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Naltrexone blocks the post-shock increase of ethanol consumption
Life Sclences, Vol. 38, pp. 841-847 Printed in the U.S.A.
NALTREXONE
BLOCKS
Joseph
THE
POST-SHOCK
R. V o l p z c e l l I ,
Pergamon Pres
INCREASE
M a r k A.
Davis,
OF E T H A N O L Jeffery
CONSUMPTION
E. Olgzn
D e p a r t m e n t s of P s y c h o l o g y and P s y c h i a t r y U n l v e r s z t y of P e n n s y l v a n i a P h i l a d e l p h i a , P e n n s y l v a n i a 19104 (Received zn final form December ii, 1985) Summary
A t t e n t i o n has r e c e n t l y focused on the p o s s i b i l i t y of an i n t e r a c t i o n b e t w e e n ethanol and the e n d o r p h i n system. In this study the opiate b l o c k e r n a l t r e x o n e p r e v e n t s the e x p e c t e d p o s t - s h o c k i n c r e a s e of ethanol c o n s u m p t i o n . This p r o v i d e s f u r t h e r e v i d e n c e that e n d o g e n o u s o p i a t e s are i n v o l v e d in the v o l u n t a r y d r l n k z n g of ethanol in rats. A link b e t w e e n ethanol and the e n d o g e n o u s o p i a t e system is d e m o n s t r a t e d by recent b e h a v i o r a l and p h a r m a c o l o g i c a l data. (i). M o r p h i n e a d m z n l s t r a t z o n s u p p r e s s e s v o l u n t a r y ethanol d r l n k z n g zn rats (2) and hamsters (3). I n t r a v e n t r l c u l a r z n ] e c t l o n s of the e n d o g e n o u s opiate, M e t - e n k e p h a l z n , also reduces ethanol c o n s u m p t i o n in rats (4). During m o r p h i n e w i t h d r a w a l rats will d r a m a t i c a l l y increase ethanol c o n s u m p t i o n (5). F u r t h e r m o r e , m i c e b r e d to p r e f e r ethanol had lower levels of w h o l e brain M e t - e n k e p h a l z n than rats that a v o i d e d ethanol d r i n k i n g (6). T h e s e results suggest an inverse r e l a t i o n s h i p b e t w e e n ethanol p r e f e r e n c e and e n d o r p h z n s t z m u l a t l o n . When e n d o r p h z n a c t i v i t y Is s t i m u l a t e d by e x o g e n o u s or e n d o g e n o u s opiates, v o l u n t a r y ethanol c o n s u m p t l o n d e c r e a s e s and when a d e f i c i e n c y in opiate s t i m u l a t i o n occurs (I.e. opiate w i t h d r a w a l ) ethanol d r l n k l n g increases. Three m e c h a n i s m s have been s u g g e s t e d to a c c o u n t for the a p p a r e n t a g o n z s t l c e f f e c t s of ethanol on the e n d o r p h z n system. The first m e c h a n i s m is s u g g e s t e d by B l u m and hls a s s o c i a t e s (i). Noting that the c o n d e n s a t i o n p r o d u c t s of ethanol and d o p a m z n e form t e t r a z s o q u i n o l z n e s and that these c o m p o u n d s can d i r e c t l y s t i m u l a t e o p i a t e r e c e p t o r s , they suggest that a similar process may occur zn vzvo with p h y s i o l o g i c a l doses of ethanol. A second p o s s i b l e m e c h a n i s m is d e m o n s t r a t e d by the o b s e r v a t i o n that e n d o r p h z n b i n d i n g zs e n h a n c e d by p h y s l o l o g z c a l l y a t t a i n a b l e d o s e s of ethanol (7). Thus ethanol may d i r e c t l y a f f e c t receptor s e n s i t i v i t y . Finally, the third m e c h a n i s m Is that ethanol s t i m u l a t e s the r e l e a s e of e n d o g e n o u s o p i a t e s (8). The TIQ h y p o t h e s i s receives support from o b s e r v a t i o n s that p y r o g a l l o l p r e t r e a t e d rats given alcohol will form s a l s o l z n o l (a TIQ) in brain tlssue (9). In a d d i t i o n f o l l o w i n g z n t r a v e n t r l c u l a r 0024-3205/86 $3.00 + .00 Copyrlght (c) 1986 Pergamon Press Ltd.
842
Naltrexone and Ethanol Consumptzon
Vol. 38, No
9, ]986
l n ] e c t l o n s of T I Q ' s rats will d r a m a t i c a l l y i n c r e a s e a l c o h o l d r i n k i n g (i0) and this e f f e c t is b l o c k e d by n a l o x o n e (ii). The s e c o n d m e c h a n i s m , that a l c o h o l d i r e c t l y a f f e c t s the b i n d i n g of o p i a t e r e c e p t o r s comes f r o m s t u d i e s that d e m o n s t r a t e a l c o h o l has d i r e c t e f f e c t s on in vitro p r e p a r a t l o n s of rat brain. S p e c i f i c a l l y at low c o n c e n t r a t i o n s , a l c o h o l s t i m u l a t e s the mu (morphine) r e c e p t o r but a l c o h o l i n h l b l t s the d e l t a r e c e p t o r in a d o s e r e s p o n s e f a s h i o n (12). The e f f e c t s of a l c o h o l on o p i a t e r e c e p t o r s c h a n g e s as a f u n c t i o n of time. A c u t e a l c o h o l e x p o s u r e i n h i b i t s o p i a t e b l n d l n g , w h e r e a s c h r o n i c (four days) e x p o s u r e i n c r e a s e s o p i a t e r e c e p t o r b i n d i n g (13,14). E m p i r i c a l s u p p o r t for the t h i r d m e c h a n i s m was d e m o n s t r a t e d w h e n i n ] e c t l o n s of e t h a n o l s t l m u l a t e d i n c r e a s e s in b l o o d B e t a - e n d o r p h l n levels In rats (8). In n o n a l c o h o l i c human s u b 3 e c t s , a c u t e e t h a n o l i n g e s t i o n c a u s e s a 400% i n c r e a s e in p l a s m a b e t a - e n d o r p h l n levels (14). The e f f e c t s of e t h a n o l on c e n t r a l o p i a t e s t i m u l a t i o n d e p e n d on the d u r a t i o n of e t h a n o l e x p o s u r e and the p a r t i c u l a r o p i a t e s t u d i e d . A c u t e e t h a n o l e x p o s u r e i n c r e a s e s m e t - e n k e p h a l l n and b e t a - e n d o r p h l n levels in the h y p o t h a l a m u s (15,16) w h e r e a s d y n o r p h l n levels did not change. F o l l o w i n g c h r o n i c e t h a n o l e x p o s u r e in rats m e t - e n k e p h a l l n , b e t a - e n d o r p h l n and d y n o r p h l n levels all d e c r e a s e d in the h y p o t h a l a m u s (15,16). Human a l c o h o l i c s also have d e p r e s s e d b e t a - e n d o r p h l n l e v e l s in the CSF w h e n a s s e s s e d 3 to i0 days after a l c o h o l d e t o x (17). If e t h a n o l i n t e r a c t s w i t h e n d o g e n o u s o p l a t e s , then opiate b l o c k e r s such as n a l o x o n e and n a l t r e x o n e s h o u l d a t t e n u a t e e t h a n o l ' s p h a r m a c o l o g i c a l e f f e c t s . Several r e c e n t o b s e r v a t i o n s s u p p o r t this p r e d i c t i o n . N a l o x o n e i n t e r f e r e s w i t h e t h a n o l e n h a n c e m e n t of l a t e r a l h y p o t h a l a m l c s t i m u l a t i o n (18), d e c r e a s e s e t h a n o l s t i m u