Psychopharmacologia (Berl.

) 8, 150--156 (1965)
From the Department of Pharmacology,
School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania,
and the Department of Psychology, Yale University, New Haven, Connecticut
Countereonditioning and Extinction
of Fear Fail to Transfer from Amobarbital
to Nondrug State*
By
HERBERT BARRY~ HI, EDWARD E. ETHEREDGE~ and NEAL E. MILLER
With 1 Figure in the Text
(Received June 18, 1964)
DOLLARD and MILLER, i n an anal ysi s of conflict behavi or , poi nt ed out
t ha t one of t he pur poses of ps yc hot he r a py is t o reduce unreal i st i c fears
whi ch pr event t he pat i ent f r om at t ai ni ng desi rabl e goals. These aut hor s
suggest ed t ha t alcohol and bar bi t ur at es, b y reduci ng t he f ear - mot i vat ed
avoi dance mor e t ha n t he y reduce t he ot her dri ves whi ch mot i va t e ap-
proach, mi ght enabl e pat i ent s t o at t ai n t he goals. I f t he dr ug has t he
desi red t her apeut i c effect, t he r ewar di ng effect of at t ai ni ng t he goal not
onl y rei nforces t he appr oach response but also eount ercondi t i ons t he
opposi ng f ear and avoi dance responses. PAr Lor r epor t ed t ha t t he aver si ve
effects of a pai nful shock coul d be weakened or even el i mi nat ed when t he y
were eonnt er condi t i oned b y bei ng i mmedi at el y followed b y food. WIL-
T,IA~S and BARleY f ound t h a t t he per f or mance of an i ns t r ument al l y
condi t i oned response was less st r ongl y i nhi bi t ed by puni shment s whi ch
were pai r ed wi t h r ewar ds r at her t ha n bei ng del i vered at separ at e t i mes.
I f t he avoi dance is not rei nforced b y puni s hment when t he f ear ed goal
is at t ai ned, as in t he case of unreal i st i c fears, t he f ear and avoi dance
responses are f ur t her weakened b y ext i nct i on.
DOLLARD and MILL]~ ci t ed exper i ment al st udi es on ani mal s (MAs-
S~MA~ and Yv ~ ; CO~OER) and clinical obser vat i ons wi t h huma n pa-
t i ent s ( GRI ~ER and SPIEGEL) gi vi ng evi dence t ha t admi ni st r at i on of
alcohol or bar bi t ur at es ma y r esul t in t he per f or mance of a response
* Research grants from the National Institute of Mental Health, U.S. Public
ttealth Service supported this research (MY 2949) and the preparation of the
article (MH 07824). Some of the replications were tested by Pit"ZLLIS MILL~ and
by ROB~TA PRITZKER. A brief report of part of the findings was included in
MILLE~ 1961 and 1964.
i 5i
whi ch ot herwi se woul d have been i nhi bi t ed by fear. Subsequent experi -
ment s wi t h ani mal s have demons t r at ed a fear-reduci ng effect of amobar -
bi t al sodi um (BAILEY and MrLL1s~; MILLER 1961, 1964).
DOLLARD and MILLE]~ also poi nt ed out t ha t a dr ug can have a l ast i ng
t her apeut i c effect onl y i f t he count er condi t i oni ng and ext i nct i on of fear,
whi ch have occurred dur i ng t he dr ugged st at e, t r ansf er t o t he nor mal ,
nondr ug st at e. I t is well known t ha t ma n y drugs pr oduce novel sensat i ons
and ot her changes in t he st i mul us si t uat i on. Therefore, l earni ng whi ch
has occurred in t he dr ugged s t at e ma y be expect ed t o suffer a st i mul us-
gener al i zat i on decr ement in t r ansf er r i ng t o t he nondr ug st at e. Exper i -
ment s on r at s have shown such t r ans f er decr ement for amobar bi t al
(BAR~Y, MI LL~, and TIDD), for alcohol (CosG~R), for pent obar bi t al
( OwnToN) , for chl or pr omazi ne (H~IsTAD ; ItUNT; OTIS), and for amphet -
ami ne and mor phi ne (BELLS~WLL~).
