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Tolerance to the anticonvulsive effect of alcohol is not influenced by Pavlovian conditioning Puttaswamaiah, Sheela D. 1984

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TOLERANCE TO THE ANTICONVULSIVE EFFECT OF ALCOHOL IS NOT INFLUENCED BY PAVLOVIAN CONDITIONING By Sheela D. B. Sc. , C a r l e t o n  Puttaswamaiah University.  1981  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS in T H E  F A C U L T Y  O F  G R A D U A T E  S T U D I E S  (Department o f Psychology)  We accept t h i s t h e s i s as conforming t o t h e r e q u i r e d  standard  THE UNIVERSITY OF BRITISH ' COLUMBIA 1  August 1984 ©Sheela  D. Puttaswamaiahi  1984  .  \  f*> •»  In p r e s e n t i n g  t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of  requirements f o r an advanced degree a t the  the  University  o f B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make it  f r e e l y a v a i l a b l e f o r reference  and  study.  I  further  agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may  be  department o r by h i s o r her  granted by  the head o f  representatives.  my  It i s  understood t h a t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain  s h a l l not be  allowed w i t h o u t my  permission.  Department o f  Psychology  The U n i v e r s i t y o f B r i t i s h 1956 Main Mall Vancouver, Canada V6T 1Y3 Date  DE-6  (3/81)  ' August  Columbia  1-5, 198*f  written  ii  ABSTRACT  Tolerance  to the A n t i c o n v u l s i v e  E f f e c t o f A l c o h o l i s not  by P a v l o v i a n  Influenced  Conditioning by  Sheela D.  The  effects  duration  of  stimulation  of  environmental  kindled were  Puttaswamaiah  seizures  measured  to  elicited  was  with  kindled  injections i n  of  received  alcohol-associated  is  received  explained  context  five  alternating  by  the  the  On  the  specific.  bidaily  with  five  i n Environment B, each f o l l o w e d  by an amygdaloid s t i m u l a t i o n .  other  be  alcohol  seizures  Environment A  injections  subjects  amygdaloid  conducted t o determine i f t o l e r a n c e t o  the a n t i c o n v u l s i v e e f f e c t  saline  the  model o f drug t o l e r a n c e .  Experiment 1 Rats  by  on  determine i f t o l e r a n c e t o t h e  anticonvulsive e f f e c t of alcohol could Pavlovian  manipulations  test  day*  alcohol bidaily  1 hr l a t e r half  the  t e s t i n j e c t i o n and s t i m u l a t i o n i n the  environment  (Environment A)  whereas  the  h a l f r e c e i v e d t h e t e s t i n j e c t i o n and s t i m u l a t i o n i n t h e  s a l i n e — a s s o c i a t e d environment  (Environment B).  d i f f e r e n c e s i n s e i z u r e a c t i v i t y between t h e seen.  The  subjects  Environment A were g i v e n  receiving  the  No  two test  groups  were  injection  in  s a l i n e i n j e c t i o n s and s t i m u l a t i o n s i n  t h i s same environment 48 hr a f t e r t h e a l c o h o l t e s t Exposure  significant  injection.  t o j u s t t h e a l c o h o l - p r e d i c t i v e cues d i d not e l i c i t a  compensatory  increase i n seizure a c t i v i t y  as  predicted  from  0  iii  the P a v l o v i a n  model o f drug  Experiment 2  was  tolerance.  