l a t e d m o t o r a c t l v l t y in mice (19), i n c r e a s e s the LD 50 of e t h a n o l tn m i c e (20), d e c r e a s e s the length of e t h a n o l i n d u c e d sleep (20), and m a y a t t e n u a t e e t h a n o l w i t h d r a w a l s y m p t o m s in m i c e (21) and rats (22). Bar press r e s p o n d i n g for e t h a n o l in m o n k e y s is r e d u c e d by n a l t r e x o n e (23) and bar press r e s p o n d i n g in rats is reduced by n a l o x o n e (24). This d e m o n s t r a t e s that the r e i n f o r c i n g a s p e c t s of e t h a n o l may a l s o be r e d u c e d by o p i a t e b l o c k e r s . In the p r e s e n t study, the e f f e c t s of n a l t r e x o n e on the r e l n f o r c l n g p r o p e r t i e s of e t h a n o l is f u r t h e r a s s e s s e d . I n c r e a s e s in e t h a n o l self s e l e c t i o n has b e e n o b s e r v e d in rats f o l l o w l n g e x p e r i e n c e with i n e s c a p a b l e foot s h o c k (25). If o r g a n i s m s d r i n k e t h a n o l b e c a u s e of e t h a n o l ' s e f f e c t on e n d o r p h l n s t l m u l a t l o n then the p o s t - s h o c k i n c r e a s e in e t h a n o l d r l n k l n g will be attenuated with naltrexone. Methods S u b j e c t s . S u b 3 e c t s w e r e 32 m a l e S p r a g u e - D a w l e y rats o b t a l n e d from H o l t z m a n Co., M a d i s o n , W i s c o n s l n . The rats w e r e 9 0 - 1 0 0 days old at the start of the e x p e r l m e n t and w e r e i n d l v l d u a l l y housed. All e x p e r i m e n t a l m a n i p u l a t i o n s w e r e c o n d u c t e d d u r i n g the 14 hr. light p a r t of the 24 hr. d a i l y cycle. T h r o u g h o u t the e x p e r i m e n t s u b ] e c t s had free a c c e s s to f o o d and both 5% (v/v) e t h a n o l and w a t e r in the home cage.
Vol
38, No. 9, 1986
Naltrexone and Ethanol Consumptzon
843
A p p a r a t u s a n d M a t e r i a l s . F l u l d was a v a z l a b l e to rats zn b o t t l e s t h a t hung on the front of z n d l v l d u a l c a g e s such that the d r z n k l n g spouts p r o t r u d e d a b o u t 4 cm. into the c a g e s and a b o u t 5 cm. from the floor of the cages. I n e s c a p a b l e shock was d e l z v e r e d zn boxes that m e a s u r e d 30 cm. long, 20 cm. wide, and 20 cm. hzgh. The boxes w e r e c o n s t r u c t e d of two a c r y l z c p l a s t z c sldes ( l e n g t h w z s e ) a n d two a l u m z n u m ends. The floor was c o n s t r u c t e d of .32 cm. d z a m e t e r s t a i n l e s s steel bars, 1.9 cm. apart. A G r a s o n - S t a d l e r shock g e n e r a t o r (model E6070B) s u p p l z e d a 0.8 ma. s c r a m b l e d s h o c k to the grzd floor and m e t a l l z c szdes of the boxes. N a l t r e x o n e was d i s s o l v e d zn a 28% s o r b z t o l s o l u t i o n zn d l s t 1 1 1 e d water. P l a c e b o c o n s z s t e d of lust the 28% sorbztol solutzon. P r o c e d u r e . A f t e r a f o u r - d a y p e r z o d zn w h z c h b a s e l z n e e t h a n o l and w a t e r c o n s u m p t l o n were d e t e r m i n e d , rats w e r e p a i r e d b a s e d on e t h a n o l p r e f e r e n c e and then r a n d o m l y a s s z g n e d to the N a l t r e x o n e or P l a c e b o group. During the next four days s u b j e c t s r e c e z v e d dally s e s s z o n s of 60, two second d u r a t i o n , z n e s c a p a b l e shocks d e l z v e r e d once a mznute. I m m e d z a t e l y after each s h o c k sesszon, s u b j e c t s w e r e r e m o v e d from the s h o c k boxes and p l a c e d in thezr home cages w e r e food, w a t e r , and e t h a n o l was a v a z l a b l e . E a c h day the fluzd b o t t l e s w e r e w e z g h e d to a s s e s s fluzd c o n s u m p t z o n d u r z n g the p r e v z o u s 24 hours. The e t h a n o l and w a t e r b o t t l e s w e r e then r e t u r n e d to the cage and r o t a t e d such that the b o t t l e on the right side d u r z n g the p r e v z o u s day was then p l a c e d on the left side of the cage. The fznal phase of the e x p e r l m e n t c o n s l s t e d of szx s h o c k - f r e e days zn which rats r e c e i v e d d a z l y s u b c u t a n e o u s z n ] e c t l o n s of i0 mg. per kg. of n a l t r e x o n e or p l a c e b o . E x c e p t for l n ] e c t z o n s , rats r e m a i n e d zn thezr home cages w h i l e fluzd c o n s u m p t z o n was m o n i t o r e d d u r z n g this p o s t - s h o c k phase. Results D u r z n g the p o s t - s h o c k phase of the e x p e r z m e n t , the P l a c e b o g r o u p d r a m a t z c a l l y z n c r e a s e d their ethanol c o n s u m p t z o n and d e c r e a s e d water c o n s u m p t i o n w h e r e a s , the N a l t r e x o n e g r o u p did not show any r e l i a b l e c h a n g e s in e t h a n o l or w a t e r c o n s u m p t z o n . T h e s e w z t h l n g r o u p s r e s u l t s are p r e s e n t e d Table I and show that the P l a c e b o g r o u p r e l i a b l y d e c r e a s e d w a t e r c o n s u m p t i o n d u r i n g the p o s t - s h o c k phase (29.0 ml. to 23.2 ml.) and n e a r l y d o u b l e d their e t h a n o l c o n s u m p t z o n (19.7 ml. to 36.2 ml.). In c o n t r a s t , the N a l t r e x o n e g r o u p d e m o n s t r a t e d small but not s t a t z s t z c a l l y r e l i a b l e , i n c r e a s e s in water (28.0 ml. to 28.5 ml.) and of e t h a n o l c o n s u m p t z o n (21.1 ml. to 25.8 ml.) d u r i n g the p o s t - s h o c k phase. As T a b l e I reveals, w h z l e n a l t r e x o n e d r a m a t z c a l l y a t t e n u a t e d e t h a n o l p r e f e r e n c e d u r z n g the p o s t - s h o c k p h a s e zt did not have an a p p r e c i a b l e e f f e c t on total fluzd c o n s u m p t z o n (59.5 ml. to 54.3 ml. n.s.). The b e t w e e n g r o u p c o m p a r z s o n s are most a p p a r a n t zn F z g u r e i. In order to c o n t r o l for l n t e r s u b j e c t v a r z a b z l z t y zn total fluld c o n s u m p t i o n and e t h a n o l p r e f e r e n c e d u r z n g the s h o c k phase, the data are p r e s e n t e d as the c h a n g e zn the p e r c e n t of fluzd d r a n k from the e t h a n o l b o t t l e d u r i n g the post shock phase, r e l a t i v e to the last two days of shock t r a i n i n g . As F z g u r e 1 reveals, the P l a c e b o g r o u p g r a d u a l l y z n c r e a s e d thezr e t h a n o l p r e f e r e n c e d u r i n g the post shock phase w h e r e a s , the N a l t r e x o n e g r o u p did not i n c r e a s e zts e t h a n o l p r e f e r e n c e .
