Self-Administration of Psychoactive Substances by the Monkey A Measure of Psychological Dependence

7/24/2019 Self-Administration of Psychoactive Substances by the Monkey A Measure of Psychological Dependence

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Psy chop harm acolo gia B EE.) 16 , 30 - -48 1969)

Self-Adm inistration of Psychoactive Substances

by the M onkey

A M e a s u r e o f P s y c h o l o g i c a l D e p e n d e n c e

GER LD DI~NEAU***, TOMOJI YANAGITA+ , a n d M . H . S E E V E R S

D ep a r t m e n t o f Pha r m aco l ogy , The U n i ve r s i t y o f Mi ch i gan Med ical Schoo l

A n n A r bor , Mi ch i gan

Rec eived Decem ber 26, 1968

Fina l Vers ion: Jun e 16 , 1969

Summary. A m e t hod has been deve l oped w h i ch pe r m i t s m onkeys t o s e l f - ad -

minis te r d rug so lu t ions , a t wi ll , th rou gh indwell ing in t raven ous ca the ters . Psy cho -

l og ica l dependence on t he e ff ec ts o f a d r ug occu r s w hen a n a i ve m onk ey vo l un t a r i l y

in i ti a tes and m ainta ins se l f -adminis t ra t ion of the d rug. I f , in addi t ion to ps ych o-

l og ica l dependence , t he d r ug a l so p r oduces psycho t ox i e i t y , e i t he r d i r ec t ly o r upon

abrupt wi thdrawal , i t has a potent ia l abuse l i ab i l i ty .

I n t he p r e sen t s t u dy m on keys deve lopedpsycho l og i cal dependence on m or ph i ne ,

codeine , coca ine , d-a mp hetam ine , pen tobarb i ta l , e thanol , a nd caffeine . Al l of these

d r ugs excep t caf fe ine p r oduced psycho t ox i c i t y . Monkeys d i d n o t deve l op psycho-

logica l dependence on na lorphine , morphinc-na lorphine mixtures , ch lorpromazine ,

mescaline or physiological saline.

Key Words: Psycho l og ica l D ependence - - Psych o t ox i e i t y - - D r ug A buse - -

D r u g D ependence - - Psy choac t i ve D r ugs .

I n tro duct i o n

I n t h i s l a b o r a t o r y a n e x t e n s i v e e x p e r ie n c e c o n c e r n i n g th e b e h a v i o r a l

e ff ec ts o f m o r p h i n e - l ik e d r u g s i a t h e m o n k e y M a c a e a m u l a t t a ) h a s

b e e n o b t a i n e d d u r i n g t h e l a s t 2 0 y e a rs . A c o n t i n u i n g p r o g r a m o n t h e

e v a l u a t i o n o f t h e p h y s io l o g ic a l d e p e n d e n c e c a p a c i t y o f m o r p h i n e - l ik e

d r u g s is i n p r o g re s s , a n d o v e r 7 0 0 c o m p o u n d s h a v e b e e n e x a m i n e d d u r i n g

t h i s p e r i o d . T h e b i o lo g i c al r e s p o n s e o f t h e m o n k e y t o m o r p h i n e - l i k e

s u b s t a n c e s , i n m o s t r e s p e c ts , p a r a l le l s c l o s el y t h e i r a c t i o n s i n m a n , a n d

* Pr e l i m i na r y r epo r t s o f t h i s s t ud y w er e p r e sen ted a t t he Fa l l Mee t ing o f t he

A m er i can Soc i e ty f o r Pha r m aco l ogy and E xpe r i m e n t a l T he r apeu ti c s , 1964. Ph a r m a-

cologist 6, 182 1964).

* * S u p p o r t e d b y U S P H S G r a n t s M H 2 8 14 a n d M H 5 32 0 a n d b y C o m m i t te e o n

Pr ob l em s o f D r ug D ependence , N a t i ona l R esea r ch Council, N a t i ona l A c adem y o f

Sciences.

*** Prese nt Address : South ern l~esearch In s t i tu te , B i rmingh am , Alabam a 35205.

+ Present A ddress : Cent ra l Ins t i tu te for Ex per im enta l A nimals , 1433, Nog awa,

K a w a s a k i , J a p a n .


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predictions for man, based upon monkey data, have been proved to be

qual itatively accurate. Although physiological dependence is a very im-

portant negative reinforcing factor in inducing drug-seeking behavior to

avoid the aversive effects of withdrawal, it develops only to substances

which have a predominantly depressant action on the central nervous

system, e.g., morphine and its derivatives, barbiturates and the pharma-

cologically related substances, alcohol and other hydrocarbons. Yet,

many stimulants such as cocaine and amphetamine do not induce

physiological dependence but are highly reinforcing in man and have

equal, ff not greater, capacity for abuse leading to psychotoxicity. Un-

fortunately, no animal model currently exists for the evaluation of what

is general ly termed psychological dependence (i. e., the volun tary ini-

tiat ion and maintenance of self-administration of drugs).

Invest igations involving self-administration of drugs by animals are

designed usually to determine whether the animal will drink water or a

drug solution. This technique has had extensive applications in small

animals, mainly mice and rats, with alcohol, morphine and other sub-

stances. Beach (1957), Nichols

e t a l

(1956) and Wikler

e t a l

(1963) have

all demonstrated that rats will show a preference for a solution of mor-

phine or other opiate over water, or for conditions formerly associated

with the experience of morphine s effects, but only after they have been

rendered physiologically dependent to this drug by injection. I n 1960,

studies were initiated in this laboratory involving self-administration of

morphine-like substances by the monkey in drinking water. These ex-

periments demonstrated that some monkeys, but not all, would choose

morphine solutions over water and continue self-administration until

physiological dependence had developed. Other morphine derivatives

like methadone, meperidine and levorphanol were not acceptable, even

to morphine-dependent animals, thus imposing serious limitations on the

general applicability of the oral method in the monkey.