designed  to  show  procedures would produce an a t t e n u a t i o n anticonvulsive e f f e c t of alcohol. alcohol  Subjects  extinction  tolerance  to the  were g i v e n  bidaily  i n j e c t i o n s and s t i m u l a t i o n s i n Environment A f o r f i v e  sessions. given  of  that  The s u b j e c t s  five  bidaily  i n t h e e x t i n c t i o n c o n d i t i o n were  saline  injections  and  Environment A, whereas t h e c o n t r o l s u b j e c t s stimulations associated  on  these  five  with alcohol.  received  days,  On  an  alcohol  Environment A.  Although  the two  s i g n i f i c a n t l y i n s e i z u r e duration,  test  and groups  procedures  i t cannot  be  a l l subjects in  differ  they both e x h i b i t e d  seizure  o f t o l e r a n c e i n t h e group t h a t had  Accordingly,  only  d i d not  that  would  given  stimulation  attenuation  procedures  zero  day,  so  alcohol,  to  were  durations extinction  close  stimulations i n  but i n an environment not  injection the  then  observing  not  have  claimed  that  any  further  undergone been  the  the  possible. extinction  affected tolerance to the anticonvulsive e f f e c t of  however t h e l e v e l o f t o l e r a n c e i n t h e  control  group  d i s s i p a t e d so r a p i d l y t h a t i t i s u n l i k e l y t h a t l e a r n i n g  played  a r o l e i n i t s development. In  Experiment 3,  preexposure  on  the  development  anticonvulsive effect i n the  Preexposure  injections  During session, and  of Group  tolerance  were  given  five  were the  with a l c o h o l administration. given  the  Subjects  bidaily  saline  subsequently Control  group  t h e same treatment but i n Environment B.  tolerance  development  a l l r a t s were g i v e n the  stimuli) to  a l c o h o l was i n v e s t i g a t e d .  development  of  sessions  and  the  test  five bidaily alcohol injections  s t i m u l a t i o n s i n Environment A.  retard  of  and s t i m u l a t i o n s i n Environment A —  t o be a s s o c i a t e d subjects  the e f f e c t o f CS ( c o n d i t i o n e d  CS  tolerance  prexposure  d i d not  to the a n t i c o n v u l s i v e  iv  e f f e c t of a l c o h o l . These  results  indicate  that,  tolerance  to  the  a n t i c o n v u l s i v e e f f e c t o f a l c o h o l can develop i n the absence conditioning systematic Pavlovian the model.  effects. demonstration  This of  model of tolerance«  study the  constitutes  failure  to  the verify  of  first the  thus l i m i t i n g the g e n e r a l i t y o f  V  TABLE OF CONTENTS  Introduction  1  Definitions Pavlovian  of* T o l e r a n c e  Theory o f Learned  2 Tolerance  3  C o n t i n g e n t T o l e r a n c e and t h e A n t i c o n v u l s i v e Effect of Alcohol  12  Rationale  16  G e n e r a l Methods  17  EXPERIMENT 1 Situational  S p e c i f i c i t y and T o l e r a n c e t o t h e  Anticonvulsive E f f e c t of Alcohol Introduction  22  Methods  22  Results  25  Discussion  30  EXPERIMENT 2 E x t i n c t i o n of Tolerance to the Anticonvulsive Effect of Alcohol Introduction  31  Methods  31  Results  33  Discussion  36  EXPERIMENT 3 The E f f e c t o f CS Preexposure  on T o l e r a n c e t o  vi  the A n t i c o n v u l s i v e E f f e c t o f  Alcohol  Introduction  37  Methods  38  Results  39  Discussion  42  H i s t o l o g y and  Blood  Alcohol Analysis  General Discussion  43 51  I n t e r p r e t a t i o n of the R e s u l t s  52  Major I m p l i c a t i o n s o f the C o n c l u s i o n s  55  Concluding  Remarks  References. .  