new consistency of the cholecystokinin satiety effect across … · 2020. 4. 2. · examined across...
TRANSCRIPT
Consistency of the cholecystokininsatiety effect across deprivation levels
Item Type text; Thesis-Reproduction (electronic)
Authors Mueller, Kathyrne Jean
Publisher The University of Arizona.
Rights Copyright © is held by the author. Digital access to this materialis made possible by the University Libraries, University of Arizona.Further transmission, reproduction or presentation (such aspublic display or performance) of protected items is prohibitedexcept with permission of the author.
Download date 15/03/2021 07:48:23
Link to Item http://hdl.handle.net/10150/348366
COtiS ISTENCY OF THE, CHOLECYSTOKININ
SATIETY EFFECT,ACROSS.
DEPRIVATION LEVELS
by
K a t h y r n e J e a n M u e l l e r
A T h e s i s S u b m i t t e d t o t h e F a c u l t y o f t h e
DEPARTMENT OF PSYCHOLOGY
In P a r t i a l F u l f i l l m e n t o f t h e R e q u i r e m e n t s For t h e D e g r e e o f
MASTER OF ARTS
In t h e G r a d u a t e C o l l e g e
THE UNIVERSITY OF ARIZONA
1 9 7 8
STATEMENT BY AUTHOR
T h i s t h e s i s has been s u b m i t t e d in p a r t i a l f u l f i l l ment o f r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t The U n i v e r s i t y o f A r i z o n a and i s d e p o s i t e d in t h e U n i v e r s i t y L i b r a r y t o be made a v a i l a b l e t o b o r r o w e r s u n d e r r u l e s o f t h e l i b r a r y .
B r i e f q u o t a t i o n s , f rom t h i s t h e s i s a r e a l l o w a b l e w i t h o u t s p e c i a l p e r m i s s i o n , p r o v i d e d t h a t a c c u r a t e a c k n o w l edgment o f s o u r c e i s made. R e q u e s t s f o r p e r m i s s i o n f o r e x t e n d e d q u o t a t i o n from o r r e p r o d u c t ion o f t h i s m a n u s c r i p t in w h o le o r in p a r t may be g r a n t e d by t h e head o f t h e m a jo r d e p a r t m e n t o r t h e Dean o f t h e G r a d u a t e C o l l e g e when in h i s ju d g m e n t t h e p r o p o s e d u s e o f t h e m a t e r i a l i s in t h e i n t e r e s t s o f s c h o l a r s h i p . In a l l o t h e r i n s t a n c e s , h o w e v e r , p e r m i s s i o n must be o b t a i n e d from t h e a u t h o r .
SIGNED: rvu^
APPROVAL BY THESIS DIRECTOR
T h i s t h e s i s •h a s been a p p ro v e d on t h e d a t e shown b e l o w :
'2'Z/ /$ ~7 OHSIAO ' ; -’A
A s s o c i a t e P r o f e s s o r o f P s y c h o l o g y D a te
ACKNOWLEDGMENTS
The a u t h o r w i s h e s t o e x p r e s s a p p r e c i a t i o n t o D r ,
Sigmund H s ia o , w i t h o u t whose a s s i s t a n c e t h i s r e s e a r c h
would n o t h a v e been p o s s i b l e . Thanks a r e a l s o d u e t o D r s .
D e n n i s C l a r k and Mary W e tz e l f o r c r i t i c a l r e a d i n g s o f t h i s
m a n u s c r i p t . The C - t e r m i n a l o c t a p e p t i d e o f c h o l e c y s t o k i n i n
u s e d in t h i s s t u d y was k i n d l y s u p p l i e d by M r . S. J , L u c a n ia
o f t h e P r e c l i n i c a l R e s e a r c h A d m i n i s t r a t i o n o f t h e S q u ibb
I n s t i t u t e o f M e d ic a l R e s e a r c h . T h i s r e s e a r c h was p a r t i a l l y
s u p p o r t e d by a U n i v e r s i t y o f A r i z o n a I n s t i t u t i o n a l
R e s e a r c h F u n d .
TABLE OF CONTENTS
Pag e
LIST OF ILLUSTRATIONS . . . . . . . . . . . . . . . v
LIST OF TABLES . . . . . . . . . . . . . . . . v i
ABSTRACT . . . . . . . . . . . . . . . . . . . . . v i i
INTRODUCTION . . . . . . . • • • . . . . • • 1
EXPERIMENT 1 . . . . . . . . . . . . . . . . . . . . 6
Method . . . '. . . . . . . . . . . . . . , . 6S u b j e c t s . , . . . . . . . . . . . . . 6A p p a r a t u s . . . . . . . . . . . . . . . 6D e s ig n . . . . . . . .. . . . . . . . . . 7T r a i n i n g . . . . . . . . . . . . . . . 7T e s t i n g ♦ • ' . . . . . . . . . . . . . . 8
R e s u l t s . . . . . , ... . . . . ... . . . . . . 9
EXPERIMENT 2 . . . . . . . . . . . . . . . . . . . 15
Method . . . . . . . . . . . . . . . . . . . 15Subj e c t s . . . . . . . . . . . . . . . 15P r o c e d u r e . . . . . . . . . . . . . . 15
R e s u l t s . . . . . . . . . . . . . . . . . . 16
DISCUSSION . . . . . . . . . . . . . . . ' 19.
REFERENCES . . . . . . , . . . . . . . . . . . . . . . 25
i v
LIST OF ILLUSTRATIONS
Mean c u m u l a t i v e i n t a k e o f l i q u i d , d i e t a f t e r i n j e c t i o n o f 0 ( c o n t r o l ) , 15, and 40 Iv y dog u n i t s / k g o f t h e C - t e r m i n a l o c t a p e p t i d e o f CCK i n t o a n i m a l s d e p r i v e d o f foo d f o r 5 o r 19 h o u r s . . » . . , . ... . . . ,
Mean body w e i g h t s t h r o u g h o u t E x p e r im e n t 1 : The a n i m a l sa r e a s s i g n e d t o 5 o r 19 ho u r d e p r i v a t i o n g r o u p s . . . . . .
Mean c u m u l a t i v e i n t a k e o f l i q u i d d i e t a f t e r i n j e c t i o n o f 0 ( c o n t r o l ) , 40 , o r 80 Iv y dog u n i t s / k g o f t h e C - t e r m i n a l o c ta .p e p t . id e o f CCK i n t o a n i m a l s d e p r i v e d o f food f o r 48 h o u r s
LIST. OF TABLES
T a b le Page
1. Mean l i q u i d d i e t i n t a k e (ml) d u r in gt h e 15 m i n u t e r e c o v e r y p e r i o d andt o t a l mean l i q u i d d i e t i n t a k e ,c o m b in in g am oun ts i n g e s t e d d u r i n gt h e 60 m i n u t e t e s t i n g p e r i o d andt h e 15 m i n u t e r e c o v e r y p e r i o d . . . . . . 12
ABSTRACT
A g a s t r o i n t e s t i n a l iiormone, cbo 1 e c y s t o k i n i n (CCK) >
h a s r e c e n t l y been i m p l i c a t e d in t h e r e g u l a t i o n o f meal
S i z e . The c o n s i s t e n c y o f t h e CCK " s a t i e t y e f f e c t ” was
exam ined a c r o s s d e p r i v a t i o n l e v e l s i n two e x p e r i m e n t s .