In 1962, Weeks described a technique for in travenous self-adminis-

tration of drugs in the rat. He demonstrated clearly that rats, rendered

physiologically dependent by programmed intravenous administration

of morphine, will then maintain the dependent state by pressing a lever

to obtain the drug. Since this technique appeared to offer a great po-

tent ial for studies in the monkey, with possible long-range application as

a screening method for psychological dependence, studies were initiated

to develop a similar technique for this species. The present paper de-

scribes this technique and presents a preliminary survey of representatives

of the principal drugs which are strongly reinforcing for man and are

subject to widespread abuse. In 1964, Thompson and Schuster adminis-

tered morphine intravenously to monkeys restrained in an experimental

chair and were able to induce self-administration patterns for morphine


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b y l e v e r - p r e s s . T h e i r e x p e r i m e n t s w e r e d e s i g n e d p r i m a r i l y t o c o m p a r e

a n d e v a l u a t e t h e r e i n fo r c i n g ca p a b i li ti e s o f m o r p h i n e v e r s u s f o o d , a n d

d i d n o t a t t e m p t t o d e te r m i n e w h e t h e r t h e m o n k e y w o u l d s p o n t an e -

o u s l y i n i t i a t e s e l f - a d m i n i s t r a t i o n f o l lo w i n g t h e f i r s t d r u g e x p e r i e n c e .

T h e p r e s e n t e x p e r i m e n t s w e r e d e s i g n e d , t h e r e f o r e , t o d e t e r m i n e

w h e t h e r a m o n k e y , h a v i n g r e c e i v e d t h e f ir st in j e c ti o n o f a n y d r u g b y

s p o n t a n e o u s l e v e r- p r e ss , w o u l d c o n t i n u e t o s e e k r e i n f o r c e m e n t b y i n -

c r e a si n g t h e n u m b e r o f l e v e r pr e ss e s a n d m a i n t a i n s u c h a p a t t e r n o f s er f-

a d m i n i s t r a t i o n f o r lo n g p e r i o d s o f t i m e . I f t h e m o n k e y f u lf il le d t h e s e

r e q u i r e m e n t s , w e a s s u m e d t h a t p s y c h o l o g i c a l d e p e n d e n c e h a d b e e n

d e m o n s t r a t e d .

Apparatus

Housing and Restraining T h e m o n k e y is h o u s e d i n a n o p e n - f r o n t

c u b i c l e . E a c h c u b i c l e i s 3 6 i n c h e s h i g h , 3 0 i n c h e s w i d e , a n d 2 6 i n c h e s

d e e p . T h e s e a r e c o n s t r u c t e d i n d o u b l e - d e c k u n i ts o f f o u r c u b i cl es e a c h.

T h e s id e w a ll s a n d t o p s o f t h e s e c u b i c le s a r e m a d e o f 5 / 1 6 -i n c h o p a q u e

t e m p e r e d p o l y e t h y l e n e t o p e r m i t m a x i m u m l ig h t. T h e f lo o r is m a d e o f

1 - i n c h m e s h s c r e e n , w i t h a d r o p - p a n b e l o w , w h i c h i s f l u s h e d a u t o m a t i -

c a l ly e v e r y 4 h o u r s f o r s a n i t a t i o n a n d o d o r c o n t r o l .

A p a n e l w h i c h i s m o u n t e d i n t h e c e n t e r o f t h e b a c k o f t h e w a l l c o n -

t a i n s t w o s w i t c h e s w h i c h t h e m o n k e y c a n p r e s s t o a c t i v a t e t h e i n j e c t o r .

P r e s s i n g o f o n e o f t h e s e s w i t c h e s r e su l t s i n a n i n t r a v e n o u s i n j e c t io n o f a

d r u g s o l u t i o n t o t h e m o n k e y . P r e s s i n g t h e o t h e r c a u s e s t h e s o l u t i o n t o

b e d e l i v e r e d b a c k i n t o t h e d r u g r e s e r v o i r w h i le a l l s o u n d s a n d o t h e r

e x t e r n a l c l u e s a r e i d e n t i c a l t o t h o s e a c c o m p a n y i n g a n a c t u a l i n j e c t i o n .

T h e w i r i n g t o t h e t w o s w i t c h e s c a n b e i n t e r c h a n g e d a t w i l l b y t h e e x -

p e r i m e n t e r . A d r i n k i n g f o u n t a i n f o r t a p w a t e r is al so m o u n t e d o n t h e

b a c k w a l l o f t h e c a g e. A s p e c i a l ly - p r e p a r e d P u r i n a m o n k e y c h o w c o n -

t a i n i n g 1 83 g m / t o n i s o n ia z i d , a s a t u b e r c u l o s i s p r e v e n t i t a t i v e 1, i s s u p -

p l ie d f r o m a b o x b e n e a t h t h e p e r c h i n a r e a r c o r n e r o f t h e c u b ic l e.

T h e m o n k e y i s r e s t r a i n e d i n t h i s c u b i c le b y a s p e c i a ll y -d e s ig n e d m e t a l

h a r n e s s ( F ig . l ) a n d r e s t r a i n in g a r m ( F ig . 2) w h i c h a f f or d s m a x i m u m

m o v e m e n t i n o r d e r t o p e r m i t e x e rc is e a n d t o e l im i n a t e to s o m e e x t e n t

t h e p h y s i c a l e ff e c ts o f r e s t r a i n t . T h e r e s t r a i n i n g a r m , a t t a c h e d i n t h e l e f t

r e a r c o r n e r o f t h e c u b i c le , i s m a d e o f s ta i n l e ss s t e e l t u b i n g a n d i s p a t -

t e r n e d a f t e r t h e h u m a n a r m . A p e r m a n e n t s il as ti e c a t h e t e r p as se s t h r o u g h

t h e a r m f r o m t h e i n j e c t o r t o t h e h a r n e s s h o u s i n g w h e r e it i s a t t a c h e d t o

t h e c a t h e t e r i m p l a n t e d i n t h e a n i m a l . T h e s h o u l d e r ( j o in t A ) p e r m i t s

s w i v el a n d h i n g e a c t i o n o f t h e w h o l e a r m ; t h e e l b o w ( j o in t B ) , h i n g e

a n d r o t a t i o n o f t h e f o r e a r m o f a b o u t 30 0 d e g r e e s ; t h e w r i s t ( j oi n t C ),

1 To provide an average daily dose of 20 mg/kg isoniazid; 6.8 g in/ton pyrido xine

HC1 is also added to p rev ent a deficiency state of the latter.