64 67  LIST OF FIGURES  Figure i  Tolerance t o the a n t i c o n v u l s i v e e f f e c t of a l c o h o l i s not s i t u a t i o n s p e c i f i c  Figure 2  The e f f e c t o f e x t i n c t i o n p r o c e d u r e s on t o l e r a n c e t o the a n t i c o n v u l s i v e e f f e c t o f a l c o h o l  Figure 3  28  CS preexposure does not a t t e n u a t e t h e development  35 of  t o l e r a n c e t o t h e a n t i c o n v u l s i v e e f f e c t o f a l c o h o l . . 41 Figure 4  E l e c t r o d e placements o f s u b j e c t s i n Experiment 1. . . 46  Figure 5  E l e c t r o d e placements o f s u b j e c t s i n Experiment 2. . . 48  Figure 6  E l e c t r o d e placements o f s u b j e c t s i n Experiment 3. . . 50  viii  LIST OF TABLES  Table 1  Studies investigating  Pavlovian conditioning  of  t o l e r a n c e t o d i f f e r e n t e f f e c t s o f d i f f e r e n t drugs. ... 9 Table 2  Blood a l c o h o l 1#  2,  and 3  l e v e l s o f s u b j e c t s i n Experiments 44  ACKNOWLEDGEMENTS  I would l i k e t o l i k e thank Dr. John P i n e l f o r h i s s u p p o r t throughout  the  duration  assistance i n the preparation like  to  thank  Michel  Mana  of  these  experiments  of t h i s thesis. and  George  I  Renfrey  and h i s  would  also  for their  i n v a l u a b l e a s s i s t a n c e i n p e r f o r m i n g some o f t h e experiments.  1  Introduction The  case o f a 24 year o l d woman r e c e n t l y admitted t o t h e  UCLA M e d i c a l described  by Johnson*  remarkable blood she  S c h o o l h o s p i t a l c o m p l a i n i n g o f abdominal p a i n was about  Noll*  and  Rodney  (1982).  What i s  t h i s case i s t h a t d e s p i t e t h e f a c t t h a t h e r  a l c o h o l l e v e l was 1510 mg/dl*  the highest  ever recorded*  was f u l l y c o n s c i o u s and had no obvious symptoms other  tremors and abdominal pain. woman  to  withstand  concentration mg/dl  —  Apparently the a b i l i t y  t h e e f f e c t s o f such a h i g h blood  &  Kalant*  1976) —  period preceding  h e r admission.  a particularly  much  of  Accordingly*  striking*  t h e 9-month this  albeit  demonstration  that  clinical  uncontrolled*  d e m o n s t r a t i o n o f t h e phenomenon o f drug t o l e r a n c e * a  alcohol  was a consequence o f t h e  f a c t t h a t she had been i n t o x i c a t e d f o r  is  this  t h e u s u a l l e t h a l dose i s between 400 and 500  (Sellers  case p r o v i d e s  of  than  that is*  i t  one o r more e f f e c t s o f a drug have  been reduced as a r e s u l t o f p r i o r exposure t o i t . The  s t u d i e s comprising  drug t o l e r a n c e .  In  this thesis  particular*  are a l l  they  studies  are a l l studies of  t o l e r a n c e t o t h e a n t i c o n v u l s i v e e f f e c t o f a l c o h o l and e f f e c t o f l e a r n i n g on i t s development. three  sections  of  types (b)  of  Accordingly*  the introduction  d e f i n i t i o n o f drug t o l e r a n c e and a factors  that  will  brief  can i n f l u e n c e  the f i r s t  include  discussion  of the (a) a of the  i t s development*  e v i d e n c e t h a t l e a r n i n g can i n f l u e n c e t h e development  tolerance  to  tolerance introduction  alcohol*  to  and  alcohol s  concludes  purpose o f t h e t h e s i s .  