844
Naltrexone and Ethanol Consumptlon
TABLE
Vol. 38, No. 9, 1986
I
W i t h i n - G r o u p C o m p a r l s o n s for M e a n E t h a n o l , W a t e r , a n d T o t a l F l u i d C o n s u m p t l o n (In m l . ) for P l a c e b o and Naltrexone Groups
Group
Shock
Placebo Water Ethanol Total Fluld
29.0 19.7 48.7
23.2 36.3 59.5
+2.62* -6.33** -4.52**
Naltrexone Water Ethanol Total Fluld
28.0 21.1 49.1
28.5 25.8 54.3
-i.00 -1.79 -2.54*
*
Post-shock
t(15)
p<0.05
** p< 0. 001
C 0 O.
E :23
30-
o
20-
(/) cO
H Naltrex0ne o---o Placebo
}-
0
s
s
c"
o
¢-
I0-
s s
I
,,t,,,,-
h_l
~
O-
t
C
° - -
~
C~ C 0 c-
-IO!
1-2
I
I
3-4
5-6
O
Days Post-Shock FIG i. E f f e c t s of n a l t r e x o n e on c h a n g e in m e a n c o n s u m e d f r o m the e t h a n o l b o t t l e d u r l n g
(SEM) per c e n t the p o s t - s h o c k
fluld phase.
Vol. 38, No. 9, 1986
Naltrexone and Ethanol Consumption
845
T h e s e o b s e r v a t i o n s are s t a t l s t z c a l l y r e l i a b l e . A g r o u p s x b l o c k s a n a l y s i s of v a r z a n c e reveals an o v e r a l l d i f f e r e n c e in e t h a n o l p r e f e r e n c e b e t w e e n the groups, F ( I , 3 0 ) = 5.17, p<0.05; a r e l z a b l e z n c r e a s e in e t h a n o l p r e f e r e n c e a c r o s s days, F ( 2 , 6 0 ) = 8.50, p < 0 . 0 0 1 ; and a r e l i a b l e g r o u p x blocks z n t e r a c t l o n F ( 2 , 6 0 ) = 17.78, p < 0 . 0 0 0 5 . Post hoc c o m p a r z s o n s reveal the s o u r c e of the z n t e r a c t z o n zs a c c o u n t e d for by the o b s e r v a t z o n that the P l a c e b o g r o u p r e l i a b l y i n c r e a s e d e t h a n o l a c r o s s days and the two g r o u p s r e l z a b l y d z f f e r d u r l n g the second and thzrd blocks but not on the inltzal post s h o c k block. (All p o s t - h o c s t a t z s t z c a l tests w e r e a s s e s s e d N e u m a n - K u e l l s ' p r o c e d u r e with p<0.05)
using
Discussion The r e s u l t s d e m o n s t r a t e that n a l t r e x o n e zs e f f e c t i v e in b l o c k z n g the e x p e c t e d p o s t - s h o c k z n c r e a s e zn e t h a n o l c o n s u m p t i o n . This p r o v i d e s further support to the n o t z o n that e t h a n o l i n t e r a c t s w z t h the e n d o r p h l n system. F u r t h e r m o r e , it s u g g e s t s that v o l u n t a r y e t h a n o l d r i n k i n g zn rats zs r e i n f o r c e d b e c a u s e of this i n t e r a c t z o n with o p i a t e r e c e p t o r s . T h e s e r e s u l t s also suggest a p o s s z b l e e x p l a n a t i o n for the c u r z o u s o b s e r v a t z o n that e t h a n o l c o n s u m p t z o n z n c r e a s e s f o l l o w z n g i n e s c a p a b l e shock. D u r i n g z n t e r m z t t e n t z n e s c a p a b l e s h o c k zn rats, the e n d o r p h z n s y s t e m zs s t i m u l a t e d and p e r i p h e r a l levels of B e t a - e n d o r p h z n are g r e a t l y i n c r e a s e d (26). If o r g a n i s m s adapt to high levels of b e t a - e n d o r p h i n (such as by d o w n r e c e p t o r r e g u l a t l o n ) , then d u r z n g the p o s t - s h o c k phase we w o u l d e x p e c t t h a t rats w z l l e x p e r z e n c e a r e l a t z v e d e f i c i e n c y in e n d o r p h l n s t l m u l a t z o n . If e t h a n o l d o e s s t i m u l a t e the e n d o r p h i n s y s t e m as s u g g e s t e d by r e c e n t p h a r m a c o l o g i c a l e v i d e n c e , then the p o s t - s h o c k z n c r e a s e in e t h a n o l c o n s u m p t z o n zs the rats' z n s t r u m e n t a l a t t e m p t to c o m p e n s a t e for the r e l a t z v e d e f z c l e n c y in e n d o r p h l n s t l m u l a t z o n . Thus an o p z a t e b l o c k e r such as n a l t r e x o n e w111 b l o c k the r e z n f o r c l n g e f f e c t s of e t h a n o l and c o n s e q u e n t l y the z n c r e a s e in e t h a n o l c o n s u m p t i o n t y p l c a l l y seen after shock. Thzs e x p e r z m e n t was not d e s i g n e d p r z m a r i l y to test the m e c h a n z s m by w h z c h e t h a n o l s t z m u l a t e s a c t z v l t y . However, sznce n a l t r e x o n e p r z m a r l l y b l o c k s mu rather than delta r e c e p t o r s we suggest that e t h a n o l d r z n k l n g zs r e i n f o r c e d by i n c r e a s e d a c t i v i t y mu a g o n z s t s such as b e t a - e n d o r p h i n rather than the d e l t a a g o n z s t s such as m e t - e n k e p h a l l n . F u r t h e r support that the mu r e c e p t o r is the c r z t z c a l szte for the r e l n f o r c z n g p r o p e r t i e s of e t h a n o l come f r o m s t u d i e s that show m o r p h z n e (a p r l m a r z l y mu r e c e p t o r a g o n l s t ) s u p p r e s s e s e t h a n o l d r z n k l n g (2) and m o r p h z n e w i t h d r a w a l z n c r e a s e s e t h a n o l d r z n k l n g (5). S u p p o r t that n o n - m u r e