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....................... =., .,.-- ~ /-T ru nn ion "X "

9 ( ~ ~ H o u s in g

/ D o r s a l Pie ~ i ~ ) ~ i : : . : : : " : : : : ~ : '

- \ ~ g I.:......~ I I ~,, H

V e n t r a l P i e c " f

5

Fig. 1 . Exp loded perspect ive vie w of th e harness designed to fit~ a m edium-sized

(4.0--4.5 kg) rhesus m onkey . The h arness i s co nst ructed of 0 .067 in . s ta inless s tee l

tubing

Joint B

12"

1

Joint A

Joint C

Trunnion "X "

F i g .2 . P e r s p e c ti v e v i e w o f t h e r e s t r ai n i n g a r m e m p l o y e d t o c o n n e c t t h e m o n k e y s

h a r n e s s t o t h e c a g e w a ll . T h e j o i n t s , A a n d B , a r e m o d i f i e d s w i v e l s f r o m p r e s s u r i z e d

l u b r i c a t i n g li n es . T h e s e a r e a v a i l a b l e f r o m a n y a u t o m a t i v e s u p p l ie r

3 PsychopharmacologiaBerl.), Bd. 16


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Mo t o r Va l v e

~ ~ 1 ~ Piston

Microswltch

S ~

Ma nual Op erationSwitches ~ . ~ ~

Fig.3. Perspective view of the injector. Mieroswitehes MS1 and /vIS2) are limit

switches which serve to stop and to reverse the motor, respectively. Valve A is a

3-way solenoid valve which permits the syringe to refill automatieMly from the

reservoir bottle. Valve B is a 2-way solenoid valve which delivers a small stream of

water, as a lubricant, to the syringe when the injector is activated

~ D r u g

ottle

~ ~ o . 18 Need le

~ 3 W a y to p o c k

both horizontM and vertical hinge action with the harness. The harness,

also made of stainless steel tubing, is adjustable within limits, a lthough

several sizes are necessary ia order to accommodate different sized

a n i m a l s

Drug In]usion Unit The injector is illustrated in Fig. 3. I t ma y be

activated by the monkey pressing the lever in the cage or by predeter-

mined programming. Activation of the motor-driven injector drives

the solution from the syringe into the catheter which traverses the re-

straining a rm to the back of the monkey, passes subcutaneously, enters

the jugular vein and terminates near the right atrium of the heart. The

position of the catheter tip near the ri ght hear t offers the most favorable

site since the large blood volume and continued turbulence assures rapid

dilution and minimal clot formation.

One ce ituid is injected wi thin 25 see and another 25 sec is required to

refill the syringe from the drug reservoir bottle before the next iniection

is available. This delay imposes a limit in t he f requency of injection which

may be a factor in establishing accurate reinforcement rates with low

drug concentrations.


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Programming and Recording T h e i n j e c t o r m a y b e c o n t r o l l e d i n f o u r

w a y s : 1. b y t h e m o n k e y a l on e ; 2 . b y a u t o m a t i c t i m e r a l o n e ; 3 . b y t h e

t i m e r i f t h e m o n k e y f ai ls t o p r e s s th e l e v e r w i t h i n a p r e d e t e r m i n e d

p e r i o d ; 4 . b y t h e m o n k e y , w i t h a t i m e r b l o e l d n g t h e c i rc u i t a f t e r i n -

j e c ti o n , p r e v e n t i n g t h e m o n k e y f r o m t a k i n g t h e n e x t i n j e c t io n u n t i l a

p r e d e t e r m i n e d t i m e h a s e la p s e d . O t h e r p r o g r a m s , s u ch a s a fi x ed o r

p r o g r e s s i v e r a t i o o f l e v e r p r e s s e s f o r in j e c t io n s , r e q u i r e e x t e r n a l a c c es -

s o r y u n i ts t o b e a t t a c h e d t o t h e m a i n c o n t r o l u n i t . T h e n u m b e r a n d t i m e

o f d a y o f e a c h in j e c ti o n , s e l f - a d m i n i s t e r e d o r p r o g r a m m e d , a n d t h e t i m e s

o f l e v e r d e p re s si o n , w h e t h e r r e i n fo r c e d o r n o t , a r e r e c o r d e d o n a n e v e n t

r e c o r d e r .

Presurgical Care

A c o n d i t io n e d m o n k e y w e i g h i n g f r o m 31/2 t o 4 k g

i s ch o s e n f r o m t h e c o l o n y a n d a h a r n e s s i s f i tt e d . T h e m o n k e y u s u a l l y

a d a p t s i t s e l f t o t h e r e s t r a i n i n g d e v i ce w i t h i n a d a y o r t w o . H i g h l y e x -

c i ta b l e m o n k e y s , w h e n r e s t r a i n e d f o r t h e f i r st t i m e , m a y m a k e v i o l e n t

e f fo r ts to e s c ap e , a n d i n s o m e i n s ta n c e s h a v e b r o k e n t h e r e s t r ai n i n g a r m .

T o a v o i d t h is , a h e a v y - d u t y t r a in i n g a r m is u s e d a n d t h e f r o n t o f t h e

c a g e c o v e r e d w i t h p l e x i g la s t o p r e v e n t e s ca p e . I f t h e h a r n e s s d o e s n o t

f i t w e ll , o r i s i m p r o p e r l y a d j u s t e d , s o r e s w i l l d e v e l o p a r o u n d t h e s h o u l d e r s

o r o n t h e b a c k o f t h e m o n k e y . A l o o se o r p o o r fi t a ls o a ll o w s t h e m o n k e y

t o i n s e r t h is f o o t u n d e r t h e h a r n e s s a n d d i s c o n n e c t o r d is l o d g e t h e c a -

t h e t e r . P r o p e r f i t t i n g c a n b e a c c o m p l i s h e d w i t h i n a w e e k .