x  with  (c) a  of  discussion of contingent  anticonvulsive a  of  statement  of  effect. the  The  specific  2  D e f i n i t i o n s of Tolerance T o l e r a n c e t o a drug i s s a i d t o have o c c u r r e d consequence  of  previous  exposure  to  the  when  as  a  drug, t h e r e i s a  decrease i n t h e e f f e c t o f a p a r t i c u l a r dose o f t h e drug and an i n c r e a s e i n t h e dose n e c e s s a r y t o produce a p a r t i c u l a r In  o t h e r words, t o l e r a n c e t o a drug i s s a i d t o  when  the  dose-reponse  consequence Kalant,  has  (Cicero,  1980;  LeBlanc,  between  three  types of  1975).  i s common  to  distinguish  changes t h a t might u n d e r l i e any p a r t i c u l a r tolerance  metabolic  l e a r n e d changes. that  changes,  instance  physiological  I n o t h e r words, i t i s commonly  t o l e r a n c e e f f e c t s can r e s u l t  the  critical  sites,  of  the  drug,  drug or  recognized  (a) from an i n c r e a s e i n t h e a  whole  or  (b) from a change i n t h e s e n s i t i v i t y o f  c e n t r a l nervous system  actions  of  changes,  r a t e o f e l i m i n a t i o n o f t h e drug from t h e body as from  occurred  s h i f t e d t o t h e r i g h t as a  o f exposure t o t h a t drug  & Gibbins,  It  curve  have  effect.  or  or  other  (c)  to  c o u n t e r a c t t h e e f f e c t s o f t h e drug.  tissues learned  to  particular  responses  I t i s important  that  not t o  o v e r l o o k two i m p l i c i t i m p l i c a t i o n s o f t h i s t h r e e - c a t e g o r y view of  drug  tolerance.  of  tolerance  mechanisms  might or*  The f i r s t be  i s t h a t any p a r t i c u l a r  attributable  f o r t h a t matter*  to  of  the  has  on  physiological  changes  t h e development  t h a t as i t may, i t i s u s u a l mechanisms  to  of  tolerance  o t h e r two c a t e g o r i e s .  m e t a b o l i c and/or p h y s i o l o g i c a l that learning  one  these  t o any combination o f them.  The second i s t h a t t h e c a t e g o r y o f l e a r n e d entirely exclusive  any  instance  assume  underlying  mediate  i s not  Presumably any  effects  o f drug t o l e r a n c e . that  metabolic  tolerance  can  Be and be  3  i n f l u e n c e d o n l y by changing t h e amount o f drug thus  that  the  effects  of  learning  on  e s t a b l i s h e d by demonstrations i n which  exposure*  tolerance  and  can  manipulations  be  of the  e x t e r n a l environment i n f l u e n c e t o l e r a n c e development. The  focus  of  the  present  thesis  e f f e c t s o f l e a r n i n g on drug t o l e r a n c e . tolerance" tolerance* to  i s sometimes  used  as  i s on t h e p o t e n t i a l  The term  "behavioural  synonym  f o r learned  a  however t h i s use appears t o r e s u l t from  clearly  a  failure  d i f f e r e n t i a t e between t h e measures used t o a s s e s s  t o l e r a n c e development on t h e one hand and t h e mechanisms are assumed Woods*  t o u n d e r l i e i t on t h e other.  and M i t c h e l l  tolerance  refers  e f f e c t of  a  behavioural  (1969). who c o i n e d t h e simply  drug  to  with  changes  a  decrease  repeated  can  term*  t o Kayan*  behavioural  i n some b e h a v i o u r a l  exposure.  Clearly  or  physiological  learning*  as  tolerance  changes  as  they  can  tolerance  by  t o a p h y s i o l o g i c a l drug e f f e c t  <e. g. * hypoglycemia) can be accounted f o r by l e a r n i n g . behavioural  such  be accounted f o r j u s t as r e a d i l y by  d i r e c t metabolic just  According  that  refers  Thus*  t o a type o f t o l e r a n c e e f f e c t *  whereas l e a r n e d t o l e r a n c e r e f e r s t o one by which t o l e r a n c e can develop.  particular  Confusing  mechanism  the two terms tends  to cloud the issues.  