c e p t o r s are i m p o r t a n t zn the r e z n f o r c z n g e f f e c t s of e t h a n o l comes from o b s e r v a t i o n s that demonstrate that centrally administered met-enkephalln also r e d u c e s e t h a n o l c o n s u m p t z o n (4). In a d d l t z o n low d o s e n a l o x o n e t r e a t m e n t ( s u f f i c i e n t to b l o c k mu r e c e p t o r s but not n o n - m u o p i a t e r e c e p t o r s ) does not reduce e t h a n o l r e i n f o r c e d bar p r e s s z n g (23). Sznce the p r e s e n t s t u d y used a m o d e r a t e l y hzgh d o s e of n a l t r e x o n e , zt zs p o s s z b l e that n a l t r e x o n e was not s e l e c t z v e in zts mu r e c e p t o r b l o c k a d e . I n d e e d so c a l l e d "pure"
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o p i a t e a n t a g o n i s t s such as n a l o x o n e and n a l t r e x o n e may a f f e c t n e u r o t r a n s m l t t e r s other than the e n d o r p h l n s y s t e m p a r t l c u l a r l y w h e n used in hlgh doses (27). It is u n l i k e l y t h a t o p i a t e s t l m u l a t l o n is the sole r e a s o n o r g a n i s m s d r i n k e t h a n o l . This e x p e r l m e n t s u g g e s t s h o w e v e r , that one of the r e l n f o r c l n g m e c h a n l s m s in e t h a n o l d r l n k l n g i n v o l v e s c o m p e n s a t i o n for r e l a t i v e d e f l c l e n c l e s in e n d o r p h l n s t l m u l a t l o n . Acknowledgements T h l s r e s e a r c h is s u p p o r t e d in part by P u b l i c H e a l t h S e r v l c e G r a n t #MH14654 a n d V A M e d i c a l R e s e a r c h S e r v i c e funds to C.P. O ' B r l e n . The a u t h o r s t h a n k Du Pont Co. for g e n e r o u s l y s u p p l y l n g the n a l t r e x o n e used in thls research. References i. K. BLUM, M.G. H A M I L T O N AND J.E. WALLACE, A l c o h o l and O p i a t e s , ed.K, Blum, p.203, A c a d e m i c Press, N e w York (1977). 2. A.K.S. HO, R.A.C. C H E N and M.J. M O R R I S O N , A l c o h o l and Oplates_~, ed. K, Blum, A c a d e m l c Press, New Y o r k (1977). 3 J.D. S I N C L A I R , J. A T K I N S and S. W a l k e r , N a t u r e 246 4 2 5 - 4 2 7 (1973). 4 A.K.S. HO, N. ROSSI, J. Pharm. P h a r m a c o l . 34 1 1 8 - 1 1 9 (1982). 5 A.K.S. HO, C.A. CHEN, A n n a l s of New York A c a d e m y of S c l e n c e s , 260 297-310 (1975) 6 K.BLUM, A.H. BRIGGS, L. D E L L A L L O , S.F.A. E L S T O N and R. OCHOA, E x p e r l m e n t l a 38 1 4 6 9 - 1 4 7 0 (1982) 7 B. T A B A K O F F and P.L. H O F F M A N , Life S c l e n c e s 32 1 9 7 - 2 0 4 ( 1983 ). 8 R. SCHULTZ, M. W U S T E R , T. DUKA, and A. HERZ P s y c h o p h a r m . 68 221-227 (1980). 9 M.A. C O L L I N S , and M.G. BIGDELI, Life S c i e n c e 16 585-602 (1975). 10 R.D. M E Y E R S and E.C. C R I T C H E R , P h a r m a c o l . Blochem. Behav. 16 827-836, (1982). ii. J.M. HILLER, L.M. ANGEL, and E.J. SIMON, S c l e n c e 214 468-469 (1981) 12. M.E. C H A R N E S S , A.S. G O R D O N , and I. DIAMOND, S c l e n c e 222 1 2 4 6 - 1 2 4 8 (1984). 13 A . P F E I F F E R , B.R. S E I Z I N G E R , and A. HERZ, N e u r o p h a r m . 20 1229, (1982). 14 D. NABER, M.G. SOBLE, and D. PICKAR, P h a r m a c o p s y c h l a t r y 14 160-161, (1981). 15. B.R. S E I Z I N G E R , K. B O V E R M A N N , D. M O Y S I N G E R , V. HOLT, and A. HERZ Pharma. Blochem. & Behav. 18 361-369, (1983). 16 R. SCHULZ, M. W U S T E R , T. DUKA and A. HERZ, P s y c h o p h a r m . 68 221-227 (1980). 17 A.R. G E N A Z Z A N I , G. NAPPI, F. F A C C H I N E T T [ , G.L. M A Z Z E L L A , D. P A R R I N I , E. S I N F O R I A N I , F. P E T R A G L I A and F. SAVOLDI, J. of Clln. E n d o c r l n . and Metabl. 55 5 8 3 - 5 8 6 (1982). 18. S.A. L O R E N S and S. S A I N T A T I , ~ I f e S c i e n c e 23 1 3 5 9 - 1 3 6 2 (1978). 19. L.D. M I D D A U G H , E. R E A D and W.O. BOGGAN, Pharmac. Blochem. B e h a v . 9 1 5 7 - 1 6 0 (1978). 20. A.K.S. HO, and C.C. HO, P h a r m a c o l . Blochem. Behav. ii 1 1 1 - 1 1 7 (1979)
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21. K. BLUM, S. F U T T E R M A N , J.E. W A L L A C E and H.A. S C H W E T N E R , Nature 265 49-51 (1977). 22. R.F. BERMAN, J.A. KAREN. L. OLSON, and M.S. GOLDMAN, Drug and Alcohol D e p e n d e n c e 13 245-254 (1984). 23 H.L. A L T S C H U L E R , P.E. PHILLIPS and D.A. F E I N H A N D L E R , Life Sclences 26 679-688 (1980). 24. H.S. S A M S O N and T.F. DOYLE, Pharm. Blochem. and Behav. 22 91-99 (1985). 25. J.R. V O L P I C E L L I , J. TIVEN, and S.C. KIMMEL, Physiol. Psych. i0 114-116 (1982). 26 J. ROSSIER, E.D. FRENCH, C. RIVIER, N. LING, R. G U I L L E M I N , and F.E. BLOOM, Nature, 270 618-620 (1977). 27. J. SAWYNOK, C. PINSKY, F.S. LaBELLA, Life Scl. 25 1 6 2 1 - 1 6 3 2 (1979)
847
NALTREXONE
BLOCKS
Joseph
THE
POST-SHOCK
R. V o l p z c e l l I ,
Pergamon Pres
INCREASE
M a r k A.