Catheter Implantation A s il ic o n e r u b b e r c a t h e t e r, 2 .2 m m O D a n d

1 .0 m m I D , i s i n s e r t e d a s e p t i c a ll y in t o t h e j u g u l a r v e i n a f t e r e x p o s u r e

b y n e c k in c i si o n u n d e r b a r b i t u r a t e a n e s t h e si a . P r o p e r l o c a t i o n o f t h e

t i p o f t h e c a t h e t e r n e a r t h e r i g h t a t r i u m o f t h e h e a r t i s a i d e d b y e i t h e r

o f t w o m e t h o d s : 1 . r e c o r d i n g t h e b l o o d p r e s s u re a t t h e t i p o f t h e c a t h e t e r

w i t h a s t r a in - g a u g e m a n o m e t e r , o r 2. r e c o r d in g t h e E K G f r o m t h e e x -

t e r n a l t i p o f t h e s a li n e -f i ll e d c a t h e t e r . V e n o u s p r e s s u r e i n t h e s u p e r i o r

v e n a c a v a is a p p r o x i m a t e l y z e r o o r a fe w m i l li m e t e r s n e g a ti v e . W h e n

t h e c a t h e t e r e n t e r s t h e a t r i u m , p u l s e p r e s s u r e is d i s c e r n a b ] e t o t h e o r d e r

o f z e r o d ia s t o l ic t o a f e w m m s y s t o li c . I n t h e r i g h t v e n t r i c l e , t h e p u l s e

p r e s s u r e is g r e a t e r . T h e P - w a v e o f t h e E K G s e r v es a s a u s e fu l i n d i c a t o r

o f t h e p o s i t i o n o f t h e t i p o f t h e c a t h e t e r . A s t h e c a t h e t e r a r r i v e s a t t h e

h e a r t a n d e n t e r s th e a t r i u m , t h e P - w a v e is n e g a t i v e b u t b e c o m e s p o s i-

t i v e a s i t n e a r s t h e A V v a l v e . I f t h e t i p e n t e r s t h e v e n t r i c l e , t h e Q I S

c o m p l e x s h o w s a d r a m a t i c i n c r e a s e i n v o l t a g e . W h e n i t is a s c e r ta i n e d

t h a t t h e c a t h e t e r i s i n t h e a t r i u m , i t i s w i t h d r a w n 1 c m a n d t i e d i n p l ac e .

A f t e r t h e c a t h e t e r i s p r o p e r l y p l a c e d , i t i s a l so f ix e d a t i t s e n t r a n c e

p o i n t i n t o t h e j u g u l a r v e i n b y l i g a tu r e s c e m e n t e d t o t h e c a t h e t e r 1 0 c m

f r o m t h e t i p in a d v a n c e o f s u r g e r y . T h e f r e e e n d is t h e n d r a w n s u b c u -

t a n e o u s l y b y a p r o b e s t y l e r t o t h e i n t e n d e d p o i n t o f e x i t t h r o u g h t h e s k i n

3


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of the back where it is attached to the catheter which traverses the

restraining arm.

Post Surgical Care.

When surgery is completed, the monkey is then

returned to the cage and programmed injections of saline solutions are

begun at intervals of 3 to 6 hours until his surgical wound heals, usually

within 5 days. The animal is then ready for experimentation.

Experimental Procedures.

Upon surgical recovery, two lever switches

are installed in the rear panel, one of which is arranged to deliver saline

when activated by the monkey. If the monkey presses the other lever

this also activates the injector but the saline (or drug solution) is deli-

vered back into the reservoir rather than into the monkey. The switch

connections on the two levers are easily interchangeable. A signal light

is also installed above the levers. The light, when on, indicates to the

monkey that he can activate the injector and receive an injection by

pressing the lever switch. For the first few days during injections of

saline, a clear glass lens is placed over the light. During this period the

monkey, a naturally curious animal, will depress a lever. When the

baseline rate of lever pressing has been observed, the saline solution is

replaced by drug solution and a colored lens is placed over the panel light.

The next depression of the proper lever by the monkey results in the

injection of a test drug. I f the monkey is lever-pressing for saline even

at a low rate at the end of the control period, it is only necessary to

substitute drug solution for saline in order to give the monkey his first

drug experience. I f the lever-pressing for saline has become extinguished,

it is necessary to use ano ther device to in itiate lever pressing when the

drug is substituted. This is done by taping a raisin or small piece of

candy to the lever with transparent cellulose tape. In his efforts to obtain

the raisin, the monkey will activate the injector. If the test drug is

positively rewarding, two or three such trials should teach the monkey

th at lever-pressing is associated with drug effects and he will increase

the number of lever presses unti l a patt ern of drug self-administration is

estab]ished. If the drug is aversive, or not rewarding, the monkey will

not attempt to extricate raisins or candy from beneath the tape in sub-

sequent trials even though he will take the raisins from the investi-

gator s hand.

When a monkey fails to initiate self-administration of a test drug,

it becomes pertinent to know if psychological dependence might develop

after fu rther exposure to the drug s effect. To tes t this possibility, in-

jections are programmed automatically at constant intervals, while at

the same time the injector can also be activated by the monkey. If the

monkey s initial indifference to the drug changes to a positive preference,

this change is indicated by monkey-activated injections during inter-

vals between programmed injections. If self-administration does not


8/19

37

begin within a month the monkey is assumed not to have developed

psychological dependence to this particular drug.

The concentration of drug solution in water or in 0.9~ saline

is prepared in such a manner th at the unit dose per kilogram administered

at each injection is contained in 0.25 ce of solution except for alcohol

which is prepared in a 20 ~ solution by weight.

Dosages All dosages are expressed in terms of the common salts of

the drugs employed.

esults

Morphine Morphine was the first drug Studied using this technique.

Eleven naive animals were studied three being retested a t two dosage

levels. Four monkeys failed to initiate lever- pressing at a dose of 0.5 rag/

kg and three out of ten failed at 2.5 mg/kg. When programmed injections

at 4-hour intervals were begun these latter three soon init iated self-

administration and ultimately achieved as high a daffy intake as the

other seven.