In E x p e r im e n t 1, 20 r a t s w e re foo d d e p r i v e d f o r 5 o r 19
h o u r s and i n j e c t e d w i t h 0, 15, and 40 Ivy dog u n i t s / k g
(U /kg) o f t h e C ^ t e r m i n a l o c t a p e p t i d e o f CCK b e f o r e consum
in g a t e s t m ea l o f a l i q u i d d i e t . In E x p e r im e n t 2 , 18
4 8 - h o u r d e p r i v e d r a t s w e re i n j e c t e d w i t h 0 , 40 , o r 80 U/kg
o f t h e C C K - o c t a p e p t i d e b e f o r e consu m in g a t e s t m eal o f a
l i q u i d d i e t . In b o t h e x p e r i m e n t s CCK p r o d u c e d a d o s e -
r e l a t e d s u p p r e s s i o n in food i n t a k e . CCK d i d n o t a p p e a r
t o become l e s s e f f e c t i v e a s d e p r i v a t i o n i n c r e a s e d : 15 U/kg
s u p p r e s s e d i n t a k e by a p p r o x i m a t e l y 30% a t 5 and 19 h o u r s
d e p r i v a t i o n ; 40 U/kg s u p p r e s s e d i n t a k e by a p p r o x i m a t e l y
50% a t a l l d e p r i v a t i o n l e v e l s ; 80 U/kg s u p p r e s s e d i n t a k e
by a p p r o x i m a t e l y 72%. T h u s , a g i v e n d o s e o f CCK p r o d u c e s
a c o n s i s t e n t s u p p r e s s i o n o f i n t a k e (w h ich c an b e b e s t
d e s c r i b e d a s a c o n s t a n t p e r c e n t ) f o r a l e n g t h o f t i m e f a r
beyond t h e h a l f - l i f e o f CCK i t s e l f . A f t e r more s e v e r e
d e p r i v a t i o n a " f a i l - s a f e ” s a t i e t y mechanism may o v e r r i d e
t h e CCK s a t i e t y e f f e c t .
. ' v i i
INTRODUCTION
A g a s t r o i n t e s t i n a l hormone, c h o l e c y s t o k i n i n (CCK),
i s c u r r e n t l y u n d e r c o n s i d e r a t i o n a s a s h o r t t e r m ( i n f l u
e n c i n g m eal t o m eal r e g u l a t i o n ) s a t i e t y s i g n a l « CCK h a s
been w i d e l y r e p o r t e d t o i n h i b i t fo o d i n t a k e and t o i n d u c e
b e h a v i o r s g e n e r a l l y a s s o c i a t e d w i t h s a t i e t y , i n s e v e r a l
s p e c i e s and i n v a r y i n g n u t r i t i o n a l s t a t e s ( s e e r e v i e w by
M u e l l e r and H s ia o n . d . ) . The p r e s e n t r e s e a r c h was u n d e r
t a k e n t o e s t a b l i s h t h e c o n s i s t e n c y o f t h i s “ s a t i e t y
e f f e c t " o v e r v a r y i n g l e v e l s o f . n u t r i t i o n a l d e f i c i t .
: In o r d e r t o r e g u l a t e i r u t r i t i o n a l and e n e r g y r e
q u i r e m e n t s an o r g a n i s m m ust a c h i e v e a b a l a n c e be tw een
e n e r g y o u t f l o w , e n e r g y i n f l o w , and p o t e n t i a l e n e r g y (Le
Magnen 1 9 7 6 ) . In t h e l a b o r a t o r y r a t c o n t r o l o f e n e rg y
i n f lo w i s a c c o m p l i s h e d by t h e c o n s u m p t io n o f s m a l l f r e
q u e n t m e a ls ( B a l a g u r a and C o s c i n a 1 9 6 8 ) . E nergy i n f l o w
can t h u s be r e g u l a t e d by a d j u s t i n g t h e o n s e t o f a m ea l ,
d u r a t i o n o f a m e a l , t e r m i n a t i o n o f . a m ea l , and i n t e r m e a l
i n t e r v a l . T hose phenomena s u r r o u n d i n g t h e i n i t i a t i o n o f
a m eal a r e r e f e r r e d t o a s h u n g e r - r e l a t e d o r h u n g e r
v a r i a b l e s and t h o s e s u r r o u n d i n g t h e t e r m i n a t i o n o f a
m ea l a r e r e f e r r e d t o a s s a t i e t y - r e l a t e d o r s a t i e t y v a r i a b l e s .
1 -
S a t i e t y , h o w e v e r , i s u s u a l l y u n d e r s t o o d a s more
t h a n t h e s i m p l e p o i n t i n t i m e c o r r e s p o n d i n g t o t h e t e r m i
n a t i o n o f a m e a l . I t can b e more p r e c i s e l y d e f i n e d a s a
complex g ro up o f e v e n t s i n c l u d i n g : t h e d e c e l e r a t i o n and
e v e n t u a l t e r m i n a t i o n o f i n g e s t i v e r e s p o n s e s , t h e r e g u l a r
o c c u r r e n c e o f p a r t i c u l a r n o n i n g e s t i v e r e s p o n s e s (w h ich
may be s p e c i e s s p e c i f i c o r c u l t u r e s p e c i f i c ) , p a r t i c u l a r
p h y s i o l o g i c a l r e s p o n s e s , and h e d o n i c e v e n t s o r e v e n t s
p o s s e s s i n g r e i n f o r c i n g p r o p e r t i e s ( s e e r e v i e w by M u e l l e r
and H s ia o n . d . ) . .
S a t i e t y seems t o d e p en d , i n p a r t , on p e r i p h e r a l
e v e n t s o c c u r r i n g i n t h e u p p e r i n t e s t i n e s . A l t h o u g h o r o
p h a r y n g e a l s e n s a t i o n s may p o s s e s s some r e i n f o r c i n g p r o p
e r t i e s , a no rm a l f e e d i n g p a t t e r n i n r a t s c an be a c h i e v e d
w i t h i n t r a g a s t r i c s e l f f e e d i n g ( % s t e i n and T e i t e l b a u m
1962) . Thus o r o p h a r y n g e a l s e n s a t i o n s do n o t a p p e a r t o
b e e s s e n t i a l i n t h e r e g u l a t i o n o f m ea l s i z e and m e t a b o l i c
b a l a n c e . The c a p a c i t y o f t h e s to m a c h , a l t h o u g h a l i m i t
i n g f a c t o r , d o e s n o t a p p e a r t o be r e s p o n s i b l e f o r t h e
r a t ’s f e e d i n g p a t t e r n . R a t s r e s p o n d t o d e p r i v a t i o n and
t o d i l u t i o n o f t h e i r foo d l a r g e l y by i n c r e a s i n g meal
. s i z e (Snowdon 1 9 6 9 ) . Vagotomy, w h ic h e l i m i n a t e s i n p u t
from g a s t r i c s t r e t c h r e c e p t o r s ( P a i n t a l 1 9 5 4 ) , q u i c k e n s
r a t h e r t h a n d e l a y s s a t i e t y (Snowdon and E p s t e i n 1 9 7 0 ) .
B oth o f t h e s e o b s e r v a t i o n s i n d i c a t e t h a t s to m a c h c a p a c
i t y i s n o t t h e e s s e n t i a l f a c t o r i n t e r m i n a t i n g m e a l s .