P a v l o v i a n Theory o f Learned The extension Solomon  Tolerance,  s o - c a l l e d P a v l o v i a n t h e o r y o f l e a r n e d t o l e r a n c e i s an of  Solomon s opponent p r o c e s s t h e o r y v  proposed  administration  that (process  the  physiological  A)  eventually  effect  According  to the original*  1973).  of  activates  (process B) t h a t appose t h e i n i t i a l drug e f f e c t s * to tolerance.  (1972*  drug  changes  thus l e a d i n g  Pavlovian  view  of  4  tolerance  proposed  by  Siegel  (e. g.  1975),  s t i m u l a t i o n o f t h e drug i s t h e u n c o n d i t i o n e d  stimulus  same e n v i r o n m e n t a l  cues ( c o n d i t i o n e d s t i m u l i ,  begin  conditioned  elicit  d i r e c t i o n t o the i n i t i a l responses, increase initial  UCRs). in  responses  effects of  (CRs),  the  they  drug  opposite i n  (unconditioned  progressively  responses  counteract  the  e f f e c t s o f t h e drug and r e s u l t i n drug t o l e r a n c e .  Although  i t is  usual  to  r e f e r t o t h i s t h e o r y o f drug  t o l e r a n c e as t h e P a v l o v i a n t h e o r y o f t o l e r a n c e (e.g. Hinson,  &  Siegel,  in  Siegel,  1981; Poulos,  press),  P a v l o v i a n theory. the i d e n t i t y  i t is  Wilkinson,  not  strictly  Crowell,  & C a p p e l l , 1981; consistent  with  There i s a major d i s c r e p a n c y with r e g a r d t o  o f t h e CR.  CR i s always i n t h e same Siegel*s  According t o Pavlov  (1927/1960), t h e  direction  UCR.  according  to  tolerance,  a CR d e v e l o p s t h a t  e f f e c t s o f t h e drug. (in  of the  CSs), t h e s e cues  As t h e c o n d i t i o n e d compensatory  magnitude,  (UCS).  i n t h e presence  When t h e s e UCSs a r e r e p e a t e d l y e l i c i t e d to  pharmacological  so-called  as  the  Pavlovian  counteracts  However,  theory  the  o f drug  unconditioned  I n a more r e c e n t r e p o r t , however*  Siegel  press)- has r e v i s e d h i s t h e o r y such t h a t t h e UCS s a r e t h e x  c e n t r a l e f f e c t s o f t h e drug and t h e responses  elicited  by t h e drug.  UCR s  the  systemic  The CS and CR remain  t h e same  x  are  as i n t h e o r i g i n a l v e r s i o n o f t h i s theory. Three  types  o f experiments  a r e commonly used t o s u p p o r t  S i e g e l " s account o f drug t o l e r a n c e .  Although  most  of  the  s u p p o r t f o r t h i s P a v l o v i a n t h e o r y has been p r o v i d e d by s t u d i e s of  morphine  suggested  tolerance,  comparable experiments  that i t applies  manifestations of  alcohol  reported herein are a l l  equally  well  tolerance.  studies  of  to  at  Because alcohol  11  s  theory,  will  be  restricted  least  some  the s t u d i e s  tolerance,  f o l l o w i n g d i s c u s s i o n o f t h e t y p e s o f experiments Siegel  have r e c e n t l y  the  supportive of  to studies of alcohol  5  effects. One type o f e v i d e n c e  f o r the  Pavlovian  interpretation  comes from demonstrations o f s i t u a t i o n a l s p e c i f i c i t y , demonstrations  that  tolerance  that i s ,  t o a drug i s m a n i f e s t e d f u l l y  o n l y when t h e drug i s a d m i n i s t e r e d i n t h e environment previously predicted i t s presentation. have  demonstrated  situational  a l c o h o l tolerance.  