e~t"'(post ho c );da ta ft Olll each s ubgr oup of animals that '
had bean pre9cr ~ened whi l-~mpneta.lI\ine wet .e us ed (A, n"9; ',B, n - 9 ; C, n -6) "so
. tha~
~
c:o lllp8l:' is~ s '
could be
' ~de
b17 tween
.
'
t he e rr..:'V Q-g ~ ~ e s of anill\ll ls
rcc~l~'~ng d"':alllphetallli ,\e' a l o ne· a nd t ~,e 8~.1rle ani m41s' c i rc:l1nll: ~. t es f Oll~wlng
d - alilphetam1neand Ad ine • • Subgroups, o f Gro ups A and B shoWed differ e,nces
thu were Tlot
Sl~nLf1cant"SUg~eat L ng ~l)a t " !'alLn~
had no effec t
o~ clr clln ~_
Ibwever , 1n t he case ' o f subgroup ~; altho"ugh a n 1l'1la ll t urn ed lps l venLvei y
...
~r
f~".110wlng d -IIlIPhetlJllll~e~at~?-te.tt~ usinll:: d-amphetallline . .i~d a~l1ne resul~ed
in
c~ nt ra ve U 1Ve
clrcrlnll: _
·... : f
',.
\
"
supports o ne hy po th e si s th at was formula ted durln~ the lIna l ys l , of t he dlltA;
.
.
.
th at l!1'(S2..~ an l ma18 wer e !1IO r e ~ l lt e l y to
untla reral n~Rr al'9-amaKe.
".,.
<: ~r c l c co n t r ~.Ye r 8 1Ve lY due
to ,
J
Although a nuebet- of fa ttors. ma;v hav e in tervened
becwe c,r th~ '" pres c reenin K and the lntranl g ral s a li ne teats ( e g . 8Uf)(ery .
habltua tio~) .
.
it was
t houg~t
this subgroup .
lo c a t e d i n the ce n t r a l por t i on
are known t o o r igi na te
a ccn rr ev er ef ve
si ~ ce
is poss ible . t ha t
It
r~peated
t ha t dama;e t o th e SNRdue to
was the fa c t o r most likel y to ha ve produced
or O
-t he
the
l.c.
t;;"jec tinns
..
c lrc llnJ! btu tn
t.l~
were gen e e a Ll y
SNR, wto,ere n t Rr o c h lll o ml c r rojcc t1ons
( Fau ll and Mehler , 1978), damage in th h
.
have ad ve'raely affected niSt-ll i efferents .
re Klun may
'
"
K.1.inlc· aC1d Iea t one in this nr en
hav e been ~ hown to produce con er ev er e t veic t r c l t ng (D IC~1ara e e 81,,1911) ,
' The r e f o re, both I n l ma.l bi as es and n lRu l'damage may ha ve affe c te d
I
,clr clll\~· r e s pon·s e s , ' a I he n ce , co ul d
dlf,flcult to delll,lnstlte ,
s Ince th ey are bas e d on a
","e 5 ulIIe d nigr a! ' dama..l:e
t~
co mpa r ab l e damage
, . of
the~NR
have eed e SP's and ' SK' s ef f ects more '
Animal .b i as e s tend t o be r e l a t iv e l y
~ ! O g i c a ! a S ymllle t r y .
is
unk nown.
"11
~ermanent
Ho....ever . t he e f f e c t of t he
gro u pe of
anlma19
s us t a i ne d
t he SNR; t he III<I jorl ty o f 'animals 'ha d 81111roximat'e Ly IS '%
.
.
dalll3gsd, while a slll31.l. number o(anilll.8ls ahc ved- ei th e r very Little
/dll~ lle (S %) or much i llr ger d amage (40 %) ', ( t he variab ility in damaRe rnay be
r e l ated t o th e f a c '
possibility
1s
tha t tnjec t ton e were made by . hand, !"<Hhe r t ha n by 4
If o ne considers' th e poten t ia l er teer e r t h is dlmeKe [h e
moto r ized pump) .
ralsed, tha~
51" s
effect on
ci rcUn~
c:ould
o.ve!"sha .dowed by a c i rc ling tendency r e sul t ing 'f r o m t he da mage
have
been
t~t
....11
n i.llf~l
enhanced by d-alllphetallline.
Tha t 1s,', in ., number " f i 'ns ta1tcea ....he r e
damage WIIS cons iderable ,
drding r esponse e l t c t t ed by a nY Pllftlcu.i a r
ec dut I c n may
h~ve
8
bee n la rge ly d ue t o d alMge t o n lg rd 'effer e nt ll, nr lome
,.
"
')
\
,,"
Co n . eq u~ n t L y .
o t hl '" ei.rc:u t t t .. po ru nt i n c:l re l t n( .
if t he bitter h y po t he l t a
It co r r e c t th e c l r e l1nR 1' e . ~n .e . elici te d I n some a" I _111 lIa1 ha ve been t he
.r e s u l t
of
ul\ l 14te'l'IoI daug e
••ph e u .1II1ne
tn J e e t l o nl,
••
~blned
o ppos e d
"',]m ',, "
vl t h
to
t he e f rec'c. o f
t he
ef fec t
/
of
s Ylltee1c: . d...
any
t n tr a"lg"'l l
. .
SP'1J lllOde o r Ilec h. nt ... o f a ct i on 11 unkno wn.
. .
",
Howeve r . if on e "II~. '
..
.,\
f o r.." lIlD ~ n t t ha t SP' , effec t In 'e e e ea rn r e gi o n s of t he s-iR 1, I nhi b i t or y . and
.
~ h.t
.
.
"
I
.
this effect 11 1Ile~lated by an 1nhl.bU nr y ~ran '11l 1tt er . ( In 8 manner '
1I1ml la r to t Mt l ugll:e l t lld by J onel And d I p!! ( 198 5) I n t he d ng u la t e ..co r te x >, a
.
.
..
nu;"ber o f condi tto be f ollow~ ,
F';lf' e 'ICa mple . o ne way .S P (o r SK) co u~ d el id t
. c:o n tr~ ver .lv~ clrc.HnR woul d be by i Rh~ bl t lng CAliA. nt g ra t e ff e r e nt' In t he
prOje~ct ~.h~ tha1;o11llu~ ,
SNR that ..
f o r lUt 10n.
~
su per i o.r
. "~f \nhibit io~
t h is . ty p__
dl l i n.h1b1 t o r y effec t
.'!.."-.th e
has
co i l i c u l u s ,
~en
to
ha ve
a
three s t ructure l ; all d if th is d is i nh i bi ti o n 11
unilatera l , Con tr a ve r s i ve c ircli ng r e s ult s (S t AI n
4
and r eti c u lar
hypot he l i z:e d
"
e t at • • 198 )) .