However, s m a l l i n f u s i o n s o f n u t r i t i v e s u b s t a n c e s i n t o
the . duodenum r e l i a b l y d e c r e a s e m ea l s i z e o r s t o p sham
f e e d i n g ( L i e b l i n g e t a l . 1975; S m i th , G ib b s , and Young
1 9 7 4 ) . Thus t h e m outh , e s o p h a g u s , and s to m a c h h a v e been
p r o g r e s s i v e l y e l i m i n a t e d a s m a jo r s o u r c e s o f s a t i e t y
i n d u c i n g s t i m u l i . I n s t e a d , two d u o d e n a l l y b a s e d mecha
n i sm s h a v e been s u g g e s t e d t o e x p l a i n t h e o n s e t o f s h o r t
t e r m s a t i e t y : a m echanism a c t i v a t e d by g l u c o s e and m ed i
a t e d by t h e v a g u s n e r v e (Novin 1976) and a h o rm on a l mech
a n i s m , p r e s u m a b l y i n v o l v i n g CCK (S m i th and G ib bs 1 9 7 5 ) .
C h o l e c y s t o k i n i n , a p o l y p e p t i d e hormone composed
o f 33 amino a c i d r e s i d u e s , i s r e l e a s e d by t h e u p p e r
i n t e s t i n e s i n r e s p o n s e t o h y d ro g e n i o n s , f a t t y a c i d s and
c e r t a i n p e p t i d e s (M akhlouf 1 9 7 4 ) . G lu c o s e d o e s n o t s t i m
u l a t e t h e r e l e a s e o f CCK. The b i o l o g i c a l l y a c t i v e p o r
t i o n o f t h e m o l e c u l e i s c o n t a i n e d i n t h e C - t e r m i n a l
o c t a p e p t i d e ( O h d e t t i e t a l . 1970) .
CCK h a s l o n g been known f o r i t s e f f e c t s on t h e
g a l l b l a d d e r and p a n c r e a s ( D a v e n p o r t 1971) b u t t h e e f f e c t
o f i n d u c i n g s a t i e t y h as been s u g g e s t e d o n l y r e c e n t l y
(S m i th and G ibbs 1 9 7 5 ) . As chyme e n t e r s t h e duodenum,
c e r t a i n o f i t s c h e m i c a l p r o p e r t i e s s t i m u l a t e t h e r e l e a s e
o f CCK, w h ic h e n t e r s t h e b l o o d s t r e a m and p r e s u m a b l y
i n t e r a c t s w i t h s a t i e t y r e l a t e d a r e a s i n t h e . b r a i n t o
t e r m i n a t e t h e m ea l ( S t e r n , C u d i l l o , and K ru p e r 1 9 7 6 ) .
S e v e r a l c r i t e r a h a v e been r e c e n t l y p r o p o s e d t o
d e t e r m i n e w h e t h e r CCK s e r v e s i n f a c t a s a s h o r t t e r m
s a t i e t y s i g n a l ( M u e l l e r and H s i a o , n . d . ) : a ) t h e s a t i
e t y i n d u c i n g e f f e c t o f CCK s h o u l d b e m im icked by i t s
a n a l o g s w i t h a common C - t e r m i n a l o c t a p e p t i d e ; b ) any
e v e n t s t i m u l a t i n g o r b l o c k i n g CCK r e l e a s e s h o u l d a l s o
a f f e c t m ea l s i z e , e i t h e r by q u i c k e n i n g o r d e l a y i n g t h e
t e r m i n a t i o n o f a m e a l ; c ) e x p e r i m e n t a l d oSes o f CCK i n
t h e p h y s i o l o g i c a l " r a n g e s h o u l d i n d u c e s a t i e t y and s a t i
e t y r e l a t e d r e s p o n s e s ; d) CCK s h o u l d i n d u c e s a t i e t y in
a d o s e - r e l a t e d f a s h i o n ; e) t h e s a t i e t y i n d u c i n g e f f e c t
o f CCK s h o u l d i n t e r a c t in a c o n s i s t e n t and a d a p t i v e
manner w i t h t h e s t a t e o f n u t r i t i o n a l d e f i c i t o f an o r
gan ism ; f ) CCK S h o u ld i n t e r a c t w i t h f e e d i n g r e l a t e d a r e a s
o f t h e b r a i n t o i n d u c e s a t i e t y ; g) S a t i e t y i n d u c e d by
CCK s h o u l d mimick m ea l in d u c e d s a t i e t y ; h) t h e s a t i e t y
i n d u c i n g e f f e c t o f CCK s h o u l d a f f e c t food i n t a k e d i
r e c t l y w i t h o u t i n v o l v i n g a d i f f u s e b e h a v i o r a l s y s t e m ;
i ) t h e s a t i e t y i n d u c i n g e f f e c t o f CCK s h o u l d b e c o n s i s
t e n t a c r o s s s e v e r a l s p e c i e s . The p r e s e n t s t u d y i n v e s
t i g a t e s t h e c o n s i s t e n c y o f t h e CCK s a t i e t y e f f e c t a c r o s s
d e p r i v a t i o n l e v e l s and r u s e s t h i s i n f o r m a t i o n t o i n f e r
in what manner COK s u p p r e s s e s i n t a k e .
The s i m p l e s t model f o r t h e n a t u r e o f t h e CCK
s a t i e t y e f f e c t , would be a c o n s i s t e n t s u p p r e s s i o n o f
food i n t a k e r e g a r d l e s s o f t h e s t a t e o f d e p r i v a t i o n o f
t h e o r g a n i s m . The e f f e c t s o f CCK on food i n t a k e h a v e
been t e s t e d a t v a r y i n g l e v e l s o f d e p r i v a t i o n — 0 h o u r s :
(H s ia o and M u e l l e r n . d . ) , 5 . 5 h o u r s (G ib b s , Young, and
Sm ith 1 9 7 2 ; G i b b s , Young, and S m i th 1 9 7 3 a ; K u lko sk y e t a l .
1 9 7 6 ) , 17 h o u r s ( A n t i n e t a l . 1975; G ibbs e t a l . 1973a;
G i b b s , Young, and S m i th 1973b; S m i th e t a l . 1 9 7 4 ) , 18
h o u r s (Koopmans, D e u t s c h , and B ran so n 1 9 7 2 ) , and 92 h o u r s
(S m i th and G ibbs 1975) - - a r i d s u p p r e s s i o n s in i n t a k e h a v e
o c c u r r e d a t e ac h l e v e l e x c e p t 92 h o u r s .
To d a t e , no a t t e m p t h a s been made t o s y s t e m a t
i c a l l y e v a l u a t e t h e s a t i e t y i n d u c i n g e f f e c t s o f CCK
a c r o s s d e p r i v a t i o n l e v e l s . T h i s i n f o r m a t i o n , in com bi-
n a t i o n w i t h i n f o r m a t i o n a b o u t t h e e f f e c t s o f d o s e l e v e l ,
c o u l d p r o v i d e i m p o r t a n t c l u e s t o t h e n a t u r e o f t h e CCK
s u p p r e s s i v e e f f e c t . E x p e r im e n t 1 e x p l o r e s t h e e f f e c t s
o f t h r e e d o s e s o f t h e C - t e r m i n a l o c t a p e p t i d e o f CCK on
food i n t a k e f o l l o w i n g two m o d e r a t e l e v e l s o f d e p r i v a t i o n .
E x p e r im e n t 2 e x p l o r e s t h e e f f e c t s o f t h r e e d o s e s o f t h e
o c t a p e p t i d e u n d e r more s e v e r e d e p r i v a t i o n c o n d i t i o n s .