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CONSUMPTION
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D e p a r t m e n t s of P s y c h o l o g y and P s y c h i a t r y U n l v e r s z t y of P e n n s y l v a n i a P h i l a d e l p h i a , P e n n s y l v a n i a 19104 (Received zn final form December ii, 1985) Summary
A t t e n t i o n has r e c e n t l y focused on the p o s s i b i l i t y of an i n t e r a c t i o n b e t w e e n ethanol and the e n d o r p h i n system. In this study the opiate b l o c k e r n a l t r e x o n e p r e v e n t s the e x p e c t e d p o s t - s h o c k i n c r e a s e of ethanol c o n s u m p t i o n . This p r o v i d e s f u r t h e r e v i d e n c e that e n d o g e n o u s o p i a t e s are i n v o l v e d in the v o l u n t a r y d r l n k z n g of ethanol in rats. A link b e t w e e n ethanol and the e n d o g e n o u s o p i a t e system is d e m o n s t r a t e d by recent b e h a v i o r a l and p h a r m a c o l o g i c a l data. (i). M o r p h i n e a d m z n l s t r a t z o n s u p p r e s s e s v o l u n t a r y ethanol d r l n k z n g zn rats (2) and hamsters (3). I n t r a v e n t r l c u l a r z n ] e c t l o n s of the e n d o g e n o u s opiate, M e t - e n k e p h a l z n , also reduces ethanol c o n s u m p t i o n in rats (4). During m o r p h i n e w i t h d r a w a l rats will d r a m a t i c a l l y increase ethanol c o n s u m p t i o n (5). F u r t h e r m o r e , m i c e b r e d to p r e f e r ethanol had lower levels of w h o l e brain M e t - e n k e p h a l z n than rats that a v o i d e d ethanol d r i n k i n g (6). T h e s e results suggest an inverse r e l a t i o n s h i p b e t w e e n ethanol p r e f e r e n c e and e n d o r p h z n s t z m u l a t l o n . When e n d o r p h z n a c t i v i t y Is s t i m u l a t e d by e x o g e n o u s or e n d o g e n o u s opiates, v o l u n t a r y ethanol c o n s u m p t l o n d e c r e a s e s and when a d e f i c i e n c y in opiate s t i m u l a t i o n occurs (I.e. opiate w i t h d r a w a l ) ethanol d r l n k l n g increases. Three m e c h a n i s m s have been s u g g e s t e d to a c c o u n t for the a p p a r e n t a g o n z s t l c e f f e c t s of ethanol on the e n d o r p h z n system. The first m e c h a n i s m is s u g g e s t e d by B l u m and hls a s s o c i a t e s (i). Noting that the c o n d e n s a t i o n p r o d u c t s of ethanol and d o p a m z n e form t e t r a z s o q u i n o l z n e s and that these c o m p o u n d s can d i r e c t l y s t i m u l a t e o p i a t e r e c e p t o r s , they suggest that a similar process may occur zn vzvo with p h y s i o l o g i c a l doses of ethanol. A second p o s s i b l e m e c h a n i s m is d e m o n s t r a t e d by the o b s e r v a t i o n that e n d o r p h z n b i n d i n g zs e n h a n c e d by p h y s l o l o g z c a l l y a t t a i n a b l e d o s e s of ethanol (7). Thus ethanol may d i r e c t l y a f f e c t receptor s e n s i t i v i t y . Finally, the third m e c h a n i s m Is that ethanol s t i m u l a t e s the r e l e a s e of e n d o g e n o u s o p i a t e s (8). The TIQ h y p o t h e s i s receives support from o b s e r v a t i o n s that p y r o g a l l o l p r e t r e a t e d rats given alcohol will form s a l s o l z n o l (a TIQ) in brain tlssue (9). In a d d i t i o n f o l l o w i n g z n t r a v e n t r l c u l a r 0024-3205/86 $3.00 + .00 Copyrlght (c) 1986 Pergamon Press Ltd.
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l n ] e c t l o n s of T I Q ' s rats will d r a m a t i c a l l y i n c r e a s e a l c o h o l d r i n k i n g (i0) and this e f f e c t is b l o c k e d by n a l o x o n e (ii). The s e c o n d m e c h a n i s m , that a l c o h o l d i r e c t l y a f f e c t s the b i n d i n g of o p i a t e r e c e p t o r s comes f r o m s t u d i e s that d e m o n s t r a t e a l c o h o l has d i r e c t e f f e c t s on in vitro p r e p a r a t l o n s of rat brain. S p e c i f i c a l l y at low c o n c e n t r a t i o n s , a l c o h o l s t i m u l a t e s the mu (morphine) r e c e p t o r but a l c o h o l i n h l b l t s the d e l t a r e c e p t o r in a d o s e r e s p o n s e f a s h i o n (12). The e f f e c t s of a l c o h o l on o p i a t e r e c e p t o r s c h a n g e s as a f u n c t i o n of time. A c u t e a l c o h o l e x p o s u r e i n h i b i t s o p i a t e b l n d l n g , w h e r e a s c h r o n i c (four days) e x p o s u r e i n c r e a s e s o p i a t e r e c e p t o r b i n d i n g (13,14). E m p i r i c a l s u p p o r t for the t h i r d m e c h a n i s m was d e m o n s t r a t e d w h e n i n ] e c t l o n s of e t h a n o l s t l m u l a t e d i n c r e a s e s in b l o o d B e t a - e n d o r p h l n levels In rats (8). In n o n a l c o h o l i c human s u b 3 e c t s , a c u t e e t h a n o l i n g e s t i o n c a u s e s a 400% i n c r e a s e in p l a s m a b e t a - e n d o r p h l n levels (14). The e f f e c t s of e t h a n o l on c e n t r a l o p i a t e s t i m u l a t i o n d e p e n d on the d u r a t i o n of e t h a n o l e x p o s u r e and the p a r t i c u l a r o p i a t e s t u d i e d . A c u t e e t h a n o l e x p o s u r e i n c r e a s e s m e t - e n k e p h a l l n and b e t a - e n d o r p h l n levels in the h y p o t h a l a m u s (15,16) w h e r e a s d y n o r p h l n levels did not change. F o l l o w i n g c h r o n i c e t h a n o l e x p o s u r e in rats m e t - e n k e p h a l l n , b e t a - e n d o r p h l n and d y n o r p h l n levels all d e c r e a s e d in the h y p o t h a l a m u s (15,16). Human a l c o h o l i c s also have d e p r e s s e d b e t a - e n d o r p h l n l e v e l s in the CSF w h e n a s s e s s e d 3 to i0 days after a l c o h o l d e t o x (17). If e t h a n o l i n t e r a c t s w i t h e n d o g e n o u s o p l a t e s , then opiate b l o c k e r s such as n a l o x o n e and n a l t r e x o n e s h o u l d a t t e n u a t e e t h a n o l ' s p h a r m a c o l o g i c a l e f f e c t s . Several r e c e n t o b s e r v a t i o n s s u p p o r t this p r e d i c t i o n . N a l o x o n e i n t e r f e r e s w i t h e t h a n o l e n h a n c e m e n t of l a t e r a l h y p o t h a l a m l c s t i m u l a t i o n (18), d e c r e a s e s e t h a n o l s t i m u l a t e d m o t o r a c t l v l t y in mice (19), i n c r e a s e s the LD 50 of e t h a n o l tn m i c