How.
if
"
t hi s . ou rce o f effer en t . ve re d es t r oy e d , a s i . t ho"'lth t t o ha ve been t he case
1'n a n"'llb.r o f . niftllh..jP (o r SK) ~ y ha ve li tt l e ~ d di tlo n a t e ffec t o n
iir cl ing 1f it were .d llin bteC"ed i n' th h
m.ain ly
t o .n ll1101 l1
tM t
r e g i on .
, ul t a i ne d nl &r at d ....ge ,
l hh
exnana t1o~
. pp Uu
Sta t ll t l ca ll y , o n ly
"
I U bgr~ of Gr o up C s holJed d iff eren c es ~ t wee ~ p~"tre" t~t· (~ -.lII phe t a llli ne
alo ne ) and co n tC"ol t Sal .nd d-a lllpheta lil ne ) cir cUllg r . te...
The ~ e fo r e. if
co nl i der t nR whole gr o",p s , Cr oups A, S.. "nd [) did no t leelll t o be s f le c t ed by
•
nigral d .~ge. 9ignH..1eantty .
In
the s e "a n l ln11 i s a na t ...r sJ.......bta.
ce n a tn l y, till i ca use of cir c li n g f ollo....i ng co n t r o l
SIID.1tIt., r ellon l ng . ppliel to SK.
HolJf!v e r . t he r . c t t h"t SK Will a b l e
PtOdu c ~ s ignifica n tly 'fre d rc ling t han
,
,.
WIlS IIlOlt
lnje c t l0 n~
t h. t aee n followi ng •• U ne
-
"
inj e c t i on s 8ugge su that i t QI.;l y . be eo r e p') (:ent
l e a st a t the t zug dose .
~han
SP to
tilt. ["eKar o ,
at
Ex peri me nt s cu mpllI"l ng the-eff ect s o r ,I ln r g e r numb er
-,
of doses al o n A; a wi de r s pe c t rum (l.e . Lnc I ud Lng s rnII ller do s e s tn t he
n",n<J ~ra ,n
range) wou ld h el p elucidate t he que s t !o" of re la t ive flotencY,~ lth r e g e r d to S I'
a nd SK,
It s hould al s o be note d ene e o ther i nves tiga to rs have 1I1Ie d i de n t i c al
; t ra lns of r a ts
(etpe and Koella, 1'::1 17) an d s ll1118r vo l u IlIe8 ilnd ra tes of
in f us io n ( Jame s an d Starr , \ 9 71 ; 19 79 ) .
.
The se t wo fa ct or s, In ~4d l t llln to
.
.t ho s e 'o f b t o Iog t ca I ac t iv ity , enzyma tic d~p;r ll da t1o n'. ahd 8 itu of t nj ec e to n
.
..--/
wer e unl i ke l y t o hav e aff ected t he r e s u lts
,
.
8 1~n l f tc a ntly .
.
Hovev e r, a
b~lJ1 c
a ssumpt ion· nade was that aU I n j e ct i o ns wou ld be l o cRl i zed comp l"e _e ly wi thi n
th e SNR.
The poss ibi Uty never t hel e s s eitists , I'It l e llst i n . t he case of t he
IOOre do r sa I SNR injec tions, tha t SP a nd SK were d tf fua tn g do r sall y 1I10n ll r no
ca nn u la tra c t an d into t he SNC.
pr e dic t , would
Thi s t ype of d if fusi on , whic h is dif fi cu lt to
comp l icate the interpre t ati on nf
s i nce i t I s waU known that ne uro ns
in
t he res u l t' , uspecilll l)'
the SNit e nd SNC o f ten
r espond tn
c ppcs t re way s to t he i on t o phore tl c: admin is tr a t ion of part icu la r s ubsta nces
•
( Dray and S tra u gh~ n ,
(9 76 )j
a nd es pec ia lly s i nce the re at- e ec r e SK t han SP
' \
•
I
rec e pto rs In th e SNf: , ( Man t )'h et a l ., 1964 ) .
, ,'
An ad di tio nal fac to r t hat l'Ie r tu co ns ide ra t ion 19 t he d:.Hllp he taml ne
tr e aeeene ,
was
The work ln J! 888ulllpt i on u s ed durl ng the desll(n o f .t he exp eri ment
be sed on
t he two - co mpone nt
.
Marsd en, 1918) .
Th is model
.r espons ible
t he
for
mode l o f
clr c:l1nR beh a vi o r . (P ycu ck a nf1
sug ges ts that · SN "c t i "Vity, 'I n pa r.t lc·lhr .
d irection o f
c l rcl1 ng j wher e:"ll
stru cture s (s t r Ia t um, nuc leus scc u e be ns , and
VTA) 111
._/
Il c t ht ~ y
.
Is '
i n o t he r "
re IlP~~lI1 b le fo~
th e
t •
50
. por'lt~ neo u. Ibltor s e c hl e y that accompanies t he ci rcl1 np: r eaponae ,
pUoe
atudl es 8ug~e' 8t ed th a t
I ntr antgr a l
a pparent e ff e c t o n c t r e l t ng , it'
W18
inj e c ti o ns o f
Si nce
SP al on e . h ad
no
pr e su me d that t h is mi g ht be du e t o the
lock o f T1Kl to r 8 t i mu l a e l on (c hat 1~ a lt houg h II bi a s may ha v e r e sul te d f r olll th e
l itrantgr a l ad ml n ls t ra ton of Sf, I ts e x pr e s atcn ma?" hav e bee n d ifficu l t to
"l!l s ure 1n t he a bs enc e of tc cceccc e stimu lat ion ) .
It ",a s t he re fo re th ou ght
t hat t he use o f a l ow do s e of d-oiIl'lp h eta mln e wou l d serve t o i ncr ease lc cc ec t o r
• aetivl t.y wit'hour ha v tn!( an y ef f ec t on t he dl~e ctts~ e1 rc l1ng .
""? "
con t r s ve rsi ve circling follov i ng un Uateral in tr a nl ,1;ral admin h t ra to n o f SP
in the ab senc e o f <j-,a"phe t a ndne pretrea t illerent h". be e n r e por te d (O l pe an d
r
lIDe ll-;;7 1977 ; James and Sta r r , L977; 1979 ) t he line o f
reaso n in~ixPtessed
abov e 18 wid e t cce pt ed, and d - ae ph eceatne has been uaed
fO;
by ,o t he r.l!I
(~
r..!!!O an d F,:a nkl1n , 1984 ).
t h: s allie pur poae .
The ,eaults o f one o t her stud y ....
(J~s a nd Star r, 19 79) suggest, however , e ec r e ~olllplelC i nt eraction be twee n
' int r8n l~
llY lldmlnlste r ed
(1 9 79 ) e e pc r
d t ha t
subs ta nc es a nd d- amphetam i ne .
.... .
."..
James a nd
St~rr
.
pr e tr e~tmeni:' wit h d-alDPhe ta mln& ( sc) .co uPl e d ' Wit h
un ilatera l i nt r ani gr al ad minis tratio n of SP eUc1te d a bi pha si c resp;;nse.