EXPERIMENT 1
Method
S u b j e c t s
The s u b j e c t s w e r e 20 a d u l t m a le H ol tzm an r a t s
o b t a i n e d from t h e Hol tzm an Company. T h e i r mean body
w e i g h t was 365 grams a t t h e b e g i n n i n g o f t e s t i n g . The .
a n i m a l s w e r e h o u se d i n d i v i d u a l l y in s t a n d a r d w i r e mesh
c a g e s and m a i n t a i n e d on t a p w a t e r , Wayne l a b o r a t o r y
p e l l e t s , and S i m i l a c PM 6 0 /4 0 i n f a n t f o r m u la ( d i l u t e d
w i t h 2 o u n c e s o f w a t e r f o r e v e r y 12 grams o f p o w der ) a s
d e s c r i b e d b e low . The l a b o r a t o r y was l i t on an a r t i f i
c i a l 12 ho u r l i g h t - d a r k c y c l e ; t r a i n i n g and t e s t i n g
o c c u r r e d i m m e d ia t e l y a f t e r t h e b e g i n n i n g o f t h e
l i g h t p e r i o d .
A p p a r a t u s
The t e s t s u b s t a n c e .was p r e s e n t e d t o t h e a n im a l
in a 25 ml c h e m i c a l b u r e t , g r a d u a t e d t o 0 . 1 ml and f i t t e d
w i t h a m e t a l d r i n k i n g s p o u t . D u r i n g t r a i n i n g and t e s t
i n g t h e d r i n k i n g t u b e s w e re s u s p e n d e d in f r o n t o f t h e
home c a g e by means o f a m o v ab le arm so t h a t t h e a n im a l
7
had t o e x t e n d h i s t o n g u e t h r o u g h t h e b a r s o f t h e c a g e
t o make c o n t a c t w i t h t h e s p o u t .
D e s ig n
The a n i m a l s w e re r a n d o m ly a s s i g n e d t o u n d e rg o 5
o r 19 h o u r s o f foo d d e p r i v a t i o n b e f o r e t e s t i n g . Each
a n im a l was t h e n t r a i n e d and t e s t e d f o r i n t a k e o f l i q u i d
d i e t a f t e r p r e t r e a t m e n t w i t h 0 Ivy dog u n i t s p e r kg (U /k g )
15 U / k g , and 40 U/kg o f t h e C - t e r m i n a l o c t a p e p t i d e o f CCK
a d m i n i s t e r e d i n a random o r d e r . To I n s u r e c o m p l e t e r e c o v
e r y from t h e e x p e r i m e n t a l c o n d i t i o n o f t h e p r e v i o u s d ay ,
48 h o u r s i n t e r v e n e d b e tw een t e s t i n g s . T e s t i n g p e r i o d s
a l t e r n a t e d s u c h t h a t no more t h a n f i v e a n i m a l s w e r e
t e s t e d on a g i v e n d a y . The i n t e r v e n i n g r e c o v e r y d ay s
w e r e c o n d u c t e d i n t h e same m anner a s t e s t i n g d a y s w i t h
t h e e x c e p t i o n t h a t no i n j e c t i o n s w e r e a d m i n i s t e r e d .
T r a i n i n g
A c c o r d i n g t o a p r o c e d u r e d e v e l o p e d in t h i s l a b ,
e ac h a n im a l was t r a i n e d f o r 10 d a y s t o consume from 33%
t o 50% o f i t s n u t r i t i o n a l r e q u i r e m e n t s in t h e form o f
l i q u i d d i e t . A 17 gram s o l i d fo o d s u p p le m e n t was admin
i s t e r e d a t t h e c l o s e o f e a c h t r a i n i n g p e r i o d . D u r in g
t h i s p h a s e t h e d r i n k i n g t u b e s w e r e c l i p p e d t o t h e
a n i m a l s ' c a g e so t h a t t h e s p o u t e x t e n d e d i n s i d e t h e c a g e
f o r e a s y a c c e s s .
8
F o l l o w i n g t h e i n i t i a l t r a i n i n g p e r i o d e ac h
a n im a l r e c e i v e d 5 d a y s o f h a b i t u a t i o n t o i t s a p p r o p r i a t e
d e p r i v a t i o n l e v e l . S o l i d fo o d was a v a i l a b l e u n t i l 5 o r
19 h o u r s b e f o r e t h e t r a i n i n g s e s s i o n . The l i q u i d d i e t
was t h e n p r e s e n t e d by means o f t h e m o vab le arm d e s c r i b e d
a b o v e . D u r i n g t r a i n i n g and h a b i t u a t i o n w a t e r was a lw ays ,
a v a i l a b l e e x c e p t d u r i n g t h e p r e s e n t a t i o n o f l i q u i d d i e t .
T e s t i n g
At t h e c l o s e o f t h e a p p r o p r i a t e p e r i o d o f d e p r i -
v a t i o n t h e a n i m a l s w e re i n j e c t e d i n t r a p e r i t o n e a l i y w i t h
a p p r o x i m a t e l y 0 . 5 cc o f t h e a p p r o p r i a t e d o s e o f t h e o c t a -
p e p t i d e ( SQ 19844, S q u ib b and S o n s , I n c . ) d i s s o l v e d i n
n o rm a l s a l i n e . The l i q u i d d i e t was p r e s e n t e d t o t h e
a n i m a l s 5 m i n u t e s l a t e r by means o f t h e m o v ab le arm and
i n t a k e was r e c o r d e d e v e r y 2 m i n u t e s f o r 30 m i n u t e s .
F i n a l i n t a k e was r e c o r d e d a t 60 m i n u t e s and t h e l i q u i d
d i e t was r em oved . The l i q u i d d i e t was made a v a i l a b l e
t o t h e a n i m a l s f o r 15 a d d i t i o n a l m i n u t e s 30 m i n u t e s
a f t e r t h e c o m p l e t i o n o f t e s t i n g . A f t e r c o m p l e t i o n o f
t h i s r e c o v e r y p e r i o d t h e s o l i d fo o d was p r o v i d e d . Water
was a lw a y s a v a i l a b l e e x c e p t d u r i n g p r e s e n t a t i o n o f t h e
l i q u i d d i e t .
R e s u l t s
C u m u la t iv e mean l i q u i d d i e t i n t a k e a t e ac h
m easu rem en t p e r i o d was a n a l y z e d w i t h an a n a l
y s i s o f v a r i a n c e (w h e re A i s t h e b e tw ee n s u b j e c t s d e p r i
v a t i o n v a r i a b l e , and B i s t h e w i t h i n s u b j e c t s d o s e
v a r i a b l e ) . F i g u r e 1 p r e s e n t s t h e c u m u l a t i v e mean l i q u i d
d i e t i n t a k e f o r e a c h d o s e and d e p r i v a t i o n l e v e l d u r i n g
t h e t e s t i n g p e r i o d . As i n d i c a t e d i n t h e f i g u r e , i n t a k e
was s i g n i f i c a n t l y ( p < .05 ) s u p p r e s s e d by t h e CCK o c t a -
p e p t i d e a t e a c h m ea su rem en t p e r i o d . The h i g h e r t h e d o s e
o f t h e o c t a p e p t i d e , t h e g r e a t e r was t h e s u p p r e s s i o n o f
i n t a k e ; 15 U/kg s u p p r e s s e d i n t a k e by a p p r o x i m a t e l y 30%
a t . b o t h 5 and 19 h o u r s d e p r i v a t i o n and 40 U /kg s u p p r e s s e d
i n t a k e by a p p r o x i m a t e l y 50% a t b o t h 5 and 19 h o u r s d e p r i
v a t i o n . The h i g h e r i n t a k e o f t h e 19 h o u r d e p r i v a t i o n
g roup r e a c h e d s i g n i f i c a n c e a t 10 m i n u t e s and r e m a in e d
s i g n i f i c a n t t h r o u g h o u t t h e 30 m i n u t e p e r i o d . The cumu
l a t i v e c u r v e s f o r t h e 19 h o u r -1 5 U/kg g roup and t h e 5
h o u r - 0 U / k g g roup a r e n e a r l y i d e n t i c a l .