The exi st ence of a st i mul us- gener al i zat i on decr ement does not
necessari l y me a n a compl et e di ssoci at i on bet ween t he dr ugged and
nondr ug st at e. I f a dr ug enabl es t he ani mal t o experi ence count er-
condi t i oni ng and ext i nct i on of f ear and avoi dance, even a l arge st i mul us-
general i zat i on decr ement mi ght not be sufficient t o pr event effect i ve
t r ansf er of t hese powerful processes f r om t he dr ugged t o t he nondr ug
st at e. The pr esent exper i ment t est ed whet her amobar bi t al enabl ed r at s
t o r esume a pr evi ousl y puni shed response and t her eby experi ence coun-
t er condi t i oni ng and ext i nct i on of t hei r f ear and avoi dance. I f t he dr ug
had t hi s effect, t he exper i ment pr ovi ded a f ur t her t es t of whet her t hi s
t her apuet i c dr ug effect t r ansf er r ed t o t he nor mal , nondr ug st at e.
Me t hods
Subjects. A t ot al of 108 mal e al bi no r at s were used, bet ween i 00 and
120 days old, of Spr ague- Dawl ey st rai n, recei ved f r om t he Hol t z ma n Co.,
Madison, Wisconsin. The y were t est ed in 7 repl i cat i ons, wi t h t he numbe r
of r at s i n each r epl i cat i on var yi ng f r om 9 t o 28. They were housed i n
i ndi vi dual cages and mai nt ai ned on a f ood depr i vat i on schedule, re-
cei vi ng bet ween 12 and 14 g. Pur i na l ab chow checkers per day,
shor t l y af t er t est i ng. Wa t e r was cont i nuousl y avai l abl e in t hei r cages.
Apparatus. Six i dent i cal oper ant - condi t i oni ng t es t boxes were used;
t hey are descri bed in det ai l b y Gnoss~A~. El ect r i c shock, wi t h vol t age
sel ect ed by t he exper i ment er , was del i vered t hr ough a 150,000-ohm
resi st or in series wi t h t he ani mal . One side of t he shock ci rcui t was
connect ed t o t he l ever, mount e d on one end wall; t he ot her side of t he
ci rcui t was connect ed t o t he ot her met al par t s of t he box (floor rods
and bot h end walls). The shock was act i vat ed i nt er mi t t ent l y, wi t h a fixed
dur at i on of 3 sec and a var i abl e i nt er val bet ween shocks of 1- - 5 sec,
152
averagi ng 3 scc. Thus t he ani mal recei ved shock at unpr edi ct abl e times,
but onl y while t ouchi ng t he lever.
Procedures. The animals were t r ai ned t o press t he l ever for food, wi t h
a single pel l et (45 mg f r om t he P. J . Noyes Co., Lancast er, New Hamp-
shire) del i vered by each l ever press. Af t er a few days t hey pressed at a
r api d and st abl e rat e. Thi s pr el i mi nar y t rai ni ng was followed by several
days of four br i ef trials per day. They general l y ear ned bet ween l 0 and
15 pellets i n each trial. These were followed by 2 or 3 days of fear-t rai ni ng
trials in whi ch l ever pressing was puni shed by shock, wi t h t he vari abl e-
i nt er val schedule descri bed above. The shock was st ar t ed at a low level
and i ncreased in l at er sessions t o a maxi mum of 368 volts, which was
high enough for al most compl et e pr event i on of t he lever-pressing re-
sponse. For all t he repl i cat i ons except t he first, each ani mal was i nj ect ed
i nt r aper i t oneal l y wi t h isotonic saline (1.5 ml/kg), 10 mi n before t he first
t ri al on each day of fear t rai ni ng, t o maxi mi ze si mi l ari t y wi t h subsequent
tests.