Fig.4 shows the self-administration patte rn of a typical animal

during a 27-week period. All animals increased their daily intake stead-

ily through the 6th or 7th week and then maintained a fairly stable

daffy dosage between 50 and 100 mg/kg. One exceptional monkey conti-

nually increased his dose for 30 weeks and finally attained an intake of

280 mg/kg/day. Although some individual variation existed the pattern

of self-administration of morphine was characterized by large diurnal

and small nocturnal intake. Some monkeys slept through the entire

period of 12 to 8 a.m. when the laboratory lights were extinguished

without self-administering any morphine.

In no instance did any animal voluntarily discontinue self-adminis-

tra tion of morphine. In a few instances when injections were interrupted

by catheter kinking plugging or breaking or by mechanical failure the

monkeys showed typical and severe abstinence syndromes during which

the y pressed the lever almost continuously in attempts to obtain mor-

phine injections.

During the period of escalating dosage the animals were drowsy and

apathetic but as the dosage stabilized these animals though less active

than controls appeared normal to casual observation. As with all

morphine-dependent animals food intake was reduced initia lly and

some temporary weight loss occurred. The longest experiment in this

series was continued for a period of 16 months. Barring infections these

animals maintained good health. Bacterial endocarditis with pulmonary

emboli was the commonest complication.

Codeine Four of five monkeys ini tia ted lever-pressing for codeine

at doses o f 0.5 and 2.5 mg/kg and gradually increased the ra te of intake


9/19

8

5 O r M o r p h i n e

o ~ m g l k g l d o y N o . 8 3 0M o le 4 . 4 k g

.~ 1 0 0 - Z 5 m g / k g / in j :

io l J l I i i i i i t ~ i f f i r I i i I t I I 1 1

I I i I I I I I I I f I I f I I I I I I I I I I I

0 5 1 0 1 5 2 0 2 5

W e e k

1 0 ~ 2 5 5 t h

week a

|m g / k g ,h , ~ , I \ I ~

M PM M PM M PM M PM M PM M PM M PM M

4 8 1 2 4 8 1 2 / B

N PM M

1 5

s

~ 5

AM

- 2 2 .5 2 5 h w e e k

m g / k g / 4 h

PM M PN M PM M PM M PM

A N

PM M PM M

Fig.4. Typical morphine serf-administration pattern. The upper graph il lustrates

the fairly constant dosage level attaine d a fter a 6-week period of rapid incremen-

ration. The lower graphs i l lustrate the day-to-day consistency of morphine self-

administration

u n t i l a h i g h p l a t e a u w a s r e a c h e d i n 5 t o 6 w e e k s ( se e F i g . 5 ). T h e f i f t h

a n i m a l r e q u i r e d a u t o m a t i c a l l y - t i m e d p r i m i n g i n j e c ti o n s b e f o r e s el f-

a d m i n i s t r a t i o n b e h a v i o r d e v e l o p e d .

C o d e i n e , a d m i n i s t e r e d i n t r a v e n o u s l y , p r o d u c e d s l i g h t d e p r e s s i o n

i n i ti a l ly b u t a s t h e d o s a g e l e v e l i n c r e a s e d t h e m o n k e y s b e c a m e i n c r ea s i ng

e x c i t a b l e a n d a l e r t . T h e p a t t e r n o f s e l f - a d m i n i s t ra t i o n d i f fe r e d f r o m

t h a t o f m o r p h i n e i n t h a t n o s i g n if ic a n t n o c t u r n a l r e m i s s i o n w a s o b s e r v e d .

V o l u n t a r y a b s t i n e n c e w a s n e v e r o b s e r v e d . M e c h a n i c a l f a i l u r e o n t h e

1 8 t h d a y o f s e l f - a d m i n i s t r a t o n , a t a d a i l y d o s a g e l e v e l o f 8 0 m g / k g ,

r e s u l t e d i n t h e a p p e a r a n c e o f a m i l d m o r p h i n e - l ik e a b s t i n e n c e s y n d r o m e .

T h e h i g h e s t a v e r a g e d a i l y d o s a g e o b s e r v e d f o r o n e w e e k w a s 6 0 0 m g / k g .


10/19


11/19

4 0

ocoine

o n v u t s i o n s t

120

T

mg/kg/doy

~ o- - .o 0.25mg/kg/ in jec t ion

100 No. 90/, M ole 3.9 kg / / / \ ,~,- - -~0.50mg/kg/ in jec t i0n

~ 4 o

-~ 2G

r

g 1 I t

I ~ r

r l I 1 ~ I ~

T

T T T I r t

O 2 4 6 8 lO 12 1/, 16 18 20 22

Day

50

25 C0nvutsi0ns

ng/kg/ / ,h

/,0 20 ~ A ~ / ~ l / , -2 0th d ny

0 l e ~ I T ~ I 1 I ~ r l I ~ l * r . _ _ r o l o l m l o l l r ~ l r I r ~ I 1 i l ~ . . t r i f 1


t 8 1 2 z~ 6 1 2

M

Fig.6. Typical c o c a i n e self-administration pattern. The graphs illustrate t h e

e r r a t i c c o u r s e o s c o c a i n e s e l f - a d m i n i s t r a t i o n

at 0.25 mg/kg) initiated and maintained self-administration at a dose

of 1.0 mg/kg. Once cocaine self-administration was initiated, the course

of intake was of rapid but erratic increase culminating in convulsions

and death within 30 days. In order to prolong the experiments beyond

30 days it was necessary to restrict the intake to 1 dose per hour. Fig. 6

illustrates a typical example in which the intake was unrestricted. The

dosage pattern was characteristic; cocaine was self-administered around

the dock until exhaustion occurred (2 to 5 days in these experiments).

The maximum intake during any 24-hour period was 180 mg/kg. Upon

exhaustion, self-administration was voluntarily discontinued for periods

ranging from 12 hours to 5 days during which the monkeys slept fitfully

and ate frequently. Cycles of self-administration were then resumed.