As shown i n F i g u r e 1, by t h e end o f t h e 60 min
u t e t e s t i n g p e r i o d mean i n t a k e s f o r a l l g r o u p s w e re v i r
t u a l l y u n c h a n g e d ( l e s s t h a n 1 m l) f rom t h e 30 m i n u t e
i n t a k e s and t h e s i g n i f i c a n t d i f f e r e n c e s n o t e d a b o v e r e
mained . I n t a k e d u r i n g t h e 15 m i n u t e r e c o v e r y p e r i o d i s
CU
MU
LATI
VE
LIQU
ID
DIET
IN
TAKE
(m
l)
28
24
20
16
12
8
4
o------- ------- o 5 hr. 0 U/kg 19 hr. 0 U/kgu i i i . u / pvy
____ A. IQ IK i 1in. iu u / y5 hr. 40 U/kg
19 hr. 40 U/kg■--------------■
A A ■- A A A * A
---- ■ --------- ■ ----------■ ----------■ ----------■ ----------■ ----------■ --------- ■— 6 — -----A---- ----A---------A----------A----------A----------A---- -----A----------A
-o-
A
O■A
□
8 10 12 14 16 18 20 22 24 26 28 30 60
INTAKE T IM E (minutes)
F i g u r e 1. Mean c u m u l a t i v e i n t a k e o f l i q u i d d i e t a f t e r i n j e c t i o n o f 0 ( c o n t r o l ) , 15, and 40 Ivy dog u n i t s / k g o f t h e C - t e r m i n a l o c t a p e p t i d e o f CCK i n t o a n i m a l s d e p r i v e d o f food f o r 5 o r 19 h o u r s — The d o se e f f e c t i s s i g n i f i c a n t ( p < .05) a t e ach m easurement p e r i o d ; t h e d e p r i v a t i o n e f f e c t i s s i g n i f i c a n t a t 10 m in u t e s and a l l s u c c e e d i n g measurement p e r i o d s .
' ' 11p r e s e n t e d i n T a b l e 1 . The 19 h o u r g roup i n g e s t e d more
t h a n t h e 5 h o u r g ro u p b u t t h e d i f f e r e n c e was n o t s t a t i s -
t i c a 1l y s i g n i f l e a n t , F (1 , 1 8 ) = . 7 8 . The d o s e e f f e c t was
s i g n i f i c a n t d u r i n g t h e r e c o v e r y p e r i o d , F ( 2 , 3 6 )—9 .99 ,
p<;.Obl, w i t h a n i m a l s r e c e . i v i n g t h e , h i g h e s t d o s e i n g e s t i n g
t h e g r e a t e s t a m o u n t .
. In s p i t e o f t h e i n c r e a s e d i n t a k e o f t h e CCK
t r e a t e d a n i m a l s d u r i n g t h e r e c o v e r y p e r i o d , t h e t o t a l
i n t a k e , c o m b in in g t h e am oun ts i n g e s t e d d u r i n g t h e 60
m i n u t e t e s t i n g p e r i o d and t h e 15 m i n u t e r e c o v e r y p e r i o d
( s e e T a b l e 1 ) , s t i l l r e v e a l e d t h e d o s e e f f e c t , F ( 2 . 3 6 ) =
4 . 7 9 , p < , 025 , and t h e d e p r i v a t i o n e f f e c t , F ( l , 1 8 ) = 1 0 .4 ,
p,<vQ05. A g a in , t h e 19 h o u r a n i m a l s consumed more t h a n
t h e 5 h o u r a n i m a l s and t h e CCK in d u c e d s u p p r e s s i o n o f
i n t a k e was g r e a t e r t h e h i g h e r t h e d o s e a d m i n i s t e r e d . At
no t i m e w e re any i n t e r a c t i o n s e v i d e n t i n t h e i n t a k e d a t a .
The a p p r o x i m a t e t i m e o f t h e o c c u r r e n c e o f s a t i e t y
was e s t i m a t e d f o r e a c h a n i m a l . The " o n s e t o f s a t i e t y "
was a r b i t r a r i l y d e f i n e d a s t h e f i r s t 2 m i n u t e m e a s u r e
ment p e r i o d w h ic h i n i t i a t e d two c o n s e c u t i v e 2 minute ,
m easu rem en t p e r i o d s o f an i n c r e a s e o f l e s s t h a n 1 ml in
c o n s u m p t i o n . V a lu e s f o r t h e o n s e t o f s a t i e t y f o r t h e
5 hour, d e p r i v e d a n i m a l s w e re 8 . 4 , 7 . 2 , and 5 . 4 m i n u t e s ,
r e s p e c t i v e l y , f o r t h e c o n t r o l , 15 U /kg , and 40 U/kg
T a b l e 1 . Mean l i q u i d d i e t i n t a k e (ml) d u r i n g t h e 15 m i n u t e r e c o v e r y p e r i o d and t o t a l mean l i q u i d d i e t i n t a k e , c o m b in in g am ounts i n g e s t e d d u r i n g t h e 60 m in u t e t e s t i n g p e r i o d and t h e 15 m i n u t e r e c o v e r y p e r i o d .
R e c o v e ry T o t a l
Dos e 5 h o u r s 19 h o u r s 5 h o u r s 19 h o u r s
c o n t r o l 3 . 0 1 2 .7 9 1 5 .3 4 2 3 .9 8
1 5 ' U/kg 4 .0 5 5 .96 1 3 .4 2 2 0 .4 0
40 U/kg 5 .5 2 • 8 . 4 6 1 1 .8 5 19 .36
13
g r o u p s . V a lu e s f o r t h e 19 h o u r d e p r i v e d a n i m a l s w e re
1 3 . 8 , 1 0 . 2 , and 7 . 4 m i n u t e s , r e s p e c t i v e l y , f o r t h e
c o n t r o l , 15 U /kg , and 40 U /k g . An 8 2 0 ( ^ 2^63 a n a l y s i s
o f v a r i a n c e i n d i c a t e d s i g n i f i c a n t d i f f e r e n c e s , d u e t o ,
d o s e , $’(2 , 3 6 ) = 1 5 .2 6 , p < .0 0 1 , and d e p r i v a t i o n l e v e l s ,
F ( 1 , 18)ss l2 .1 3 , p< .005 . A g a in , no i n t e r a c t i o n
was p r e s e n t
Mean body w e i g h t s o f t h e a n i m a l s a t t h e b e g i n n i n g
o f t h e e x p e r i m e n t (day 1 ) , t r a i n i n g (d a y s 2 - 10 ) , , h a b i t
u a t i o n t o t h e r e s p e c t i v e d e p r i v a t i o n s c h e d u l e s (d a y s 11-
1 5 ) , t e s t i n g (d a y s 1 6 -2 1 ) and r e c o v e r y (d a y s 22 and 23)
a r e p r e s e n t e d in F i g u r e 2 . The mean: body w e i g h t c u r v e s
o f t h e 5 h o u r and 19 h o u r g r o u p s a r e a p p r o x i m a t e l y p a r
a l l e l t h r o u g h o u t t h e h a b i t u a t i o n and t e s t i n g p e r i o d s .