A  number  t h a t has  of  studies  s p e c i f i c i t y f o r some t y p e s o f  I n one such study, Le> Poulos, and C a p p e l l  (1979) i n j e c t e d r a t s i n t r a p e r i t o n e a l l y w i t h 2. 5  g/kg  alcohol  once every  nine  alcohol  2  days  administrations  smaller 10th  days.  t h e mean hypothermic  11th  sessions,  the  and  respectively.  in  On  the  the  injection.  subjects  were  By t h e On  not p r e v i o u s l y  session,  the  the  i n j e c t e d with  alcohol-associated  10th  dim  response t o a l c o h o l was much  a l c o h o l i n a d i s t i n c t i v e environment alcohol  by  by t h e sound o f s t a t i c from a r a d i o .  than t h a t e l i c i t e d by t h e f i r s t  and  with  These  took p l a c e i n a room made d i s t i n c t i v e  i l l u m i n a t i o n and ninth t r i a l ,  f o r 18  associated  environment,  mean hypothermic  response was s u b s t a n t i a l l y l a r g e r than t h a t on t h e 9 t h a l c o h o l session,  that i s , the subjects  alcohol's environment. hypothermic during of  showed a l o s s o f  hypothermic  effect  when  During  11th  session,  responses  the  similar  the 9th a l c o h o l session.  situational  specificity  in  tested  Clearly  in  subjects  magnitude  provide  tolerance  to  such  strong  a  the  I n comparable  situational  studies,  specificity  of  those seen  demonstrations support f o r t h e confirmed  the  e f f e c t of  hypothermic  and found t h a t t h e same h o l d s f o r t h e  hypnotic 1980.  effects  1981).  of  alcohol  in  drug  r e s e a r c h e r s have  a l c o h o l i n r a t s ( C r o w e l l e t a l . , 1981; M a n s f i e l d 1980)  novel  exhibited  theory that environmental f a c t o r s a r e involved i n learned tolerance.  to  & Cunningham,  hypothermic  mice ( M e l c h i o r  and  & Tabakoff,  6  The second Siegel^s  common  Pavlovian  type  of  by  placebo  compensatory  injections  d r u g - a s s o c i a t e d environment. investigators*  evidence f o r  i n t e r p r e t a t i o n o f a l c o h o l t o l e r a n c e comes  from s t u d i e s i n which s o - c a l l e d elicited  experimental  Crowell  have  administered  Three  et  CRs  independent  been  in  the  teams  of  a l . (1981). Le e t a l . (1979). and  M a n s f i e l d and Cunningham (1980)* have r e p o r t e d e l i c i t a t i o n such  a  compensatory  tolerance.  CR  following  F o r example*  conditioned  Le  compensatory  et  development  a l . (1979)  hyperthermic  injected  response  saline  D u r i n g t h e t e s t session*  injection  environment o r i n an with a l c o h o l  either  i n this  environment  (the home cage).  The  rats  subjects  not  subjects  received  alcohol-associated  previously  associated  Whereas t h e s u b j e c t s r e c e i v i n g  the p l a c e b o i n j e c t i o n i n t h e showed  in  a  w i t h a l c o h o l e v e r y o t h e r day f o r 8 days i n t h e  same environment. a  alcohol  demonstrated  t o l e r a n t t o t h e hypothermic e f f e c t o f a l c o h o l . were  of  of  presence  of  non-alcohol  s m a l l hypothermic responses* s u b j e c t s r e c e i v i n g  i n t h e presence  of  alcohol  cues  exhibited  a  cues  saline  compensatory  hyperthermia. The  third  type  o f f e r e d i n support o f tolerance  has  been  e x t i n c t i o n procedures tolerance. 1980)* or*  on  of  experimental  Siegel s x  provided can  evidence  Pavlovian by  interpretation  experiments  facilitate  the  frequently  showing  decline  of  that drug  I n one such a l c o h o l s t u d y ( M a n s f i e l d & Cunningham*  r a t s were i n j e c t e d once every 48 hr w i t h e i t h e r alternate  trials*  saline.  