Foll#Wing._t_he SP i n je c ti on, ,a n.l ma la { i r s t c irc le d cont ravers ive ly , but a fe:or
lIi n"u t es l ai:~r bega n t o c i relli t pe tve r e t ve I v ,
explain thh e ff e c t .
The a ~t hor s di d not' at te mpt t o
I n li~ h t o f t hue su r pr h i nlJ da ta (tha t faU t o ;'e
.'
elf,.'1lain/Jld by t he
t wo-componen t
model
of
c l rc:l lnl()
/~
th e (<:I-a mpheta mine
pr e er e a r e e n r llI8y a l so have pla yed a n i mportan t r ole i n c i r c li ng , a r c Le t hat
"~. "" ~~'l"".lY .. ,,~.• , .
.,
\
.
.
W'it'h ee e c eee t o Apo ; unila te rlll in t ta·n1.'lral adnln l a tration of
thl~
iubsta,nce has be en r eported t o hllve -n o ef f e ct on th e c i rc U n.ll: behavio r o f )
"
i nta ct
IIn lmals (Glick and Crane, L978 ; Ke1te)' and !b or e, 19711; Kozlowsk i ,
Sawyer, and Marshall , 1980}.
Howeve r , APO I n.J tto n s 1:[0 t he media l SNC
el1et ted Lps Lve r s Ive c Lr c Hng when anlllla is were g i ve n d-amphetllld ne pr to e t o
Apo (va ccar t oc and Franklin , 1984 ).
Kodo wsk l e t Ill . (l9 S0) repo rted tha t
,
intranlgra lly a dmi nis t e r ed " PO elic i t ed ccnt r e ve r e t v e c:irc llrlR in a n i ma ls
~
th a t we re pr etreated wit h a DJ. r e c e p t or bloc ker for one week p r lo r to.• lind a t
the time of
-t a f ee e
--
Apo inj ect ion.
ljal\t p u.l
The con'eeavee s I ve c irc l1nK ch llt f e Ll oced t he
a t l on aug gea ced t ha t Apo may hav e ec t ed o n non-DAer p;i c ee ~'!. \
be ILeved t~ be 'GABAerglc si nc e the c t r ct r ng ....;'18 b,l~cked by pi c r ur odn (ae) .
>'1 1.
KozLows ki et
hypo thes ized t hat "PO cou ld
a c t on GABAergl c n-lg r a l
aff erents ( stt"ia t on l l1;rlll ) o r GABAerg ic nig u .l eff et"en t s ( n i ~ rotha lalJl ic ) .
In
t he
pr esent st udy
Apo si.llnU ican t ly
ci rcli ng in o nly one of t o ur g roups tes t e4.
This
i ncr e a s e d cnn tcaver8 Ive
in;on; i s ~ent
.
Apo effec t .le
.
To
beg ~n
wi t h,
interest l a y maInly in ccepae tng th e effec ts of SP to
tho~ 1Il,
tlf
diff icul t to
in terp re t fo r a nu mber of r e a so ns,
e t n ce o ur
.
Sit, pl;lpt i dea
were inj e c t ed early in the ser i es of i nj ec tio ns (ke e pi ng i n mind c ha t the
probabili ty
of
pt"o duc ing
injec t io ns made ) .
ne ur al
da mage
i nc r e a s ed
",it h
ch e
n umber ' of
T he f a c t thar no comparison 'co u l d be ma de be tw een' Apo' ,
effec t v he n I n j e c..tel:! f uat i n the se rie a , a nd Its -effec t ''''he n ~je ~t e d h at
ma~es
it dif fic ult t.D
c i rc ling.
d;a~ II t irm~tlUS iOIl \li t h
veeee e mc and
Fr~l1n ( 198~) hav~
r egard to
i t jeff e ct on
s uggeeced that d'"'lllllp hetallline
can co n dit ion a nllll8ll1 t o th e eff e c ts pr od u ced by ot he r dru~s; tb llt Le , if o ne
conats tently e Uc i t}
~ur n ing
in t r an h :r all y
an
lI~Phet~mllle
la te r
afte r
i n one dt're ct.i o n by a dmi nlst'e r ing a Su bsta nc e
an i!"4.1 hq
bee n' ad,\i n ls t ered d-lllllpbe t l1l11l ne .
.lione 3 i .e. in the ab ae nce of 811 lIIt r ll n i gral in j e ctio n)
e U cit
a r e spon s e' Sllll1la,r
to
t he
d-
~ould
one pr evi~ud~ ellc lte. by ,t he
52
1I1 t tl n l ~ u.l l y
. d.lII t't er ed s u bs ta nce .
The refo r e ,\po', e ff e c t o n c i r c U n,ll:
co uld be exp la i ne d by th e la tte r cond i t io n i ng e ffe c t , or , cou ld nave be en du e
to
IlOCle o f t he f a c t or , Mntlo ne d e arlie r (l. e. an lQAl bt.. a nd n i g r a I da ll3ge ).
r e . ~l\I e .
Clrc l1 nliC
elic i t e d
by
I nc ranl gTal
t he
s o lu t i o n • .
" d llin i _ tere d he re la ck e d a nUllIber o f f eat ,;,re l al llllllOn 11 o bse rve d f ollowi ng
ch ellical lIIti mul.1tlon o f t he SNR COI p e an d KDella,
If _It he
ledoRa
at l ""!htio n
of
n~gr o.tr la t al
't he
1917>,unilater a"1 6-0H~A
pa t h wa y (Ung ersted t ,
SM" :( Ar but hno t t
.
a nd
Crow ,
.
.
mani pu l a t i o ns hav e ..b..e en r epo rted t o produ t e
oil
1911)
or ,
e le ~ t rlca l
~ 1 97 l) ~ The8~ la tt e~~
.
fOf m of c i rc l i ng char acte r ized
by r igidit y and t i gh t c i rc ling , sucb t ha t t he .ff ec t ed s n l M i 's h ind pawl
r e cut" r e b t Lve l y l ta t l o nar y. while Lt l fo reli. bl pr o vi de th e req u i r e d f or c e
f or
llp vement.
10 o u r
hi nd s
unlla te rd
6 ~ OHD"
lu io n,
a nd e lectrica l
I t hru l a t ion o f t he SN a ll., e ltc1 t t h is f o r ll at clr cUnR; v here aa lntr anl gr a l
a d.in i a tu t i o n o f t he varlou a .ol ut i o n s de s cri bed he u di d not have a 11.11 a r
effe c t .
Ani_ h -i n this l!II:pe ri-ent
s ho~d
v i de c:1rcU nlt t hat v,u f requ e n tl y
I.ntetrupted b y gr oollli ng In d ex p l or atory be havid'r :
The cOJlpuh lo n to t urn
s e en , f o r exalllpl~ . f ~Uovin g ele e tr i ~ lt i llUlat ~o n o f _t he SN va s c l e ar ly ·
a b. en t .