In s p i t e o f t h e d e p r i v a t i o n s c h e d u l e s b o t h g r o u p s o f
a n i m a l s e x h i b i t e d s t e a d y w e i g h t g a i n s . The 19 h o u r
a n i m a l s m a i n t a i n e d t h e i r body w e i g h t s a t a p p r o x i m a t e l y
94% w h i l e t h e 5 h o u r a n i m a l s d i d n o t a p p e a r t o s u s t a i n
any w e i g h t l o s s .
MEA
N BO
DY
WEI
GHT
S (g
ram
s)
4 2 0
4 0 0
3 8 0
3 6 0
3 4 0
3 2 0 h
3 0 0
o 5 hr. + 19 hr.
o -
Training ^-Habituation^
I I 1 I I I I I L
— Testing----- ► ■•Recovery*
J I I I l I l I i19 21 2 3
F i g u r e 2 . Mean body w e i g h t s t h r o u g h o u t E x per im en t 1: t o 5 hour o r 19 hour d e p r i v a t i o n g r o u p s .
9 II 13 15 17
DAYS OF EXPERIMENT I
The a n im a l s a r e a s s i g n e d
EXPERIMENT 2
Method
S u b j e c t s
The s u b j e c t s w e re 18 a d u l t m a le H ol tzm an r a t s
w h ic h had p a r t i c i p a t e d i n E x p e r im e n t 1 and w h ic h w e re
h o u se d and m a i n t a i n e d a s d e s c r i b e d e a r l i e r . At t h e b e
g i n n i n g o f E x p e r im e n t 2 t h e mean body w e i g h t was 458
g r a m s . The d r i n k i n g t u b e s and m ov ab le arm p r e v i o u s l y
d e s c r i b e d w e re u se d f o r t e s t i n g and t r a i n i n g i n
E x p e r im e n t 2 .
P r o c e d u r e
The a n i m a l s w e re t r a i n e d f o r 5 d a y s t o consume
from 33% t o 50% o f t h e i r n u t r i t i o n a l r e q u i r e m e n t s i n t h e
form o f l i q u i d d i e t i n t h e same manner a s i n E x p e r im e n t
1. D r i n k i n g t u b e s w e re c l i p p e d t o t h e a n i m a l ’s c a g e
d u r i n g t h e f i r s t 4 d a y s o f t r a i n i n g and a t t a c h e d t o t h e
m ovab le arm d u r i n g t h e . f i n a l day o f t r a i n i n g . A f t e r t h e
f i f t h t r a i n i n g s e s s i o n s o l i d fo o d was a v a i l a b l e c o n t i n u
o u s l y f o r 24 h o u r s .
The a n i m a l s w e re d i v i d e d i n t o h i g h and low c o n - .
s u m p t io n g r o u p s a c c o r d i n g t o t h e mean l i q u i d d i e t i n t a k e
16
f o r t h e l a s t 5 d a y s o f t h e 10 day t r a i n i n g s e s s i o n in
E x p e r im e n t 1 . The a n i m a l s in e a c h c o n s u m p t io n group
w e r e ran d o m ly a s s i g n e d t o t h e t h r e e e x p e r i m e n t a l g ro u p s
w h ic h r e c e i v e d 0 U /kg , 40 U /kg , o r 80 U/kg o f t h e C-
t e r m i n a l o c t a p e p t i d e o f CCK.
A f t e r 48 h o u r s o f d e p r i v a t i o n t h e a n i m a l s w e re
i n j e c t e d i n t r a p e r i t o n e a l l y w i t h a p p r o x i m a t e l y 1 cc o f
t h e a p p r o p r i a t e d o s e o f t h e o c t a p e p t i d e (SQ 19844,
S q u ib b and Sons , I n c . ) d i s s o l v e d in no rm al s a l i n e . The
l i q u i d d i e t was p r e s e n t e d t o t h e a n i m a l s 5 m i n u t e s
l a t e r by means o f t h e m o vab le arm and i n t a k e was re-?
c o r d e d e v e r y 2 m i n u t e s f o r 30 m in u t e s . F i n a l i n t a k e
was r e c o r d e d a t 60 m i n u t e s and t h e l i q u i d d i e t was r e -
m oved . W ater was p r e s e n t c o n t i n u o u s l y d u r i n g t e s t i n g
e x c e p t when t h e l i q u i d d i e t was a v a i l a b l e t o t h e a n i
m a ls . T r a i n i n g and t e s t i n g w e r e s t a g g e r e d s u c h t h a t
o n l y t h r e e a n i m a l s , one from e a c h d o s e c o n d i t i o n , w e re
t e s t e d e a c h d a y .
R e s u l t s
D u r in g t h e 48 h o u r s o f d e p r i v a t i o n , t h e a n i m a l s ’
body w e i g h t s w e r e r e d u c e d by a p p r o x i m a t e l y 11%. Cumu
l a t i v e mean l i q u i d d i e t i n t a k e a t e a c h m ea su rem en t p e
r i o d was a n a l y z e d w i t h an S^gCAg) a n a l y s i s o f v a r i a n c e
(w h e re A i s t h e be tw een s u b j e c t s d o s e v a r i a b l e ) . The
17.
a r e r e p r e s e n t e d in F i g u r e 3, w h ic h i n d i c a t e s t h e cumu
l a t i v e mean l i q u i d d i e t i n t a k e f o r e a c h d o s e l e v e l d u r
in g t h e t e s t i n g p e r i o d . As i n d i c a t e d , i n t a k e was
s i g n i f i c a n t l y ( p < .0 5 ) s u p p r e s s e d by t h e CCK o c t a p e p t i d e
a t 8 m i n u t e s and a l l s u c c e e d i n g m easu rem en t p e r i o d s .
The h i g h e r t h e d o s e o f t h e o c t a p e p t i d e , t h e g r e a t e r was
t h e s u p p r e s s i o n i n i n t a k e ; 40 U/kg s u p p r e s s e d i n t a k e by "
a p p r o x i m a t e l y 48% and 80 U/kg s u p p r e s s e d i n t a k e by a b o u t
72%. By t h e end o f t h e 60 m i n u t e t e s t i n g p e r i o d mean
i n t a k e s f o r a l l g r o u p s had c h an g e d by l e s s t h a n 2 ml
from t h e 30. m i n u t e i n t a k e s and t h e s i g n i f i c a n t d i f f e r
e n c e s n o t e d a b o v e r e m a i n e d . A t no t i m e w e r e any i n t e r
a c t i o n s e v i d e n t i n t h e i n t a k e d a t a .
The mean o n s e t o f s a t i e t y was 1 1 . 3 , 6 . 7 , and 4 . 3
m i n u t e s r e s p e c t i v e l y , f o r t h e c o n t r o l , 40 U /kg , and
80 U/kg g r o u p s . An 8 %gOAg) a n a l y s i s o f v a r i a n c e i n d i
c a t e d t h a t t h e d i f f e r e n c e s a r e s i g n i f i c a n t , F ( 2 , 1 5 ) =
1 3 . 3 , P 4 . 0 0 1 .