a l l subjects received a  injections  i n the alcohol—associated  total  of  seven  illumination*  size*  alcohol  environment and seven  s a l i n e i n j e c t i o n s i n t h e s a l i n e - a s s o c i a t e d environment. environments  alcohol  D u r i n g t h i s phase o f t h e  experiment*  two  of  The  were d i f f e r e n t w i t h r e s p e c t t o n o i s e l e v e l * and  smell.  By  the seventh  alcohol  7  injection/  there  was  hypothermic e f f e c t During  of  a  significant  the  alcohol  t h e e x t i n c t i o n phase,  were  given  13  bidaily  alcohol-associated environment.  saline  treatment  Upon c h a l l e n g e  rectal  in  the  temperature.  s u b j e c t s i n the e x t i n c t i o n group  environment.  received equivalent  on  reduction  injections  in  the  and  the  control  in  the  saline-associated  but  subjects  w i t h an a l c o h o l i n j e c t i o n i n t h e  a l c o h o l - a s s o c i a t e d environment.  subjects  group  temperatures than the c o n t r o l  exhibited  subjects, their  lower  rectal  in  t h a t i s . the e x t i n c t i o n s u b j e c t s  tolerance  the  had  extinction  lost  more  of  t o t h e hypothermic e f f e c t o f a l c o h o l than had  the c o n t r o l s . In  a  subsequent  hypothermic  effect  r e s t group  as  a  demonstration  of  of  extinction  alcohol. Crowell  control.  After  while  tolerance  difference.  Crowell  environment  can  saline  a l c o h o l s hypothermic three  situational a  development of same  a  of  decline  drug-related  in  tolerance to  is  given  can  %  alcohol  the  injections  environment  interpretation  animals  were  and  (b) have l e n t a g r e a t  Pavlovian and  CRs.  of  have a g r e a t e f f e c t on t h e  receiving  placebo given.  of  exactly  deal such the  i n j e c t i o n s displayed  d i f f e r e n t degrees o f t o l e r a n c e depending upon t h e i n which  Mansfield  the  (a) c l e a r l y e s t a b l i s h e d t h a t t h e  Siegel s of  in  compensatory  I n each experiment,  pattern  procedural  experiments—demonstrations  o f t o l e r a n c e t o i t and to  this  effect.  types  drug  support  effects.  to  specificity.  extinction—have  Despite  injections  contribute  %  which  i n t h e i r home  e t a l . confirmed the f i n d i n g of  and Cunningham t h a t  in  development,  the experimental subjects r e c e i v e d s a l i n e i n the  a l c o h o l - a s s o c i a t e d environment.  These  the  e t a l . (1981) used a  s u b j e c t s i n t h e r e s t group were l e f t u n d i s t u r b e d cages  to  environment  Thus, t h e view t h a t  8  repeated  exposure t o a l c o h o l i s  tolerance  is  no  a  longer tenable  sufficient (LeBlanc,  condition  Kalant,  &  for  Gibbins.  1976). Although such s t u d i e s have never literature  on  Pavlovian  alcohol  theory  demonstrations  of  been  tolerance. tolerance  reported  support has  (see  investigated  the  Table  1).  effect  For  of  CS  morphine s analgesic effect.  also  example,  c o n d i t i o n i n g o f the UCS LoLordo.  1979).  drug-associated  Consequently,  period.  environment  The  hot  environment.  control  subjects  d u r i n g the preexposure period. a c q u i s i t i o n period, alcohol  and  environment,  one  might expect t h a t  this  retard  tolerance  plate  in  during  the  left  i n the  Siegel  exposed them the  future  preexposure  i n the home cage  A f t e r undergoing the  tested  become  prediction.  