It ha l blIln lugllel t e d that s till\ll i tion o f t he
l1~ elY
is .ar e
.
n i~o l tr llt a l
pa t hway
to pro duce c i rc ling t hit; 11 o f t.he .a. bu la t o r y t y pe ( vid e
c i rel ing); whe r e .. 8t ll1lulat iol\ of pa thll ay. o r . t r u c t ur e . closer t o neuro n
. /'
-,
'
~
'
":
.
poo l. l o ca t ed in t he sp inal cord ",111 bring a bo ut t i gh t er a nd IMre compulsiVe
ci r eUn p::
"Th h ,l ~
pre lumab ly due t o" t he f a ct
~hat 1.e ~8 ~ine
t uning occur a th e
' < .f ur t he r " v e II'lO ve down. tream fr OIll t h e baaal gin p;l1a ( Fra nk lin .
cOllal n i Cl t l o n) .
per sonal
.
"
I~
addition to these behav io ral observations f Ius ht ng c I the e ar s and
paW's wa s nc c rceab te f o llo wing the I n tr a n l gr al adrllinis tr'l
Al t h o ug h flush ln p; Will not
qUII~;1fled.
Intense vasodi latio n than SK. Thls
(Holzer - Petsche e t 111. , 1985) .
on o f 51' 'a n d SK.
SP showed a tendency to pr oduc
o~t10n !lltree'
Fl u s hi ng norma lly appeared )0 to flO eco nds
fo,llowln!!: the start of the In trllnlgra l , I nj e c t i o n lind a ll II
seconds .
more
with r ecen t fin l.n Rs
Saltne lind Apo were neve r
ob8~rve~
t o pro duc
a a t e d 6U
visible ~~ of
flushing . '
General Conc1uslons
Alt hough
II
tafl'll! number of s t ud i e s have focuse d o n the neuroanatomy
a nd' electro physiology of
t he SN. descr ipt ions of
neuronal mechanIsms and
interactions within the ~N a re, at t he ~men t . larllely hypo t he t Lca l ,
lkith 51'
and SK probab ly playa role i n the pecce se r eg of info rlll8tion wit hin the SN.
The importance and nat ure of t hi !! r ole still r el'l.lin to be elucid ated .
te e
.
example, alt houg h lntrsnigu ladminhtration of SP i nc re ases the alllOunt n f DA
re leased i n the striatum ( .ra_ s and Starr . 19 77) a nd decr e ases the amount o f
.
den dritically r e Le a sedDa i n the SNR (Cher a my e e e L, , 1981) , i ta
with in t he
S~
is unk nown .
Does it act presynap t ically o r
Does SP serve a neu tOlJl)du latory fu nct ion?
other ne urotransmitters kncwn to
mod~
of actiol'l
poIt 8yn~p ~~ yf
[f so, how do es i t i n t er a ct wit h
he presen t i n the
SN? ~ Tlieae queations
rema in for t he most pa rt 'unanswered .
With respect t o circ li ng behavior, o f keytmpo r ta nce t e t he notio n
tha t th1a be hav i or 19 t he pro~ uc t of comp lex ne ur onal i nt er a ~ ti on8 t ha t t a ke
p lace wit hi n the SN 18 well 41 be t we en th e S N an d ve r te ue
(ell ' lI[ r latulII, tha l amulI, a nd lIupe rio r co ll1c u l ulI).
o ther' 8 ~ r uc [ urea
"'h ile s t udia ll .b ssed on
1II.I "l puh t lon~
o f lnt r .n l",r.l .yltefU be "efl t ou r underet an d lng of e lr c l1ng
be ha v i o r. t he
~o lllP IU rnte~;"t.~Yo~ln'g".
above 11 of
C:~C 1;d
hporunc e .
\
nu .ber o f struc:: t ure s de sc ri bed
'
rt': In tr."ljfral effects o f SP and
d r c Ung be ha v ior ••nd I n l nte rp re tat)o n ~; t he r e s u l t s s ugge l te d th.at
The s t ud y presen ted he re f oc used 0'1
5Kon
5K .... 1 IIIOre po te n t tltl n SP in e U d t l"8 c l )cUn g at • p ar t i c u la r dca e ,
The
l llport ."ce o f thil " 11I101 r~ nd !~Jt,! I_11 _0-" IY. be t-a'rae clel.r ai, .dd l tlonal eeeeeeen
, l~vQ, lv l ng
5K, 18 ca r r I ed o u t.
(
(
\
. \~
1-
/
"nden, N. E., Dahl strom , A. , Puxe , K. and Lees e on , K. Fy.nctlonal rol ofof t he
• n rg eo -necs c r r e t a t dopa fll1 ne ne or en s , ," e t a Pn ulU c ol.Tox!co!., 24 ;
263-279 ( 1966).
_
.
Arbuthno~~ila~~~~l a~:l~::w ~fTd~~II~i~~II~~~: ;~e C
n°t"l,\f,:"terftaltv:l ~~:~1~:~ ~~
rats.
EXfl. Neur ol ••
I
30 : 484-49 1 (1971).
Ave ndan o, ,Co , Relnoso-Suarez . .. F., and Llamlls; A. Project tone t o lI:yru9
dgmold eus from the ' s u bs r a n t h nigra 10 th e ,cat i1.8 eevea Led by the
ho r se radi sh peroxida se r e tr o. r a de - cn-ns po r r te chnique . se urc ec t •
Let,t ••, 2 ; 61 -65. ( 1976).
•
Beck stea~heR;~b~ t ~~~ : l~~~i:~ ' :ri-d~~:n~~~~a ~e~~~~~~ 1 ;~~: r:~[t~:n~:~~ tO~:a~~
Res ., 175:
191-21 7 (1)9 79 ) .
•
Brown ste~~ . :~::;a~;:Z'/~~~! :~~~::~:I '~~~e~:~::~i~'s~' (~~Dc)he l~rl~~:
s ubs t an t i a ni.'lra . Bf'llin Res • • , 135 : 3 15-323 (19 77).
'-/
.
\
Buck , S. H., ' Bur c he r , E. , Shu l t!; .. C.W., tc ve nbe rn , W. , a nd--Ot Donohue, t . L.
Novel pharl'lacoloKY Qi ,l substance K- blnd i nll; sit es: a th ird type o f
tachykin i n r ecept or . S cienc e . 226: 987 -989 ( 191J3) .
\
Bunne y, . B.S .
a nd AghaJ ani a n . ,G.K .
rhe
precise
:~~~~e~~: .i.!\ ~~;/~~;~j~~~;;~)~.bY
I OCllliz lltioo of
a r e t r og r ade tr1clng
nt;l(u l
t echn~qUe.