e (20), d e c r e a s e s the length of e t h a n o l i n d u c e d sleep (20), and m a y a t t e n u a t e e t h a n o l w i t h d r a w a l s y m p t o m s in m i c e (21) and rats (22). Bar press r e s p o n d i n g for e t h a n o l in m o n k e y s is r e d u c e d by n a l t r e x o n e (23) and bar press r e s p o n d i n g in rats is reduced by n a l o x o n e (24). This d e m o n s t r a t e s that the r e i n f o r c i n g a s p e c t s of e t h a n o l may a l s o be r e d u c e d by o p i a t e b l o c k e r s . In the p r e s e n t study, the e f f e c t s of n a l t r e x o n e on the r e l n f o r c l n g p r o p e r t i e s of e t h a n o l is f u r t h e r a s s e s s e d . I n c r e a s e s in e t h a n o l self s e l e c t i o n has b e e n o b s e r v e d in rats f o l l o w l n g e x p e r i e n c e with i n e s c a p a b l e foot s h o c k (25). If o r g a n i s m s d r i n k e t h a n o l b e c a u s e of e t h a n o l ' s e f f e c t on e n d o r p h l n s t l m u l a t l o n then the p o s t - s h o c k i n c r e a s e in e t h a n o l d r l n k l n g will be attenuated with naltrexone. Methods S u b j e c t s . S u b 3 e c t s w e r e 32 m a l e S p r a g u e - D a w l e y rats o b t a l n e d from H o l t z m a n Co., M a d i s o n , W i s c o n s l n . The rats w e r e 9 0 - 1 0 0 days old at the start of the e x p e r l m e n t and w e r e i n d l v l d u a l l y housed. All e x p e r i m e n t a l m a n i p u l a t i o n s w e r e c o n d u c t e d d u r i n g the 14 hr. light p a r t of the 24 hr. d a i l y cycle. T h r o u g h o u t the e x p e r i m e n t s u b ] e c t s had free a c c e s s to f o o d and both 5% (v/v) e t h a n o l and w a t e r in the home cage.
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A p p a r a t u s a n d M a t e r i a l s . F l u l d was a v a z l a b l e to rats zn b o t t l e s t h a t hung on the front of z n d l v l d u a l c a g e s such that the d r z n k l n g spouts p r o t r u d e d a b o u t 4 cm. into the c a g e s and a b o u t 5 cm. from the floor of the cages. I n e s c a p a b l e shock was d e l z v e r e d zn boxes that m e a s u r e d 30 cm. long, 20 cm. wide, and 20 cm. hzgh. The boxes w e r e c o n s t r u c t e d of two a c r y l z c p l a s t z c sldes ( l e n g t h w z s e ) a n d two a l u m z n u m ends. The floor was c o n s t r u c t e d of .32 cm. d z a m e t e r s t a i n l e s s steel bars, 1.9 cm. apart. A G r a s o n - S t a d l e r shock g e n e r a t o r (model E6070B) s u p p l z e d a 0.8 ma. s c r a m b l e d s h o c k to the grzd floor and m e t a l l z c szdes of the boxes. N a l t r e x o n e was d i s s o l v e d zn a 28% s o r b z t o l s o l u t i o n zn d l s t 1 1 1 e d water. P l a c e b o c o n s z s t e d of lust the 28% sorbztol solutzon. P r o c e d u r e . A f t e r a f o u r - d a y p e r z o d zn w h z c h b a s e l z n e e t h a n o l and w a t e r c o n s u m p t l o n were d e t e r m i n e d , rats w e r e p a i r e d b a s e d on e t h a n o l p r e f e r e n c e and then r a n d o m l y a s s z g n e d to the N a l t r e x o n e or P l a c e b o group. During the next four days s u b j e c t s r e c e z v e d dally s e s s z o n s of 60, two second d u r a t i o n , z n e s c a p a b l e shocks d e l z v e r e d once a mznute. I m m e d z a t e l y after each s h o c k sesszon, s u b j e c t s w e r e r e m o v e d from the s h o c k boxes and p l a c e d in thezr home cages w e r e food, w a t e r , and e t h a n o l was a v a z l a b l e . E a c h day the fluzd b o t t l e s w e r e w e z g h e d to a s s e s s fluzd c o n s u m p t z o n d u r z n g the p r e v z o u s 24 hours. The e t h a n o l and w a t e r b o t t l e s w e r e then r e t u r n e d to the cage and r o t a t e d such that the b o t t l e on the right side d u r z n g the p r e v z o u s day was then p l a c e d on the left side of the cage. The fznal phase of the e x p e r l m e n t c o n s l s t e d of szx s h o c k - f r e e days zn which rats r e c e i v e d d a z l y s u b c u t a n e o u s z n ] e c t l o n s of i0 mg. per kg. of n a l t r e x o n e or p l a c e b o . E x c e p t for l n ] e c t z o n s , rats r e m a i n e d zn thezr home cages w h i l e fluzd c o n s u m p t z o n was m o n i t o r e d d u r z n g this p o s t - s h o c k phase. Results D u r z n g the p o s t - s h o c k phase of the e x p e r z m e n t , the P l a c e b o g r o u p d r a m a t z c a l l y z n c r e a s e d their ethanol c o n s u m p t z o n and d e c r e a s e d water c o n s u m p t i o n w h e r e a s , the N a l t r e x o n e g r o u p did not show any r e l i a b l e c h a n g e s in e t h a n o l or w a t e r c o n s u m p t z o n . T h e s e w z t h l n g r o u p s r e s u l t s are p r e s e n t e d Table I and show that the P l a c e b o g r o u p r e l i a b l y d e c r e a s e d w a t e r c o n s u m p t i o n d u r i n g the p o s t - s h o c k phase (29.0 ml. to 23.2 ml.) and n e a r l y d o u b l e d their e t h a n o l c o n s u m p t z o n (19.7 ml. to 36.2 ml.). In c o n t r a s t , the N a l t r e x o n e g r o u p d e m o n s t r a t e d small but not s t a t z s t z c a l l y r e l i a b l e , i n c r e a s e s in water (28.0 ml. to 28.5 ml.) and of e t h a n o l c o n s u m p t z o n (21.1 ml. to 25.8 ml.) d u r i n g the p o s t - s h o c k phase. As T a b l e I reveals, w h z l e n a l t r e x o n e d r a m a t z c a l l y a t t e n u a t e d e t h a n o l p r e f e r e n c e d u r z n g the p o s t - s h o c k p h a s e zt did not have an a p p r e c i a b l e e f f e c t on total fluzd c o n s u m p t z o n (59.5 ml. to 54.3 ml. n.s.). The b e t w e e n g r o u p c o m p a r z s o n s are most a p p a r a n t zn F z g u r e i. In order to c o n t r o l for l n t e r s u b j e c t v a r z a b z l z t y zn total fluld c o n s u m p t i o n and e t h a n o l p r e f e r e n c e d u r z n g the s h o c k phase, the data are p r e s e n t e d as the c h a n g e zn the p e r c e n t of fluzd d r a n k from the e t h a n o l b o t t l e d u r i n g the post shock phase, r e l a t i v e to the last two days of shock t r a i n i n g . As F z g u r e 1 reveals, the P l a c e b o g r o u p g r a d u a l l y z n c r e a s e d thezr e t h a n o l p r e f e r e n c e d u r i n g the post shock phase w h e r e a s , the N a l t r e x o n e g r o u p did not i n c r e a s e zts e t h a n o l p r e f e r e n c e .