The fear t rai ni ng was followed by one day wi t h four trials, spaced
2 t o 3 mi n apar t , in which t he shock was t ur ned off. On t hi s day, 10 rain
pri or t o t he first t ri al each ani mal was i nj ect ed i nt r aper i t oneal l y wi t h
one of t hr ee dosages (10, 20, 30 mg/kg) of amobar bi t al sodi um in a
l 0 mg/ ml saline solution, or wi t h saline placebo. The pl acebo group was
di vi ded among subgroups gi ven t hr ee vol umes of saline, equal t o t he
t hr ee vol umes of drug solution (1, 2, 3 ml/kg). The placebo, 10, 20, and
30 mg/ kg groups cont ai ned, respect i vel y, 40, 22, 26, and 20 rat s. This
was t he t est of t he effect of amobar bi t a] on count ercondi t i oni ng and
ext i nct i on of fear. On a subsequent day four more trials were given,
wi t h i dent i cal procedures as in t he t est for effect of amobarbi t al , except
t ha t t he y were preceded by i nj ect i on of pl acebo for all t he animals. Thi s
was t he t est of whet her count ercondi t i oni ng and ext i nct i on of fear t rans-
f er r ed f r om t he drugged t o t he nondr ug st at e.
Some differences among t he seven repl i cat i ons in cert ai n details of
procedure shoul d be not ed. I n repl i cat i ons 6 and 7, any di st ract i ng
audi t or y and visual st i mul i were mi ni mi zed by closing t he door of a
chamber which enclosed each t est box. The dur at i ons of t he sessions
were 30, 40, or 60 see for di fferent replications. Duri ng t he fear t rai ni ng,
t he severe shocks were i nt r oduced more suddenl y or more unpr edi ct abl y
in t he l at er replications, wi t h t he purpose of reduci ng t he percent age
of animals in t he pl acebo group which r esumed l ever pressing.
I n t he first five replications t her e were f our fear-t rai ni ng trials on
each of 2 days ; i n repl i cat i on 6 t her e were 2 on t he first day, one on t he
second, and four on t he t hi r d; in repl i cat i on 7 t her e were four on each
of 3 days. I n repl i cat i on 6 t he t est for t r ansf er was di vi ded i nt o 2 days
153
wi t h t wo trials each, separ at ed by a day of t wo addi t i onal trials in
which t he t est for effect of amobar bi t al was repeat ed.
Since t he general per f or mance and t he dr ug effects were r easonabl y
equi val ent in t he seven repl i cat i ons, t he differences in procedures con-
t r i but e t o t he gener al i t y of t he conclusions.
Re s ul t s
Fig. 1 shows t he per cent age of animals which pressed t he l ever on
each t ri al duri ng t he t est for t he effect of amobar bi t al and duri ng t he
subsequent t est for t r ansf er f r om t he drugged t o t he nondr ug st at e. The
l ef t - hand por t i on of t he gr aph shows t ha t each of t he t hr ee drug dosages
30
: / k g / \
~% 20 !..." P/aaebo
0
/ 2 3 ~/ / 2 3 l/
Trials Trials
Fig. 1 a a n d b. P e r c e n t a g e o f a n i m a l s w h i c h m a d e the previously p u n i s h e d response d u r i n g the test
for effect o f a m o b a r b i t a l o n oounteroonditioning a n d extinction o f fear-motivated avoidance, w i t h
separate groups given placebo or different drug dosages (10, 20, 30 mg/kg), and during the subsequent
test for transfer of counterconditioning and extinction from the drugged to the nondrug state, with
all the groups given placebo, a test for effect of amobarbital; b test for transfer to nondrug state
ai ded t he ani mal s t o resume t he previ ousl y puni shed lever-pressing re-
sponse. The difference bet ween t he pl acebo group and t he combi ned
drug groups was st at i st i cal l y significant i n each of t he 4 trials ( Xsquar e
= 8.70, d/---- I , p ~ .01 f or per cent age of animals whi ch pressed t he
l ever i n t he f our t h t ri al ).