Chang , M.H•• Leeman. S.E . an d Ntall, H. D. Amino-acid s equence o f substa nce
P. Nat .Ne w 8i?I • • 232: 86 ~8 7 ( 19 71) .
Cheney,
D.L • • LeFevre , H.F ., and Racagni , G. lCho U ne ecet y l nr ens t e r-a ae
"activity and maS8 fragmen tO l{ra ph ic measu reme nt of ace tylcholine In
specifi c nucl e i and tracts of rat br ain . ' tWur oph a r mBc o l. , 14 :, BOIJ
809(1975) .
t '
L
Che r amy , A., Le vi el , V., and Glowtn skt·, J. Uend r l t lc re t e e ee of d pllllll ne In
ihc s ubstantia nigra. Nature , 289: 5~~ .54 2 0 r81),
' -""Co l lin b ~ l d lle ,
C. L"
James , t .A. , _lUltl Macleod, ~ , K . Neuroc hemical lin d
e l e c t r ophys i ol og t c a l ev idence J o r a p rojec ti on frolll t het l o c u e
co~ r 'W0 s to the sobstanth nigra.
J . Physiol. , 290 : 44P ( 1979).
ceeeee ,
t.,
ace e ,
D.R. ,
a nd
Snyder ,
S.II.
Dopamine · r ece pt o r · b l nd l nR
~"
ss
en hance _lit
I CCOlllPanlel
ae n l1tJ, vl ty."
s e t eece , 191: 596-5 98 Ug H }.
l e s i on - i nduc e d
be lavto r &!
l u pe r -
Clle llo , A.C . , Prl e ttl y . J . Y. and Hathe" ' i !'t.R . Loc al ha t l o n of
s u b, c"n c e P i n neu r on a l pac,""" y , . t" : Sub 'U ncll!' P t n t he ; e r vOUI
lyU t i!! ( elba Fo unda tIon .I }'lIpo s t u",· 91 ) Po rter . R. I nd O'Conno r . H.
( Ed •• ) P~t "' R . Lond on : SS- 8 J ( 198 2 ) .
Oahllt ro_,
A.
and
'Ullie ,
K.
Evidence
for
the
ext e ee ne e
.,.cea.
o f 1IOlIo• • t n. -
co n ta lnt n/{ ne ur o" . I n the ce nt r a l nervou s
L, DellOnB c ra tl o n
o f .ana l . t ntl I n the c e ll bod ies o f ch I br atn s ce lll ne u r ons . Act a
Phy.lol .S cand. , 62 : Su pp l.2l2 : I- 55 ( 19~4) .
~
-,
.
I Davlea , J . Rnd Dra y ; A. Subs t a nce P 1n th e s ub.tllltia IItKra .
107 : 623 -627 ( 1916) .
-,Bra i n "r e s • •
.
.
DICh iara , 1';. , Mor elli, ~l • • IllIperato, A' I an d Porcedd u, Ii.L. A r e~ va l ua t l o"
o f t he r o l e
t he lIupe r lo r c:o ltl.1.c:u lli s ln tu r ni ng be hav i our . Brai n
Re s . , 23 7: 6 1-77 ( 198 2).
'
or
D1Ch la r .. , G" Ol la'HllI, 11. , ne t Pteccc , M•• Span o , P .F. , and Ta g ll ;l;lflo nte , A.
I nt r a n i llr al Itainle a c l d Is evidence tha t nlllni no n-d opaml ne r a:l e
neu rcnee c::ontro l pOll[ ure . Natu re , 268 : 74 3-745 (1977) .
I
Di Chia r a , G. , Poreooddu; M.t.. , Hu'lllS, N. L., and Ceu .. , G. L. Subs t antia I'Ilgr a
ss an output .tat lQn f o r ,t ri a ta l lto palii ne rg le re , PG?:se,: rol e o f a
GABA.....e d l.t ed lnhlbi t ion of ph. r etlc:: u la t. ne rons . HaunynS.c::hlllledeberg" Arc::h.Pharaac::ol ., 306 : ~ 5 )- 1S9 (I 97 ~ •
Dor na n , 101 .-'" Hallbury , C. W. , a nd Penne y , R..B. Fa c::lllu.UQD o f l o r do,h b y
injeu \ on of lIubatanc::e P mee t he at d b u ln c::entral Itra y . Subll Hted
fo r pUbUc::atlon .
,.
Duy , A. The ph y.l010P:1 and ph.mac::o loRY of
Prog.Neurob lol •• 14: 221-335 ( 1 9 80 ) ~
Or .y , A. lind St ra ugh.n, 0 .101. Syna pt ic:: TlIe c::hanh u
J. Pha r •• Phareaeol • • 28: 400- 40 5 (1976) .
"ClU llan basal
g a ngHa .
i n t he s u bs tan t La nLgrll.
Eu le r , U. S. vo n and C:addul'll , J.II•. An unLdentH led depree ecr s ub_ te ne e Ln
certain ti nue ex t rac t s . J. Phya lo l. (Lond .) 72 : 74 ~87 ( 193 1) .
Fa llo n ,
J . N. , kLls y , J . N., a nd Hoor e , · R.Y. ,SUbs t a n t i a nl Rr a do parll1ne
ne ur o ns : .eparate popu la tL on . pr oj e ct t o ne oa t r Lat um a nd a lloco rtex.
Ne~L.Let t . , 7 : 15 7-1 62 (1 978)
Fa ull, ' R. t. . H. a nd Meh le r , W.R. ,,-nte cella o f o r Lgtn o f nllJr ot e c"taI ~
nig r otha lal'llic
and
nllt r o_t r l at llL
pr ojec tions
In
t he
ra t .
Neu ro ad e nc e , · 3 1 989-100 2 ( 197 8) .
Fl bLgar ,
.
~ .C\
,
lind Hil le r,
J.~.
An
~ -
anatomical a nd e le c t r o phyaLo l oJ(Lca l
\ ",
-
"
lnve~lon oft heser otonerl{l<:p roje<:tlonfrolll thedonll1raphe
nuc Laua
to the s ubstantia nh;ra 11'1 the re'r ,
Neueosc r ; , 2: 915-98 1
(1977).
F1t~~Til\o~9.
o~
J .T. Angi Otensi n and other peptldes in the contro l
"-Odium i n t a ke. Prot .R .S o c .Lond • • 210 : 16 ~- 182 ([')80).
"lit e r 'In o.!
Freder ickso n, R.C.A ., Burdll , V" Harrell, C.E ., a nd. Edw4rds, J . D. J)UIl!
s e c rene of substance P on noclcept lon : Possl ble r ol e of endcaenous
opLo l d s . Science, 199 : 135 9-1362 ( 1978) .
Fung,
S. J . , Strahlendorf , . H. K. , Strah lendo~'t, J .e. , and ba r ne.'! , C.D .
At t e nua t i on o f nucleus nc cuebe ne induced i nh i b i t i on of lu bll tlln t la
nl g r a u n itactiv Lty by b t.c u c u f l Lne , Soc .Ne urosc i. Aba tr . 5 : 71
(1979) .
",
Gar cia-Nunoz, 0'1 "
Nicolaou, N.H ., Tulloch,
I .F ~ . Wrl Kh t , A. K.j
lind
Arb u thnott. G.W. Stdatonigral fibres - - feedback l oo p or ou t pu t
pa t hway ? Natu~e . 26 $ : 363 -3 6 ') (1977) .