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TABLE
Vol. 38, No. 9, 1986
I
W i t h i n - G r o u p C o m p a r l s o n s for M e a n E t h a n o l , W a t e r , a n d T o t a l F l u i d C o n s u m p t l o n (In m l . ) for P l a c e b o and Naltrexone Groups
Group
Shock
Placebo Water Ethanol Total Fluld
29.0 19.7 48.7
23.2 36.3 59.5
+2.62* -6.33** -4.52**
Naltrexone Water Ethanol Total Fluld
28.0 21.1 49.1
28.5 25.8 54.3
-i.00 -1.79 -2.54*
*
Post-shock
t(15)
p<0.05
** p< 0. 001
C 0 O.
E :23
30-
o
20-
(/) cO
H Naltrex0ne o---o Placebo
}-
0
s
s
c"
o
¢-
I0-
s s
I
,,t,,,,-
h_l
~
O-
t
C
° - -
~
C~ C 0 c-
-IO!
1-2
I
I
3-4
5-6
O
Days Post-Shock FIG i. E f f e c t s of n a l t r e x o n e on c h a n g e in m e a n c o n s u m e d f r o m the e t h a n o l b o t t l e d u r l n g
(SEM) per c e n t the p o s t - s h o c k
fluld phase.
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Naltrexone and Ethanol Consumption
845
T h e s e o b s e r v a t i o n s are s t a t l s t z c a l l y r e l i a b l e . A g r o u p s x b l o c k s a n a l y s i s of v a r z a n c e reveals an o v e r a l l d i f f e r e n c e in e t h a n o l p r e f e r e n c e b e t w e e n the groups, F ( I , 3 0 ) = 5.17, p<0.05; a r e l z a b l e z n c r e a s e in e t h a n o l p r e f e r e n c e a c r o s s days, F ( 2 , 6 0 ) = 8.50, p < 0 . 0 0 1 ; and a r e l i a b l e g r o u p x blocks z n t e r a c t l o n F ( 2 , 6 0 ) = 17.78, p < 0 . 0 0 0 5 . Post hoc c o m p a r z s o n s reveal the s o u r c e of the z n t e r a c t z o n zs a c c o u n t e d for by the o b s e r v a t z o n that the P l a c e b o g r o u p r e l i a b l y i n c r e a s e d e t h a n o l a c r o s s days and the two g r o u p s r e l z a b l y d z f f e r d u r l n g the second and thzrd blocks but not on the inltzal post s h o c k block. (All p o s t - h o c s t a t z s t z c a l tests w e r e a s s e s s e d N e u m a n - K u e l l s ' p r o c e d u r e with p<0.05)
using
Discussion The r e s u l t s d e m o n s t r a t e that n a l t r e x o n e zs e f f e c t i v e in b l o c k z n g the e x p e c t e d p o s t - s h o c k z n c r e a s e zn e t h a n o l c o n s u m p t i o n . This p r o v i d e s further support to the n o t z o n that e t h a n o l i n t e r a c t s w z t h the e n d o r p h l n system. F u r t h e r m o r e , it s u g g e s t s that v o l u n t a r y e t h a n o l d r i n k i n g zn rats zs r e i n f o r c e d b e c a u s e of this i n t e r a c t z o n with o p i a t e r e c e p t o r s . T h e s e r e s u l t s also suggest a p o s s z b l e e x p l a n a t i o n for the c u r z o u s o b s e r v a t z o n that e t h a n o l c o n s u m p t z o n z n c r e a s e s f o l l o w z n g i n e s c a p a b l e shock. D u r i n g z n t e r m z t t e n t z n e s c a p a b l e s h o c k zn rats, the e n d o r p h z n s y s t e m zs s t i m u l a t e d and p e r i p h e r a l levels of B e t a - e n d o r p h z n are g r e a t l y i n c r e a s e d (26). If o r g a n i s m s adapt to high levels of b e t a - e n d o r p h i n (such as by d o w n r e c e p t o r r e g u l a t l o n ) , then d u r z n g the p o s t - s h o c k phase we w o u l d e x p e c t t h a t rats w z l l e x p e r z e n c e a r e l a t z v e d e f i c i e n c y in e n d o r p h l n s t l m u l a t z o n . If e t h a n o l d o e s s t i m u l a t e the e n d o r p h i n s y s t e m as s u g g e s t e d by r e c e n t p h a r m a c o l o g i c a l e v i d e n c e , then the p o s t - s h o c k z n c r e a s e in e t h a n o l c o n s u m p t z o n zs the rats' z n s t r u m e n t a l a t t e m p t to c o m p e n s a t e for the r e l a t z v e d e f z c l e n c y in e n d o r p h l n s t l m u l a t z o n . Thus an o p z a t e b l o c k e r such as n a l t r e x o n e w111 b l o c k the r e z n f o r c l n g e f f e c t s of e t h a n o l and c o n s e q u e n t l y the z n c r e a s e in e t h a n o l c o n s u m p t i o n t y p l c a l l y seen after shock. Thzs e x p e r z m e n t was not d e s i g n e d p r z m a r i l y to test the m e c h a n z s m by w h z c h e t h a n o l s t z m u l a t e s a c t z v l t y . However, sznce n a l t r e x o n e p r z m a r l l y b l o c k s mu rather than delta r e c e p t o r s we suggest that e t h a n o l d r z n k l n g zs r e i n f o r c e d by i n c r e a s e d a c t i v i t y mu a g o n z s t s such as b e t a - e n d o r p h i n rather than the d e l t a a g o n z s t s such as m e t - e n k e p h a l l n . F u r t h e r support that the mu r e c e p t o r is the c r z t z c a l szte for the r e l n f o r c z n g p r o p e r t i e s of e t h a n o l come f r o m s t u d i e s that show m o r p h z n e (a p r l m a r z l y mu r e c e p t o r a g o n l s t ) s u p p r e s s e s e t h a n o l d r z n k l n g (2) and m o r p h z n e w i t h d r a w a l z n c r e a s e s