The di fferent dr ug dosages had differential effects. Most of t he animals
gi ven 30 mg/ kg were mar kedl y at axi c and a few of t hem pressed t he
l ever wi t hout eat i ng t he food pellets which t hey earned, whereas 10 mg/ kg
was insufficient t o pr oduce any not i ceabl e at axi a. I n t he first trial,
shown on t he l ef t - hand por t i on of t he graph, t he 3 dosage groups differed
significantly f r om each ot her (X square -~ 12. 2i, d / 2, p ~ .01), wi t h
t he hi ghest pr obabi l i t y of l ever pressing by t he group gi ven t he i nt er-
medi at e dosage. However , in t he f our t h t ri al t her e was no significant
difference among t he drugged groups ( X square == 1.99, d / = 2).
154
Even wi t hout t he t her apeut i c ai d of t he drug, some ani mal s in t he
pl acebo group vent ur ed t o press t he l ever and t hus exper i enced count er-
condi t i oni ng and ext i nct i on of f ear and avoi dance. The r epeat ed ex-
posures t o t he t es t si t uat i on ma y also have pr ovi ded some ext i nct i on
of f ear and avoi dance, shown in t he pr ogr essi vel y i ncreasi ng per cent age
of ani mal s in t he pl acebo gr oup which pressed t he l ever duri ng t he ei ght
successive trials. Each of t he ot her groups likewise t ended t o show a
rising pr obabi l i t y of l ever pressi ng duri ng t he four successive t ri al s under
t he same condi t i on. However , all t hr ee amobar bi t al dosage gr oups
showed a decrease in per cent age of ani mal s whi ch pressed t he l ever, f r om
t he l ast t r i al under t he dr ug t o t he first nondr ug t ri al . Thi s decrease, for
t he t hr ee groups pool ed t oget her , was hi ghl y significant ( X2 = 7.60,
df = 1, p < .01). Ther ef or e t he eount er eondi t i oni ng and ext i nct i on of
f ear and avoi dance, which occurred under t he ixifiuence of amobar bi t al ,
fai l ed t o t r ans f er t o t he nondr ug st at e.
Cont r ar y t o a ny i ndi cat i on of even a weak t r ansf er of count er-
condi t i oni ng and ext i nct i on f r om t he dr ugged t o t he nondr ug st at e, t he
r i ght - hand por t i on of Fig. 1 shows t ha t t he per cent age of ani mal s press-
ing t he l ever was gener al l y l ower for t he gr oups whi ch had been under
amobar bi t al t ha n f or t he pl acebo group.
Ther e was an i nverse r el at i onshi p bet ween t ot al numbe r of l ever
presses in t he four t ri al s of t he t es t for t r ansf er and t he dosage of amo-
bar bi t al (placebo, 10, 20, 30 mg/ kg) in t he pr i or t est , wi t h a st at i st i cal l y
significant difference among t he four groups ( Xs qua r e = 8.05, d] ~-3,
p < .05, t est ed by t he Kr uskal - Wal l i s One- Way Anal ysi s of Vari ance
for r ank- or der ed scores ; SIEGEL). The r i ght - hand por t i on of Fig. 1 also
shows an i ndi cat i on of an i nverse rel at i onshi p bet ween pr obabi l i t y of
l ever pressi ng and dosage of amobar bi t al in t he pr i or t est , but wi t h t hi s
less sensi t i ve measur e of per f or mance t he four groups di d not differ
si gni fi cant l y.
Di s c u s s i o n
The dose-response effects of amobar bi t al were consi st ent wi t h what
mi ght be ant i ci pat ed. Wi t h a dosage hi gh enough t o pr oduce anest hesi a,
t her e woul d be no r espondi ng dur i ng t he t es t for dr ug effects and no
t r ans f er of ext i nct i on t o a subsequent nondr ug t est . The ani mal s gi ven
30 mg/ kg were close t o t hi s ext r eme effect. They showed less response
duri ng t he t es t for dr ug effects t ha n di d t he i nt er medi at e dosage gr oup
(20 mg/ kg). Dur i ng t he t es t for t r ansf er t hei r pr obabi l i t y of r espondi ng
was less t ha n t ha t of t he pl acebo group, which showed t he benefi t of
some ext i nct i on of avoi dance due t o t he pri or exposur es t o t he t es t
si t uat i on under t he same pl acebo condition. The i nt er medi at e dosage
gr oup (20 mg/ kg), duri ng t he t es t for t r ansf er , was superi or t o t he
155
highest-dosage group but i nferi or t o t he pl acebo group. I n compari son
wi t h t he hi gher dosages, t he lowest dosage (10 mg/kg) pr oduced a smal l er
effect on per f or mance and also a smaller decrease in per f or mance due t o
t he t r ansf er t o t he nondr ug st at e.