CU
MU
LATI
VE
LIQ
UID
DIET
IN
TAKE
(m
l) 20 -e 0 U/kg o 4 0 U/kg ^ 80 U/kg24
20
16
12
8
4
20 22
INTAKE T IM E (minutes)
F i g u r e 3 . Mean c u m u l a t i v e i n t a k e o f l i q u i d d i e t a f t e r i n j e c t i o n o f 0 ( c o n t r o l ) , 40, o r BO Ivy dog u n i t s / k g o f t h e C - t e r m i n a l o c t a p e p t i d e o f CCK i n t o a n i m a l s d e p r i v e d o f food f o r 43 h o u r s — The means a r e s i g n i f i c a n t l y d i f f e r e n t ( p < .0 5 ) a t 3 m in u te s and a l l s u c c e e d i n g measurement p e r i o d s
DISCUSSION
The S y n t h e t i c . C - t e r m i n a l o c t a p e p t i d e o f CCK p r o
d u ced a d o s e r e l a t e d s u p p r e s s i o n o f l i q u i d d i e t i n t a k e a t
a l l d e p r i v a t i o n l e v e l s t e s t e d ( r a n g i n g from a n e a r no rm a l
i n t e r m e a l i n t e r v a l t o a r e l a t i v e l y s e v e r e d e g r e e o f n u t r i -
t i o r t a l d e f i c i t ) up t o 105 m i n u t e s a f t e r i n j e c t i o n . The
" o n s e t o f s a t i e t y " was a l s o q u i c k e n e d i n a d o s e r e l a t e d
f a s h i o n by t h e exogenous CCK. A l t h o u g h t h e CCK " s a t i e t y
e f f e c t " h a s been w i d e l y d ocum en ted ( s e e r e v i e w by M u e l l e r
and H s ia o n . d . ) , t h i s i s t h e f i r s t d e m o n s t r a t i o n t h a t a
g i v e n d o s e o f CCK c o n s i s t e n t l y s u p p r e s s e d i n t a k e a c r o s s
w id e v a r i a t i o n s i n t h e s t a t e o f n u t r i t i o n a l d e f i c i t o f
t h e o r g a n i s m ( t h r o u g h 48 h o u r s o f food d e p r i v a t i o n — an
a p p r o x i m a t e w e i g h t l o s s o f 11%) and t h a t t h i s s u p p r e s s i o n
is . b e s t d e s c r i b e d by a c o n s t a n t p e r c e n t . F i f t e e n U/kg
s u p p r e s s e d i n t a k e by a p p r o x i m a t e l y 30% a t b o t h 5 and 19
h o u r s d e p r i v a t i o n ; 40 U/kg s u p p r e s s e d i n t a k e by a p p r o x
i m a t e l y 50% a t 5, 19, and 48 h o u r s d e p r i v a t i o n . Thus
CCK i s c l e a r l y e q u a l l y e f f e c t i v e a t s u p p r e s s i n g food
i n t a k e from 5 t o 48 h o u r s o f fo o d d e p r i v a t i o n .
T h e s e r e s u l t s may i n d i c a t e s o m e th in g a b o u t t h e
n a t u r e o f t h e CCK s a t i e t y e f f e c t . F o r exam ple , t h e
f i n d i n g t h a t CCK s u p p r e s s e s i n t a k e by a c o n s t a n t p e r c e n t
r a t h e r t h a n a t a c e r t a i n t i m e , may h a v e f u n c t i o n a l s i g
n i f i c a n c e . I f a g i v e n d o s e o f CCK had s u p p r e s s e d i n t a k e
a t a c o n s t a n t t i m e r e g a r d l e s s o f t h e s t a t e o f n u t r i t i o n a l
d e f i c i t o f t h e o r g a n i s m , t h e m ere p r e s e n c e o f a g iv e n
d o s e o f CCK w ould be s u f f i c i e n t e x p l a n a t i o n f o r t h e s u p
p r e s s i o n . As i n d i c a t e d in E x p e r i m e n t s 1 and 2 , however ,
t h e o n s e t o f s a t i e t y v a r i e d c o n s i d e r a b l y a s a r e s u l t o f
b o th d o s e and d e p r i v a t i o n . Only t h e p e r c e n t s u p p r e s s i o n
o f i n t a k e d e s c r i b e d t h e d a t a a c r o s s a l l d o s e and d e p r i
v a t i o n l e v e l s t e s t e d . Thus t h e p h y s i o l o g i c a l mechanism
o f t h e s u p p r e s s i o n o f i n t a k e m u s t . i n y o l v e c h a n g e s due t o
b o t h d o s e and d e p r i v a t i o n .
The f a i l u r e o f CCK t o s u p p r e s s i n t a k e a t 92
h o u r s d e p r i v a t i o n (S m i th and G ibbs 1975) i s a l s o im por
t a n t . A s i m p l e e x p l a n a t i o n would h a v e been t h a t CCK
becomes s l i g h t l y l e s s e f f e c t i v e a t s u p p r e s s i n g i n t a k e a s
d e p r i v a t i o n i n c r e a s e d b u t t h i s h y p o t h e s i s i s no l o n g e r
t e n a b l e . A p p a r a n t l y , CCK s u p p r e s s e s food i n t a k e in a
c o n s i s t e n t manner t o 48 h o u r s d e p r i v a t i o n and som etim e
b e f o r e 92 h o u r s d e p r i v a t i o n i s " o v e r r i d d e n " by some
o t h e r s a t i e t y m echan ism . Such a s h i f t i n l o c u s o f c o n
t r o l w ould r e q u i r e a p h y s i o l o g i c a l c h a n g e o c c u r r i n g
be tw een 48 and 92 h o u r s d e p r i v a t i o n w h ic h c o u l d t r i g g e r
a s e c o n d s a t i e t y m echanism , a " f a i l - s a f e " m echan ism .
T r a n s i t i o n s f rom u t i l i z a t i o n o f b lo o d g l u c o s e in t h e
f r e e f e e d i n g a n im a l t o t h e u t i l i z a t i o n o f body f a t and
f i n a l l y body p r o t e i n d u r i n g s e v e r e d e p r i v a t i o n ( B o l l e s
1967) may p r o v i d e j u s t s u c h a p h y s i o l o g i c a l s i g n a l „
The s h i f t i n l o c u s o f c o n t r o l o f m eal s i z e i s
n o t w i t h o u t p r e c e d e n t . A n e u r a l s h o r t t e r m s a t i e t y
mechanism h a s r e c e n t l y been d e m o n s t r a t e d w h ic h i s a c t i -
v a t e d by g l u c o s e and m e d i a t e d by t h e v a g u s n e r v e . . T h i s
mechanism i s d u o d e n a l l y b a se d u n d e r f r e e f e e d i n g c o n d i
t i o n s , b u t h e p a t i c p o r t a l l y b a s e d a f t e r 22 h o u r s o f food
d e p r i v a t i o n ( N o v i n , S a n d e r s o n , and V a n d e r w e e le 1 9 7 4 ) .
S i m i l a r l y , d u r i n g s e v e r e d e p r i v a t i o n t h e CCK mechanism
may be r e p l a c e d by some o t h e r s a t i e t y f a c t o r - - a “ f a 11-
s a f e n m e c h a n i sm .
The CCK s a t i e t y e f f e c t was e v i d e n t up t o 105
m i n u t e s a f t e r i n j e c t i o n ; t h e t o t a l i n t a k e in E x p e r im e n t
1, c o m b in in g t h e 60 m in u t e t e s t i n g i n t a k e w i t h t h e 15
m in u t e r e c o v e r y i n t a k e , s t i l l r e v e a l e d t h e d o s e and
d e p r i v a t i o n e f f e c t . T h i s seems r e m a r k a b l e i n v iew o f
t h e s h o r t h a l f - l i f e o f t h e CCK b c t a p e p t i d e , w h ic h i s l e s s
t h a n 16 m i n u t e s ( B e r r y and F lo w e r 1971; M u e l l e r and
H s ia o n . d . ) . A p p a r a n t l y t h e e x p e r i m e n t a l l y i n t r o d u c e d
CCK s u p p r e s s e d food i n t a k e p r e m a t u r e l y , b u t n o t b e f o r e
s u f f i c i e n t l i q u i d d i e t had been consumed t o s t i m u l a t e
22
t h e r e l e a s e o f e ndogenous CCK, w h ic h s u p p r e s s e d i n t a k e
t h r o u g h o u t t h e r e m a i n d e r o f t h e t e s t i n g p e r i o d .