e t h a n o l d r z n k l n g (5). S u p p o r t that n o n - m u r e c e p t o r s are i m p o r t a n t zn the r e z n f o r c z n g e f f e c t s of e t h a n o l comes from o b s e r v a t i o n s that demonstrate that centrally administered met-enkephalln also r e d u c e s e t h a n o l c o n s u m p t z o n (4). In a d d l t z o n low d o s e n a l o x o n e t r e a t m e n t ( s u f f i c i e n t to b l o c k mu r e c e p t o r s but not n o n - m u o p i a t e r e c e p t o r s ) does not reduce e t h a n o l r e i n f o r c e d bar p r e s s z n g (23). Sznce the p r e s e n t s t u d y used a m o d e r a t e l y hzgh d o s e of n a l t r e x o n e , zt zs p o s s z b l e that n a l t r e x o n e was not s e l e c t z v e in zts mu r e c e p t o r b l o c k a d e . I n d e e d so c a l l e d "pure"
846
Naltrexone and Ethanol Consumptlon
%'ol 38, N,~ 9, 1986
o p i a t e a n t a g o n i s t s such as n a l o x o n e and n a l t r e x o n e may a f f e c t n e u r o t r a n s m l t t e r s other than the e n d o r p h l n s y s t e m p a r t l c u l a r l y w h e n used in hlgh doses (27). It is u n l i k e l y t h a t o p i a t e s t l m u l a t l o n is the sole r e a s o n o r g a n i s m s d r i n k e t h a n o l . This e x p e r l m e n t s u g g e s t s h o w e v e r , that one of the r e l n f o r c l n g m e c h a n l s m s in e t h a n o l d r l n k l n g i n v o l v e s c o m p e n s a t i o n for r e l a t i v e d e f l c l e n c l e s in e n d o r p h l n s t l m u l a t l o n . Acknowledgements T h l s r e s e a r c h is s u p p o r t e d in part by P u b l i c H e a l t h S e r v l c e G r a n t #MH14654 a n d V A M e d i c a l R e s e a r c h S e r v i c e funds to C.P. O ' B r l e n . The a u t h o r s t h a n k Du Pont Co. for g e n e r o u s l y s u p p l y l n g the n a l t r e x o n e used in thls research. References i. K. BLUM, M.G. H A M I L T O N AND J.E. WALLACE, A l c o h o l and O p i a t e s , ed.K, Blum, p.203, A c a d e m i c Press, N e w York (1977). 2. A.K.S. HO, R.A.C. C H E N and M.J. M O R R I S O N , A l c o h o l and Oplates_~, ed. K, Blum, A c a d e m l c Press, New Y o r k (1977). 3 J.D. S I N C L A I R , J. A T K I N S and S. W a l k e r , N a t u r e 246 4 2 5 - 4 2 7 (1973). 4 A.K.S. HO, N. ROSSI, J. Pharm. P h a r m a c o l . 34 1 1 8 - 1 1 9 (1982). 5 A.K.S. HO, C.A. CHEN, A n n a l s of New York A c a d e m y of S c l e n c e s , 260 297-310 (1975) 6 K.BLUM, A.H. BRIGGS, L. D E L L A L L O , S.F.A. E L S T O N and R. OCHOA, E x p e r l m e n t l a 38 1 4 6 9 - 1 4 7 0 (1982) 7 B. T A B A K O F F and P.L. H O F F M A N , Life S c l e n c e s 32 1 9 7 - 2 0 4 ( 1983 ). 8 R. SCHULTZ, M. W U S T E R , T. DUKA, and A. HERZ P s y c h o p h a r m . 68 221-227 (1980). 9 M.A. C O L L I N S , and M.G. BIGDELI, Life S c i e n c e 16 585-602 (1975). 10 R.D. M E Y E R S and E.C. C R I T C H E R , P h a r m a c o l . Blochem. Behav. 16 827-836, (1982). ii. J.M. HILLER, L.M. ANGEL, and E.J. SIMON, S c l e n c e 214 468-469 (1981) 12. M.E. C H A R N E S S , A.S. G O R D O N , and I. DIAMOND, S c l e n c e 222 1 2 4 6 - 1 2 4 8 (1984). 13 A . P F E I F F E R , B.R. S E I Z I N G E R , and A. HERZ, N e u r o p h a r m . 20 1229, (1982). 14 D. NABER, M.G. SOBLE, and D. PICKAR, P h a r m a c o p s y c h l a t r y 14 160-161, (1981). 15. B.R. S E I Z I N G E R , K. B O V E R M A N N , D. M O Y S I N G E R , V. HOLT, and A. HERZ Pharma. Blochem. & Behav. 18 361-369, (1983). 16 R. SCHULZ, M. W U S T E R , T. DUKA and A. HERZ, P s y c h o p h a r m . 68 221-227 (1980). 17 A.R. G E N A Z Z A N I , G. NAPPI, F. F A C C H I N E T T [ , G.L. M A Z Z E L L A , D. P A R R I N I , E. S I N F O R I A N I , F. P E T R A G L I A and F. SAVOLDI, J. of Clln. E n d o c r l n . and Metabl. 55 5 8 3 - 5 8 6 (1982). 18. S.A. L O R E N S and S. S A I N T A T I , ~ I f e S c i e n c e 23 1 3 5 9 - 1 3 6 2 (1978). 19. L.D. M I D D A U G H , E. R E A D and W.O. BOGGAN, Pharmac. Blochem. B e h a v . 9 1 5 7 - 1 6 0 (1978). 20. A.K.S. HO, and C.C. HO, P h a r m a c o l . Blochem. Behav. ii 1 1 1 - 1 1 7 (1979)
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21. K. BLUM, S. F U T T E R M A N , J.E. W A L L A C E and H.A. S C H W E T N E R , Nature 265 49-51 (1977). 22. R.F. BERMAN, J.A. KAREN. L. OLSON, and M.S. GOLDMAN, Drug and Alcohol D e p e n d e n c e 13 245-254 (1984). 23 H.L. A L T S C H U L E R , P.E. PHILLIPS and D.A. F E I N H A N D L E R , Life Sclences 26 679-688 (1980). 24. H.S. S A M S O N and T.F. DOYLE, Pharm. Blochem. and Behav. 22 91-99 (1985). 25. J.R. V O L P I C E L L I , J. TIVEN, and S.C. KIMMEL, Physiol. Psych. i0 114-116 (1982). 26 J. ROSSIER, E.D. FRENCH, C. RIVIER, N. LING, R. G U I L L E M I N , and F.E. BLOOM, Nature, 270 618-620 (1977). 27. J. SAWYNOK, C. PINSKY, F.S. LaBELLA, Life Scl. 25 1 6 2 1 - 1 6 3 2 (1979)
847