During self-administration of cocaine the monkeys became apprehen-

sive and restless, showed almost constant choreiform movements,

stereotypy, dysmetria, tremors, mydriasis, pile-erection and gross ataxia

during the first several days. As the dosage increased in daffy amount

and duration, signs o f somatic and psyehotoxicity increased. The mon-

keys showed an extremely rapid loss of muscle mass and grand mal con-


12/19

4

vulsions became frequent. Behavior consistent with visual hallucinations

(staring and grasping at the wall) and tactile hallucinations (continued

scratching and biting of the skin of the extremities, to the point of pro-

ducing extensive wounds and even amputation of the digits) was con-

sistently observed. The monkeys also appeared to become unaware of

their surroundings in that they ignored raisins and candy which were

proffered by the experimenters. These manifestations of toxicity were

rapidly reversible when cocaine administration was discontinued. During

periods of high drug intake all monkeys pressed the inactive lever as

frequently as the active lever.

Morphine Cocaine.

Four monkeys were implanted with dual-lumened

catheters. The lumens were connected to two separate injectors which in

turn were activated by separate lever switches in the monkeys cages.

One injector supplied 2.5 mg/kg morphine per dose, and the other

supplied 1.0 mg/kg cocaine. The monkeys could self-administer either

or both drugs as they wished by pressing the appropriate lever.

Within a few days all four monkeys established a pattern of self-

administration of both drugs, cocaine being the predominant choice

during the day and morphine during the late evening and night. Within

7--10 days the monkeys became so disoriented that no particular dosage

pattern was discernable. Although fewer convulsions developed than

when cocaine was the only drug of self-administration, combined toxic

effects of the two drugs consisted of delirium, marked motor impairment,

anorexia and emaciation. The experiments terminated in death within

2--4 weeks.

The Am~ohetamines. Five monkeys initiated and maintained self-

admin istrat ion of 0.1 mg/kg d-amphetamine. The frequency of self-

administration was rapidly increased until a maximum daffy dosage of

9 mg/kg was attained in 2 --3 weeks. Self-administration of amphetamine

was characterized by irregularity of daily intake. Periodic voluntary

withdrawals lasted from 1 day to 2 weeks. During periods of high intake

self-administration continued day and night. Substitution of meth-

amphetamine (0.1 mg/kg/dose) in two of the monkeys for 5 weeks did no t

produce any detectable change in the behavioral pattern.

The somatic and behavioral toxic effects were similar to, but some-

what milder than, those of cocaine. No grand real convulsions were

observed nor d id chewing of the forearms or digits occur. One monkey did

pluck all of the hair off his arms and abdomen, however, indicating th at

mild tactile hallucinations may have been present. As with cocaine, all

monkeys became confused and pressed both levers indiscriminately

during periods of high dosage. The catabolic effect associated with cocaine

admin istrat ion was also observed in the monkeys which self-administer-

ed the amphetamines.


13/19

42

15 r

mg/kg/dey

12

N

~ 4

o f f e i n e

No 050 emote 2kg o

~ ~ ~ l 0 m g / k g / in ] e c t io n

[ I ~ ~ I l I r I ~ I I I l

2 4 6 8 10 12 14 16 18 20

Week

20F20

= Img/kgl4h

10

10

0

AM PM AM PM AM PM AM PM AM PM AM PM AM PM AM

4, 8 1 2 / 8 1 2 4

A M P M A M

Fig. 7. Ty pica l pa tte rn of caffeine self-administration illustrating ~he unpredictable

course of drug in take

Ca/]eine T w o m o n k e y s f a i le d t o i n i t ia t e s e l f - a d m i n i s tr a t i o n o f 1 .0 m g /

k g c a f f e in e . O n e i n i t i a t e d a n d o n e f a i l e d t o i n i t i a t e s e l f - a d m i n i s t r a t i o n a t

2 .5 m g / k g a l t h o u g h p r i m i n g w i t h a u t o m a t i c i n j e c ti o n s c a u s e d t h e

l a t t e r t o b e g i n s e r f - a d m i n is t r a ti o n . A t a d o s e o f 5 .0 m g / k g , o n e m o n k e y

o f f o u r i n i t i a t e d s e r f - a d m i n i s t r a t io n v o l u n t a r i l y a n d t w o o t h e r s d i d s o

w i t h p r i m i n g .

T h e p a t t e r n o f s e l f- a d m i n i s t r a t io n o f c a f f ei n e w a s i n

l l

c a s e s s p o r a d i c

- - i r r e g u l a r i n t e r v a l s o f s e lf - a d m i n i s t r a ti o n a l t e r n a t e d w i t h p e r i o d s o f

v o l u n t a r y a b s t in e n c e. T h e r e w a s n o t e n d e n c y t o i nc r e as e t h e d o se n o r t o

s e l f -a d m i n i s t e r t h e d r u g a t n i g h t . N o n e o f t h e m o n k e y s s h o w e d a n y o v e r t

s ig n s o f d r u g e f fe c t o r o f t o x i c i t y d u r i n g p e r i o d s o f s e r f - a d m i n i s tr a t i o n o f

c a f f e in e n o r u p o n w i t h d r a w a l . A t y p i c a l e x p e r i m e n t i s i l l u s t r a t e d i n

F i g . 7 .

Mescaline N o n e o f f o u r m o n k e y s i n i t i a t e d s e l f - a d m i n i s tr a t i o n o f

m e s c a l in e e i t h e r s p o n t a n e o u s l y o r a f t e r 1 m o n t h o f p r o g r a m m e d a d m i n is -

t r a t i o n a t d o s e s o f 1 , 5 o r 10 m g / k g e v e r y 2 h o u rs . S a l i v a ti o n w a s o b s e r v e d

a f t e r e a c h i n j e c t i o n i n d i c a ti n g n a u s e a a l t h o u g h n o n e o f t h e m o n k e y s

v o m i t e d . T h e a n i m a l s s h o w e d m y d r i a s is a n d p i l e - e r e c t io n a n d w e r e v e r y


14/19

4

5 0 0 n

m g / k g / d a y

4 O O

3 0 0

2 0 0

1 0 0

I r

e n t o b o r b i t o [

N o . 9 9 6 M o l e 3 S k g

3 m g k g / i n j .