The present exper i ment shows one l abor at or y si t uat i on i n which
count ercondi t i oni ng and ext i nct i on of fear and avoi dance furled t o
t r ansf er f r om t he drugged t o t he normal , nondr ug state. Ot her experi-
ment s ma y det er mi ne whet her this finding i t sel f t ransfers t o ma ny ot her
si t uat i ons. We woul d expect t he pr esent finding t o be val i d for a wide
range of si t uat i ons, because t r ansf er failed t o occur wi t h several drug
dosages and under exper i ment al conditions which were vari ed in t he
di fferent replications. Moreover, t he failure for t r ansf er t o occur was
at t r i but abl e nei t her t o a well-established nor t o an i nt ense f ear - mot i vat ed
avoi dance. The avoi dance t rai ni ng was compl et ed in 2 or 3 days of br i ef
t est sessions; even wi t hout t he aid of t he drug, mor e t han hal f t he
pl acebo ani mal s r esumed l ever pressing by t he end of t he ei ght h sub-
sequent session. I n general, t he pr esent findings suggest t ha t t he t hera-
peut i c effect of amobar bi t al is not l i kel y t o t r ansf er t o t he nondr ug st at e.
Some changes in conditions ma y be identified as being l i kel y t o
i mpr ove t he pr obabi l i t y of t r ansf er f r om t he drugged t o t he nondr ug
st at e. A l arger number or longer dur at i on of sessions under t he drug
mi ght be helpful. I n part i cul ar, allowing t he animals t o cont i nue re-
sponding while t he dr ug effects are gr adual l y weari ng off mi ght faci l i t at e
t ransfer. Per haps a di fferent drug woul d pr oduce more t ransfer. Exper i -
ment al i nvest i gat i on of t hese and ot her vari abl es mi ght yi el d i nf or mat i on
which could be appl i ed in t he ma ny si t uat i ons where i t is desirable for
t he t her apeut i c dr ug effect to t r ansf er t o t he nondr ug st at e.
Summary
Thr ee dosages of amobar bi t al sodi um all ai ded albino r at s t o resume
a pr evi ousl y puni shed lever-pressing response. This finding was obt ai ned
in a t est of count ercondi t i oni ng and ext i nct i on of f ear - mot i vat ed avoid-
ance, wi t h 108 animals di vi ded i nt o groups which were gi ven pl acebo or
one of t hr ee dosages of amobar bi t al (10, 20, or 30 mg/kg). I n a subsequent
t est for t r ansf er of count ercondi t i oni ng and ext i nct i on t o t he nondr ug
st at e, wi t h pl acebo gi ven t o all t he animals, t he superi or per f or mance
under t he dr ug failed t o t r ansf er t o t he nondr ug st at e. On t he cont r ar y,
t her e was t he suggestion of an i nverse rel at i onshi p bet ween per f or mance
in t he t est for t r ansf er t o t he nondr ug st at e and drug dosage duri ng t he
pri or t est for effect of amobarbi t al . Thi s exper i ment demonst r at es t ha t
t he st i mul us-change decr ement pr oduced by a shi ft f r om t he drugged
t o t he nondr ug st at e ma y pr event t he t her apeut i c r et r ai ni ng under t he
drug f r om t r ansf er r i ng t o t he nondr ug st at e.
156
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Dr. I-I]mBERT BXaRr, III,
Dept. of Pharmacology,
School of Pharmacy, University of Pittsburgh,
Pittsburgh, Pennsylvania, U.S.A.