Pa t i no . P • • W r i ~h t , A.J •• and Arbu th nott , (l .W.• The
anatomi~al s u bs t r a t e of the turnin~ behav iou r se en ofter l e s l on s ln
the nigrostdata l dopam ine system. Ileurosc i . , 8: 87 -9') (19 83) .
nar c i a-etcnca , H• •
Gef f e n , L. B• • Jessell , T. H. , Cue l lo. A. C• • Mid Iversen , L .L . Re l e as e o f
dopa mine f ro m dendrites in the rat sub s t an t La nig ra . Nature, 260:
258 - 260 ( 1976).
~
.
Gil lian. L. The n uc Ie ar pattern of tha non - te ct;>l port ions of the midb ra i n
and isthmus I n r ode n t s . J .COlllp.Neuro l • • 78 : 2 1) -25 1 (1943 ) .
I
• GU ck. 5.0. and Cr a ne , L..'\ . Funct i on of n l p,rlll dopalll lne r e c e pt ors ? Br81 n
Res • • 156 : 380 -38 1 ( 1978).
Gratton ,
r
A. a~d wise , R. A. Happi ng of eencrave r e t ve an ,J tp a t ve r s t ve
c t r c H ng responses t o ven t r et te~mental and substa nt ia n i gr a
erece.etcar IJt l mu l a t i o.n. Phv.s lol . Beh •• 3'): .61 -65 (1985) .
.
crc vcoe e , J.W • • J a mie so n , A• • Ta rpey. A.V • • a nd 'fo-phall\. L. Dj! Furt ~ er - ­
ev idence for mul tiple t a chykil\ ln receptors . Europ .J .P h arllllcol. ,
86: 59-64 (19 8 3) .
-
'-
".
Gulley .
sR:b:ta~~~:;a.R·~·is8~~e C~ ~~: ~:t r~~;~;;o (fl9 ;~)~ona
..in--t.he r ltt
s.r.
'(J.
Iluyene t;, P .G ., x rce , E.... . . Asr;h a jllnhn . G.K • • a nd Leeoeo ,
-./>elsYl!d
Ic n ec pho eec re ejec t io n of subs tance P f-rolll 818811 Illl croP
t-t~ :
correla t ion with t i me cou rs e. o f neu ro n,,1 eKcl ts tlon n v tve ,
- Ne u r opha r ma co l . , 18: ,')53- 558 (1979).
Hanaway, J • • McConne l. J.A. , a nd Netsk y,
M.G .
Cyto a rc h it ect u re
of
th e
,-
l ...• · ·
sa
s ubst a nt i a nl g r s I n the rat.
Anl.J . Anat • • 129: 4 17- 43 8 ( 19 70 ) .
Hatto rt, T. , MeGeer, P . L• • Fib tg er , II.C • • And ~1cGe e t , E.G. On t he ac ur ce of
GABA-con t al nl n.lt te rmi na l s t n t he s u bstanti a nil{r ll. U-e etron
l:ji e r 08e op i c 1I1"lto ra d io g ra ph y an d bio ch emica l stud i e , . Brai n Re a • •
54 : 102- 114 U~!.~"~ _ _
Herreu- Harl eh wi U , 11., Hokf el t , T. , 'Unge r s t e d t , U. , 'rerenr us , L. , and
~~~;:~1~ I f r~~n\e~~~e:~d :~;~::ea;:~;:;Ph:~j:~t::;:tl~~a1d::~~~:;
In the r a t . Eurp. J . pha r mac o l . , 102: 213 -227 ( 1984 ) .
,
.
Hess .
•
Hypothal amus
(1 9 56) .
'
W.R.
HOI~~S ,
snd
Tila lamus .
St u ttga r t , Geo rR Th~
e
Ve~lig
,
•
,.
cl~CUng,
L.J . an\ Wi se, R.A. Oopamlne-d epende nt con tra
. la t er I
I nd uce d b; ne uro t e osin a pp lied unU stera U y t o t he ven tr I t eg mental
area I n r 'at a . Br Ain . Re a . Bull ., "15: S'37 - S3a (19 85) .
•
Hol t e r -Pe t s c he , U. , 'SChllllec:k , E. , Amann . R., a nd teebe ek , F . 'i t v1 vo a nd In
vit r o a e t I one o f mammalill n t,.,c yk i n ina. Naunyn-S~~ede berR 's
Ar c h.fharlllco1., 330: 130 -13 5 (198 5) .
a
InIl~ak1 .
Dist rl~ut io"
~kephalin-like
sf!l and Pu e n t, A.
of substance P and
hnmunor eact lvi ty in t he su bs.t ant ia nig ra of th e r at . c a t ibd"""laonkey .
"Br ai n Re s .Bull . , 13: 319-3 29 (1984).
,
'
Initra lll, W.R .., Rans on , S .W'., a nd Hanne t t , P.I. The dir e ct s timulat io n o f the
•
red nu cl e us I n" cats . ': . l'Ie ur ol . Pathol., 12 : 2 19-23 0 (1 932).
l nni a ,'" R. II•.,--xndud e , R. , an~haJanian , G.K . ' Subs t a nc:e K ' rxdtes
s lSbstant a nlltra n euron s~ r a t . Soc . Neur os el . Abst r . , 10: 8 12
(1 984) .
tn n is ,
.
R. B., Andrll.de, R. an d Aghll.j a nlan, c;. K. Substance K QXCites
dop am1nergi c and non -'do pa l'lll ne rg i c neur ons i n r a t SUbst ant ia n i gr a .
Brai n Res., 335 : :381- 383 (1 98 5).
. .,
tva raen.' w~~~~~ ,Ha~:~~ : Ms'u~;t:~;~beprg;e~~~~:~~ ~~ ;' ~h:' ~::;::k ~y~'t~~' :~~ "
~~~:~:~ ~o:~~J,:'I~m ~~ ) s:::ttea:~~. Pan~n b~~~n::,err.v~~a (:J:.t)mpi~~:~
London : 18b- 20 S ( 198.2 ) .
J ack s on , l!:.A, an d Kelly , P. H. NIll:rd dopa llline rgi c llIechanisllll In
Induced circling. Brain Res,Bull . , 1 1 : bos-Ifl l ( 1983).
Jac q ue t ,
d rug ~
Y. Met( 5)-e nke pha l1 n : potent c:onttllve r.ai v8 r otation sfte r
e r e ee t nj e e ere n in ra t subs,t a nH . nigra . Brain Res ., 264: )40-)4)
(1983).
.
,.
l.
Jame s,
'.
"
a nd St ar r, M.S . B,Ehsv l ou r a l and b loch&,l1 cal Olf fe c:u o f
substance P i njec ted I nt o the substantia .,lll: ra of the r at ,
J .Pharlll.Pharrnac •• 29 : 161-162 ( 19 77).
t. A.