2 5 6 7 B s

W e e k

4 1 2 5 t h w e e k

3 0 1 9 rr0 / k g / 4 h

0 1 ~ r I I 9 I I r I I I [ 1 1 r I [ I f I I I 1 i I t I t T T r T T I f ~ I r I 1 1


4 8 2 4 B

H I ~

Fig. 8. Typic l pa tte rn o f pentob rbit l self-administr tion. Th e gr phs illus~r te

the predictable and nea rly maximal pa tter n of self-administration of pentob rbital

a p p r e h e n s i v e , e v e n o f c o m m o n l a b o r a t o r y n o i s e s . N o a b s t i n e n c e s i g n s

w e r e o b s e r v e d u p o n d i s c o n ti n u a t io n o f t h e p r o g r a m m e d a d m i n i s t ra t i o n .

Pentobarbi ta l F i v e m o n k e y s i n i t i a t e d a n d m a i n t a i n e d s e l f- a d m i n i s tr a -

t i o n o f 3 m g / k g d o s e s o f p e n t o b a r b i t a l . B y t h e e n d o f 1 w e e k a l l m o n k e y s

w e r e t a k i n g t h e m a x i m u m d o s e t h e y w e r e p h y s i c a l l y c a p a b l e o f s elf -

a d m i n i s t e r in g . A s s o o n a s t h e y r e c o v e r v e d s u f fi c ie n t l y f r o m t h e l a s t

i n c a p a c i t a t i n g d o s e , t h e y i m m e d i a t e l y s t r u g g l e d t o d e p r e s s t h e l e v e r

s w i t c h . A s t i m e e l a p s e d , t o l e r a n c e d e v e l o p e d , e n a b l i n g t h e m o n k e y s t o

i n c r e a se t h e i r t o t a l d a f f y i n t a k e u n t i l a p l a t e a u w a s r e a c h e d i n 5 o r 6

w e e k s . T h e m a x i m u m a v e r a g e d a i l y do s e f o r a n y s i n gl e w e e k w a s 4 2 0 r ag /

k g . A t y p i c a l e x p e r i m e n t is i l l u s t r a t e d i n F i g . 8 . S e l f - a d m i n i s t r a t io n w a s

m a i n t a i n e d d u r i n g th e n i g h t a t a p p r o x i m a t e l y h a l f o f t h e d a y t i m e l e v e l

o f i n t a k e . A l l m o n k e y s a b s t a i n e d 3 0 - - 4 5 m i n e a c h m o r n i n g a n d e a c h

a f t e r n o o n w h il e t h e y c o n s u m e d g r e a t e r t h a n a v e r a g e m e a ls . T h e a n i m a l s

m a i n t a i n e d g o o d p h y s i c a l c o n d i t i o n a n d g a i n e d w e i g h t t h r o u g h o u t t h e

c o u r s e o f t h e e x p e r i m e n t .

P r o l o n g e d v o l u n t a r y a b s t i n e n c e n e v e r o c c u r r e d . I n t h e e v e n t o f

m e c h a n i c a l f a i l u r e o r d e l i b e r a t e l y c o n d u c t e d w i t h d r a w a l s , v e r y s e v e r e

a b s t in e n c e s y n d r o m e s w e r e o b s e r v e d w i th i n 4 - - 6 h o u rs . T h e s y n d r o m e s


15/19

4 o - 8 A t c o h o t o / ~ ~

9 m / k g / d o y

N o . 1 0 4 6 F e m a t e

3 0 6 O 2 2 w e e k s

E O Om g l k g l i n ] .

2 0 4

1 0 2 ~ T ~ T y l i I t T r T t i T t T t i

2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2

W e e k

2 0 ~ 1 3 t h w e e k

~ 5


l~ig.9. Ty pica l pa tte rn of alcohol self-administration. T he graphs illustrate th e

periodic vo lun tar y abstinence interspersed between periods of high dosage

w e r e c h a r a c t e r i z e d b y e x t r e m e r e s t l e s s n e s s , t r e m o r s , g r a n d r e a l c o n v u l -

s io n s a n d a p p a r e n t h a l l u ci n a t io n s .

E thano l

F o u r o f fi ve m o n k e y s i n i t i a t e d s e l f - a d m i n i s t r a t io n o f e t h a n o l

a t a d o s e o f 2 0 0 m g / k g . T h e r e f r a c t o r y m o n k e y d i d n o t i n i t ia t e se lf=

a d m i n i s t r a t io n e v e n a f t e r p r o g r a m m e d i n j e c ti o n s o f 2 00 m g / k g / h r f o r

4 w e e k s . O n e w h i c h i n i t i a t e d s e l f - a d m i n i s t r a t io n d i s c o n t i n u e d a f t e r o n e

m o n t h a n d n e v e r r e s u m e d . T h e m a x i m u m i n t a k e o f t h o s e w h ic h m a i n-

t a i n e d s e l f - a d m i n i s t ra t i o n w a s 8 . 6 g m / k g / d a y f o r a 1 - w e ek p e ri o d .

I n s p i te o f t h e o c c u r r e n c e o f s e v e r e a b s ti n e n c e s y n d r o m e s , t h e m o n -

k e y s v o l u n t a r i l y a b s t a i n e d f o r p er i o d s o f 2 t o 4 d a y s t h r o u g h t h e f i r s t

4 m o n t h s o f s e r f - a d m i n i s tr a t io n ; t h e r e a f t e r s u c h p e ri o d s o f v o l u n t a r y

w i t h d r a w a l s e l d o m e x c e e d e d 2 4 h o u r s . S e e F i g . 9 ) .

D u r i n g s e l f - a d m i n i s t r a t i o n t h e m o n k e y s s h o w e d s e v e r e m o t o r i n c o -

o r d i n a t i o n a n d s t u p o r , e v e n t o t h e p o i n t o f l i g h t a n e s th e s i a. D u r i n g

w i t h d r a w a l , a c h a r a c t e r i s t ic a b s t i n e n c e s y n d r o m e w i t h t r e m o r , v o m i t i n g ,

h a l l u c i n a t o r y b e h a v i o r a n d c o n v u l si o n s o c c u r r e d a s s o o n as 6 h o u r s a f t e r

t h e l a s t d o s e .