The r e s u l t s o f t h e s e e x p e r i m e n t s a l s o p r o v i d e
f u r t h e r e v i d e n c e t h a t CCK i s a n a t u r a l s a t i e t y f a c t o r .
C r i t e r i o n e ) , t h a t CCK s h o u l d s u p p r e s s food i n t a k e i n a
c o n s i s t e n t m anner a c r o s s d e p r i v a t i o n l e v e l s h a s r e c e i v e d
p a r t i a l s u p p o r t . A l t h o u g h CCK s u p p r e s s e d i n t a k e c o n s i s
t e n t l y a c r o s s d e p r i v a t i o n l e v e l s , w h e t h e r i t s a c t i o n s
a r e a d a p t i v e i s a n o t h e r q u e s t i o n . The f a i l u r e o f CCK
t o s u p p r e s s i n t a k e a t 92 h o u r s d e p r i v a t i o n seems a d a p
t i v e , and on t h i s b a s i s a s i m i l a r f a i l u r e was e x p e c t e d
a t 48 h o u r s d e p r i v a t i o n . An 11% w e i g h t l o s s i s f a r from
■ t h e 43% a t w h ic h d e a t h a c e u r s (C am pb e l l and W i l l i a m s
1961) and c a n n o t t h e r e f o r e be c o n s i d e r e d l i f e t h r e a t
e n i n g , b u t i t i s a l o s s h i g h l y u n l i k e l y t o be e x p e r i
enced by a r a t i n i t s n a t u r a l e n v i r o n m e n t . The q u e s t i o n
o f a d a p t i b i l i t y o f a CCK i n d u c e d s u p p r e s s i o n o f i n t a k e
a f t e r 48 h o u r s o f foo d d e p r i v a t i o n i s u n c l e a r .
C r i t e r i o n g ) , t h a t s a t i e t y i n d u c e d by CCK s h o u l d
be b e h a v i o r a l l y s i m i l a r t o m eal i n d u c e d s a t i e t y , ha s a l s o
been s u p p o r t e d . In E x p e r im e n t 1 t h e 5 h o u r d e p r i v a t i o n
g roup d i d n o t a p p e a r t o s u s t a i n any w e i g h t l o s s and can
t h e r e f o r e be c o n s i d e r e d t o a p p r o x i m a t e a n o rm a l f e e d i n g
s i t u a t i o n . . N o te t h a t t h e p a t t e r n o f i n t a k e o f t h i s
g ro u p ( s e e F i g u r e 1 ) i s n e a r l y i d e n t i c a l t o t h a t o f t h e
19 h ou r 15 U/kg g r o u p . Thus t h e 15 U/kg o f t h e CCK
o c t a p e p t i d e seem t o h a v e f u n c t i o n a l l y l o w e re d t h e s t a t e
o f ’ d e p r i v a t i o n from 19 h o u r s t o 5 h o u r s ( o r a f r e e
f e e d i n g s i t u a t i o n ) . The s i m i l a r i t y o f i n t a k e p a t t e r n s
i n t h e c o n t r o l and e x p e r i m e n t a l g r o u p s seem t o p r o v i d e
s u p p o r t f o r t h e h y p o t h e s i s t h a t CCK i s a n a t u r a l
s a t i e t y f a c t o r .
The o n s e t o f s a t i e t y a s d e f i n e d i n t h e c u r r e n t
s t u d y was a f a i r l y c r u d e m e a s u r e : t h e f i r s t 2 m in u t e
m easu rem en t p e r i o d w h ic h i n i t i a t e d two c o n s e c u t i v e 2
m i n u t e m easu rem en t p e r i o d s d u r i n g w h ich an i n c r e a s e in
i n t a k e o f l e s s t h a n 1 ml o c c u r r e d . How e v e r , even t h i s
c r u d e m e a s u r e was s e n s i t i v e t o d i f f e r e n c e s i n d o s e and
d e p r i v a t i o n . In t h e f u t u r e more e x a c t e s t i m a t e s o f t h e
t i m e c o u r s e o f s a t i e t y may be u s e f u l t o i n f e r m ore a b o u t
t h e n a t u r e o f t h e CCK s a t i e t y e f f e c t .
The c o n t r o l i n t a k e o f t h e 48 h o u r d e p r i v e d a n i
m a ls i n E x p e r im e n t 2 was l e s s t h a n t h e c o n t r o l i n t a k e o f
t h e 19 h o u r d e p r i v e d a n i m a l s in E x p e r im e n t 1 . One p o s
s i b l e e x p l a n a t i o n i s t h e t i m e l a p s e be tw een t h e two
e x p e r i m e n t s d u r i n g w h ich no l i q u i d d i e t was a v a i l a b l e .
The a n i m a l s r e c e i v e d 15 da y s o f h a b i t u a t i o n t o t h e
l i q u i d d i e t in E x p e r im e n t 1 i n C o n t r a s t t o 5 d a y s o f
h a b i t u a t i o n i n E x p e r im e n t 2 . A n o t h e r p o s s i b l e e x p l a - :
n a t i o n i s t h a t 48 h o u r s d e p r i v a t i o n may h a v e been
- 2 4
s u f f i c i e n t t o c a u s e a d e g r e e o f p o s t - s t a r v a t io n a n o r e x i a ,
r e d u c e d f e e d i n g f o l l o w i n g a f a s t (H a m i l to n 1 9 6 9 ) .
In summary, o v e r a w id e r a n g e o f n u t r i t i o n a l
d e f i c i t a g i v e n d o s e o f CCK p r o d u c e s a c o n s i s t e n t s u p
p r e s s ion o f i n t a k e (w h ich can be b e s t d e s c r i b e d a s a
c o n s t a n t p e r c e n t ) f o r a l e n g t h o f t i m e f a r beyond t h e
h a l f - l i f e o f CCK i t s e l f . A f t e r more s e v e r e d e p r i v a t i o n ,
a " f a i l - s a f e " s a t i e t y mechanism may o v e r r i d e t h e CCK
s a t i e t y e f f e c t . T h e s e c o n c l u s i o n s w e re b a se d upon group
d a t a and t h e i r a p p l i c a b i l i t y t o t h e i n d i v i d u a l i s a
s u b j e c t f o r f u r t h e r r e s e a r c h . In view o f t h e t h e o r e t
i c a l i m p o r t a n c e o f t h e e f f e c t s o f CCK a t 92 h o u r s d e p r i
v a t i o n , f u r t h e r r e s e a r c h d u r i n g , s e v e r e d e p r i v a t i o n a l s o
seems w a r r a n t e d .
r e f e r e n c e s
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25
26
G i b b s , J . , Young, R. C . , and S m i th , G. P . C h o l e c y s t o k i n i ne l i c i t s s a t i e t y in r a t s w i t h open g a s t r i c f i s t u l a s . N a t u r e , 1973b, 245 , 3 2 3 - 3 2 5 .
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