J a me s, T ."' . lin d St ar r, M. S . Eff ec u o f s u bs ta nc e P .Injected (ntOo t h.. '\.
s u bs u nt l11 ni g r a . Br.J .P harma c . , 6 5 : 4 23-429 ( 197 9 ) .
•
-e,
Je ru es i , T. P. and GI Lc k , S.D . Oru Jt-tnd uce f1 r ct at Icn in rata Wlt .hou t 1e 11 01'1 8 : - /
beh a vioral a nd neu r ocherdcal i ndi c e s of a nOl'mdl aSyllOJletry In n lRI"o •
s t riata l f un c t 't d n.
Ps ychop.!!!!macol. . 41 : 249 -260 ( 1976) .
'
JOMS , R.S.C. and Olp e. H. ...a.
.
.
l'achyklnln responses I n the rat ,(:l ngu 1Il t lll
co rtex : a co mpa r i so ll of the effe ct s . o f lon t opho ret lcfl lly app l1ed
s u bs t ance P add neurokini n_ A. , Europ. J.Pharlll8co l •• 11~: 113- 116
(1 985 ).
•
-
J uraska , J.I1 . , Wilson , C. J . , an d Grove s, P. M. The subs ta nt i " n ig ra of th e
!..t : ,. GoI g ! study. J.C omp.Neurol., 172 : -585-600 (1977) .
'
.
.
Kal1 vas . P .W.,. Deutch, A.'( ., Magll;io, J .E • • ~Iantyh. W., and Roth, R.-thSubstance K and s ubstance P t n the '(ent r al te gmenta l a rea .
Neur oa c LsLe t t , , 57: 241-246 (1985) .
Kaltlata , K. , Kameyama, T., Okuyama, ' 5. " Ha s hi mot o , S. , and, Aihai'a , H.
Co ntr a lat e r a l c i r clinil behavi or i ndu c e d by I n t ranL g r al I nj e c t l o ns of
t "lI r lne <lnd, GA8A In rats . Bn! n Res . , J 4 ) : 275-282 ( 1985) •
...-fuazawa~l~~~ ~~~::;~ 'W ~~~'h ~::e~:~~:h ~~;~Xl~;:':~~£lt:h t:~~~~a~a~e~~~:~::t::
,--..,
f ibres frol:l . t ne
(1916 ) .
Kelly ,
.
aub t ha Larat c
nu cleus .
" r aI n Ree, ,
15 :
4H5-491
P . M. and eree re , K. £ . Mesolilllbic doperrl ne r g t c neu r ones 1n t he
ro tational: model o f ni gr os tria t al fun et Ion , Nature , 26 ) : 695 -696 '
(1976) .
J
'
,
Khachal:urian , ' H. , loIataon, S .J. , Lewi s , ~t . E • • C_oy, D. , Gol dste In . A., " 'nd
..
Akil , H. Dyno rphlncllllllUn~ cyt oc hemht r y tn t h e rat ce ntral ,!,er volu
syStem . , Peptides , 3 : 94 1-954 (1982) .
•
, Koz l owsk i , M.R. , Sawye r, 5 . , and Ha n ha ll , J . F.
Beha vi·gural ef fe cts and
~~~~::~~;~;~v~~~5:ol:;;~~~ n i lC r a l ~paQi'1 r e c e pt o r 8 t lm~la tlon ••
,
,
Kr i eger .
"
tI
.
,
r
i).T. BraIn pep t Ldea t what, where, why1
(1983) .
'
,
Science 222 : 975 -91'15
h.'. rn , T.• II., O'Donohue, ;r. t . , Shul ta , C.'w • • Chue , T.N. , and W:l te tR., J. R·.
The e ff ects of io n tO Phoretically app lied 8u b atal\ce K ( SK). on s l nc le
IIMt ac t lv lty i n t h e ra t subatan t la' nl~r.a (S N). ' Soc.Neuroscl .
Abs Ct'. , 10 : 1121
(19J4>:
".
./
\ .~ .
•
I.
'0
« ,
_ . J -
..
"','.
.
p~xtnol'l . ·
.
:w~tB~n.
Go- : ni:l.
C. The ' ra t btd n
(4 c..dellli,c .P.ree r ; N. y •• 1 9 6i ) . ~
p~rl\Ov :;a .( Sllb8ta~ce
"
"',:,:.
--" ', ,"
..
P.
~
.
Ph: rn..col. Re v. , l S i
., '
..
.
t; ls te ·re.o tadc: .. c:oordln~·tea-I·
.
,
85~141 ( 1 983)~
..
.
(
;ratn.Huntt ngt on '~
Pe r rY,T .L . , Ha ns e n , So, 'a n d Klo8 te r, H.
f ~ ;~;';-~'1 n O bu t yr l e add In
cho rea: de fi c iency I n
Ne... Enll;l".,', J ~ Hed • • ~2.':JII: 331 -3102
Pinnoc.k, R. O. and Dray, A. DHfe rentlal sena l t f v l ty o f pr eslIIned
. dopsI1 1ne r gtc and non-dOf' ''nl lI1 er~tc neu rune s I n [ ;Jot' subst \n t la nl /{fn
to elecr ropho riltlc:ally app lied s ubs tance P .
153- 158 (1 982 ) .
Neu roac l .\.e tt . , 29 ;
'
'
Piss , M., a nd Szech tm;l.n, H. Ls ter al iz in,l( e ff e c ts o f'sp n",orp h lne on t ad a ,
o.
pos tu ral suppnr t a ndJ:ota t ton I n t llU . PraR . Neuro phar maco l . Bi oi .
Payeh tst ., 9 : 52,5-S3l (19 85)
\
Patr ie! . L.J., n tg ue ee , 11. and Msrcll and. q" Cnl'lpara tl ve mor phololtY , uf tile
sub s t a ntia nigra arid ven e ee t re p;llIent al a re a In t he mo nke y , e ll t a l\d
ra t . Brain Res .B ull . , II: )71"'397 ( 198 j.,). ·
..
ec ve
n,
D. , Leema n ,'-S . ~ 'rr egc ee , G: W. ;
. Ra.d10 1I111l1u noauay f or SU?lItllnce P.
~t11 ll, H; D., a nd ~o_t't a , J >r •
Ne\l · Bio l . ~
241: 2 52-254 ( 1973) .
Pyco ck , C. J . ·and Mars de n, C.D. The rot ating r ode nt : a two compo nen t sy a t ell?
t.;
•
Eu .rop·. J .·Pharmaco l.: . 47: ,1 67- 17 5 ( l'i 78) .
,
QUi r io n, o R. , ' :ahlt!-ts, C. W., ,Hoo dy , T.Jlo.. Pert, C.B. , Chase , T. N. an d
O'Oonohue , T.L • . Allto r adograp h ic d11ltrlbll t 1Qon of lIubllt,sn ce P
r eceptors I n rat ce nt r a l ne rvoea sYlltelll ' Na"t u r e , 30]: 714 - 716
(J9~3) ·
""
'
I
"
Quiriori , R. Mul tl p'l; - t llc hyk 1 n i~ ' r ec ep ·i::btll . Tren,J s Neuro ..d . 8: I HJ-I H5 '
-.( 1985) .