F o o d i n t a k e d u r i n g t h e c o u r s e o f e t h a n o l s e r f - a d m i n i s t r a ti o n w a s

m i n i m a l ; a ll m o n k e y s sh o w e d m a r k e d w e i g h t l os s a n d c a c h e x ia .

T w o m o n k e y s d i e d d u r in g t h e c o u rs e o f t h e e x p e r i m e n t s d u e t o

s u f f o c a t io n fr o m r e s p i r a t o r y o b s t r u c t i o n d u r i n g a n e s th e s ia .


16/19

4 5

C h [ 0 r p r 0 m o z i n e

No.961 M ole 3.Tkg

CP Z: 0.1mg/kg/ in] .

/ \

/ \

/ \

\

/ T imer program

~ I ~ I I I ~ 1 I ] I 1 I

2 4 6 8 10

Week

12

o 1 .2 i

8 th end 9th week

08

0.4

I l I l I I l I I T ~ I 1 q

0 50 52 54 56 58 5v 62

Boy

F i g

1 0 . P a t t e r n

o f c h lo rp ro m a z in e

s e l f a d m in i s t r a t io n o b s e rv e d

i n 2 o f 6 m o r t k c y s

after periods of automaticallyprogrammed

njections

Chlorpromazine

None of six monkeys initiated self-administration of

chlorpromazine at doses of 0.1 or 0.5 mg/kg. The three at 0.5 mg/kg

received programmed injections every 2 hours for 4 weeks and even then

failed to take any additional injections voluntarily. Upon withdrawal of

programmed injections however, two of these monkeys took 2 to 5 injec-

tions per day for several weeks and then abstained completely see Fig.10).

During programmed administration, the monkeys showed typical

phenothiazine effects of reduced spontaneous activity and responsiveness,

narrowed palpebral fissures and slight miosis but no major dyskinesias

were observed. Upon withdrawal no signs which could be construed as

an abstinence syndrome were observed.

Saline

Throughout the study frequent attempts, including the use of

raisin inducements, were made to establish physiological saline as a

reinforcing agent in naive monkeys; none was successful.

i scuss ion

Previous investigations which involved self-administration of drugs

by laboratory animals have employed subjects already made physiologi-

cally dependent upon the drug under stud y- -in most instances, morphine.

Interp retation of subsequent self-administration of the drug by the

subjects is complicated by the existence of the state of physiological

dependence. It is possible that the animals might have been motivated


17/19

46

by either of two distinct, but quite different, mechanisms--escape

avoidance, in which the ameliorating effect of injected morphine upon

the distress of the abstinence syndrome was quickly learned, or positive

reinforcement, in which, under the circumstances prevailing, the animals

preferred to exist under the influence of the drug s effects.

The initial conditions of the present experiments make it possible to

distinguish which of the alternative motivations leads to the animals,

self-administration of drugs. The use of naive, rather than physiologically

dependent, animals rules out the escape-avoidance mechanism since no

distressing abstinence syndrome existed at the beginning of the experi-

ments when the serf-administration of the various drugs began. Under

such conditions a monkey s refusal to serf-administer a drug or a monkey s

development of self-administration behavior is, in either case, the mon-

key s unhindered decision and a direct reflection of his preference. Since

a majori ty of monkeys initiated and maintained self-administration of

morphine, codeine, pentobarbital and ethanol, one must conclude that

they developed psychological dependence--a preference to exist under

the influence of the drugs effects--before sufficient time had elapsed or

dosage administered for physiological dependence to develop. I t is quite

likely, however, that as physiological dependence developed, the relief of

the distress of the abstinence syndrome, afforded by self-administration

of the drug, soon became a secondary motivation for continuing the self-

administration behavior.

The conclusion that psychological dependence is the primary motiva-

tion for drug abuse is further strengthened by the fact th at monkeys self-

administered cocaine and d-amphetamine, neither of which produces

physiological dependence. With such drugs the only possible motivation

for continued self-administration is psychological dependence. Seevers

(1968) has discussed this point at length in a recent symposium.

In the present experiments the monkeys serf-administered those drugs

which man abuses severely, yet they developed minimal or no self-

administration behavior for nalorphine, chlorpromazine and mescaline--

drugs which people seldom abuse. The manifestations of somatic and

behavioral toxicity observed during drug administration, and in some

cases during withdrawal periods, were similar to the well-known toxicities

of these drugs in man. If such parallelisms should continue as similar

studies are conducted with representative members of the remaining

classes of psychoactive drugs, this technique could prove to be valuable

for predicting potentia l abuse liability of new psychoactive agents. The

major limitation of the present technique is that drugs which are not

water soluble cannot be tested. The evaluation of such important sub-

stances as the active ingredients of marihuana must await fur ther refine-

ments of methodology.


18/19


19/19

48

W e e k s , J . R . : E x p e r i m e n t a l m o r p h i n e a d d i c t i o n : l~ [e th od f o r a u t o m a t i c i n t r a v e n o u s

in j ec t i ons i n un re s t r a ined r a t s . Sc i ence 138 , 143 - -144 1962).

W i k l e r , A . , W . R . M a r t i n , F . T . P e s e o r , a n d C . G . E a d e s : F a c t o r s r e g u l a t i n g o r a l

c o n s u m p t i o n o f a n o p i o i d E t o n i t a z i n e ) b y m o r p h i n e - a d d i c t e d r a t s . P s y c h o -

pha rm aeo log i a Be rh ) 5 , 55 - -7 6 1963).

G . A . D e n e a u

D r u g A b u s e D i v i s i o n

S o u t h e rn R e s e a r c h I n s t i t u t e

2 0 0 0 N i n t h A v e n u e S o u t h

B i r m i n g h a m , A l a b a m a 35 20 5, U . S . A .

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Self-Administration of Psychoactive Substances by the Monkey A Measure of Psychological Dependence

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