.
.
.
"
Reav1l 1 ,
C. , t1u aClI.tt, S. , Leigh , P.N .'";'"'Jen ne r, P., a nd Mars"'e n, C.D .
E nhanc~d ' GABA
fun c t i on
in
t he an p;uls f ; co lllp l ~ lI:
{l a te r al
perlllqueduct al g r eY:llIa tte r and a dj acent r et i cul ar f ormllt1 0n) alte re
t he .. pOl t u fli l compone nt o f IItrls u l - or n ilt Ta t " ue r l ve d c1 rc l1 nR.
&JI:p.Bfll l n. Res . , '~ 6 : 1-11 ( 1984 ) .
.
..
'
Reub-i,', J .-C. , I v e rs en , L. L. , a nd , Je8lleU, ,' T.H . oOpa~1 ne lIe1e c tl ve l y
-:\ : l nc rella es ( 3H! - GAU r el~ Jl' 8e ' f r o lll d.1c e ll o f rM 8ubs t llnt la nlp; ra lO:-: _ ~
.
v i t r o NS,tu r e , 268 : 6Jf.>.654 ( 1977) .
.
<
Ruff l eux, A. and Sc hu l tz, 14. Oo palll iner~ l c ac;Uva Uon o f'reticulst ll neueenea .
1n th e s ubs ta n t ia nig ra . Nat u.re : 28 5- 2116 (1 980).,
•
/" I
$.,
•
,
Sakai , K. , ' Tour e t , tr:, 'Salve r t ,
Le~e;, L_ ,AQd Jou vet, H. Af fs ; e nt
p roj e ction s t o t he Ca t l oc us coerule usrlll v1811d 1:r:e d by t he
• . !loreera ,J.i 8h pero:xldll.8e . t ec hn1q u e . Br ai n Ru. , 1.19 : ~ - 4 1 (19 77) . 10
..
~.
s~~ lt i, ;i;i; n::C:l'ndS;: ' ~ 1:~:c~:~ s;bStIlCn~:ep a~~P{~;~::~1nO:nOo...n~~~~'at;ri~~
"\.
,
I
K) : "ee .. t ransllitt ere 10 rat b t ~1 n .
.
,..
PIIl·Pt id u " .: 34]-345 ( 19 8 5) .
j,
' -
,
"
Sh1,l1u , COW" Yaj l • • , Ho , Gullner. HoC• • Chale , ToN. and O' !»nohue . T.L .
DellOnltu t U,n .n'(j.-d tl t r l bu t lo n al 1I.
... lnln-11.. e ~ t e r l al ( .uba t . nce
K) I n t he r at c e n tra l ner vou s aylte•• J .Ke urochell. , ""', : )S 2-))8
(1985).
ser ee r , R. S• • Hai ti , A., an d 's n id e r , S . R. CerlHlb r pa t h" Ays to ve tl t rll
1I 1d ~u tn an d dIU.
EIlp oNeuJ ot . , 53 : 1 14·728 (1976) .
Star r , H.S • • Su_s hflyel , H. , lind K.11pat rl ck, I . C. t nt er actlon t be t ween
.
dopaatne oan d " .IIIro1 -a la1no oo t yra te
In
the
su b, ean t h ' n igra :
I .plicat l o n. f or t he I t rb to n!gr a l h ypo tne ah . Neuros ci • • 8 :' 547· '
559 . (l 9 ~) .
St e wart , J.H.
-,
St l nu I ,
.
..
•
Pr o b l e lll I n the use o f su bltan t e P .
Skt. bane k , P. a nd ' ovell , O. (E d s. ) Ilooie
~ • • Kill ey', ' A.E : ••n~' Ive·r~en.
In :
s ull'u-snc.e
Pr l!t . ~
P ( Dub li n) .
Dubl1 n: 6- 7 (1983 ) .
In~reued .pontan~ou. activ~ tY
S. D.
. f o U o lii ng s ubs ta nce P inf us ion i nt o AIO dopa llli,ne rgic a rea . Nature , '
276: 616- 6 18 ( 1978 ).
'
,
Vnlle r .tede', U ~ Po.uynapdc 'I,lpers e na lt lv ity a fte r ' 6 ~h yd r o x y d';pa ml n .
i nduced' dege ner a t i on of th e ni gt o - st r ia tal do paefne ay iu lII. Acts
Pt-i ~.!O l:.::a ndi n . Suppl • • 367 : 69";~] (1 97 1) .
' ,
•
. Vngen te d t f' V,. a Dd Arbl,lt hno t t . -C. W. , QUa nti ta tive re co rding o f ro ta t i o nal
be ha vi or
in r a t • .t t e r " 6- hydrox y-d o ps lfti ne l e .lo n. ' of
t he
nig r o i t ria t'. l do pn ln e s,at ea . ' Bra in Rei • • 24 : 485; 49 3 (1 970).""0Vnlll:e r i te d t . V" 8utc her . L.L• • But ch e r ; S. C" Anden , N. -E . a nd 'F uxe, It.
- Di r e c t ctM! 'deal n illU l. t io n of clopa.. i ner gi c III!cl\ariil.s 1n the
nec" tr h t l,lll of th e ra t . Bn,ln Res • • 14 : 46 1-4 71 ( 1969) .
V.c c ar 1no , Y.J . a nd Fr a nklin. It.B : J. Do~."'ine .ed lAtes I p~l- and
con tr \ ver slve ·. cir cling e li ci ted frO Ill t he ' ub, t a nt la ' nig ra .
Phar .. c .BjCbell.BehaV• • 17: 431-434 ( 1982) .
v~ccart no . ... ' .J:
'n~klin .
l~.l~er', R. J • • Ka~P. J . A: .
-
'-;
loco~tor U)1lllMltri~s ·
and
1t. ;.J . Opposit e
e ndtd frail t he lIled la l and latera l SN by IIll)dula t i o n of ~N OA
r e ce pton . Phar mac . l i oc.hu . Beh.av• • ,21: ·13- 11 (198 4) . ·
'
,
•
VaJ I_.
H.: ~itagava .
K •• a nd Wood:uf f .• G. N.
:~:;:~ ::ur:~saUl:c~~ :;/.lM!s:Xn:e:Plhll~lns.rlar,~~~~( ~~~6)~d
Tt e
aub.tanth
./
J.R.'
,"8u:czak , B.L . IIo nd W.t t e r s .
Dopamin e IIXI\Ull\flon of t he ef fe c ts or ~
g.1llIU ~' lI l nobu t yrlc acid o n s ubs t ant l' ni r a l't!r s l' et lc u lau neu r on s .
Sc iencs, :NO: 2 18-22 1 (1 983) .
.
. '.-:--.
..
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, ,
"
.
.