i n which a l l s u b j e c t s were  subsequently  the  1959s  subsequently  would  were  to  r e t a r d s subsequent  group o f r a t s w i t h s a l i n e and  non-functional  morphine-predictive  (1977)  i f c o n d i t i o n i n g were  would  In a study t o c o n f i r m  (1977) i n j e c t e d one  Siegel  with those C S s (Lubow & Moore.  exposure t o the environment which  a  from  x  t o p l a y a r o l e i n t o l e r a n c e development,  to  come  preexposure on t o l e r a n c e  CS without s i m u l t a n e o u s exposure t o the UCS  development.  Siegel*s  I t i s known t h a t exposure t o  x  the  for  the  t h a t CS preexposure can r e t a r d the development  of t o l e r a n c e  Randich *  in  tolerance  injected  with  morphine-predictive  the c o n t r o l s u b j e c t s e x h i b i t e d g r e a t e r  tolerance  than the preexposure s u b j e c t s . Although Pavlovian alcohol*  descriptions  theory  of  studies  and  studies  the  involving  measures not mentioned i n t h i s t h e s i s .  1 summarizes r e c e n t examples o f every has  of  o f t o l e r a n c e were c o n f i n e d t o t h o s e i n v o l v i n g  t h e r e have been q u i t e a number o f  o t h e r drugs  supportive  been i n v e s t i g a t e d w i t h r e g a r d  tolerance  to i t s Pavlovian  effect  Table that  features.  Table 1  Studies  1nvestIgating  classical  Dependent Var table  Author  Year  Drug  Thompson & Ostlund  1965  morphine  rats  amount of 1ngested  Korol.Sletten & Brown  1966  atropine  dogs  s a l 1 vat ion  Wlkler & Pescor  1967  morphine  rats  tremors  Lang,Rush & Pearson  1969  atropine  dogs  s a l 1 vat ion  Roffman,Reddy, & Lai  1973  morphine  rats  hyper therm 1 a  S1ege1 -  1975  Insulin  rats  hypoglycem1 a  Siegel  1977  morphine  rats  ana 1ges1 a— hot p l a t e  S k l a r & Amlt  1978  morphine  rats  lethality  Le.Poulos & Cappel1  1979  ethanol  rats  1979  morphine  rats  Siegel.Hlnson & Krank  1979  morphine  rats  Mansfield & Cunningham  1980  ethanol  rats  Sherman  Subj e c t s  c o n d l t l o n t n g of drug to Ierence  drug  hypotherm1 a hypertherm 1 a ana Iges 1 a l e t h a l 1ty hypotherm1 a  SS  Effects CR  Investigated EX CS PR Pr  Table  1  (continued)  Author  Year  Drug  Subjects  Dependent Variable  Cappel1.Roach & Poulos  1981  pentobarbital  rats  hypothermia  CrowelI.Hinson & Siege!  1981  ethanol  rats  hypothermia  Etkelboom & Stewart  1981  morphine  rats  hyper therm 1 a  Krank,H1nson S tegel  1981  morphine  rats  analgesiapaw 1 ick  Me)chior & Tabakoff  1981  ethanol  mice  hypothermia sedat ion  Mucha,Vo1kov— s k i s & Kalant  1981  morphine  rats  1ocomot ion  P o u l o s , W i 1 k t n— son, & Cappe11  198 1  d-amphetamine  rats  anorex t a  Tiffany & Baker  1981  morphine  rats  ana 1ges1 a— j unip | f 1 i nch  Siegel  1982  heroin  rats  morta1 1 ty  Deme11 week & Goudie  1983  d-amphetam 1 ne  rats  anorex1 a  T 1 f f a n y , P e t r le Mart i n & Baker  1983  morphine  rats  analges i a tail flick  Krank.Hinson & Stegel  1984  morphine  rats  ana 1ges1ahot p l a t e  Wa1ter 6 R 1 cc i o  1984  morphine  rats  ana 1ges1ahot p l a t e  SS  + +  Effects CR  +  Investigated EX CS PR Pr  Note : SS - S i t u a t i o n a l S p e c i f i c i t y CR — Compensatory CR EX - E x t i n c t i o n CS Pr - CS Preexposure PR — P a r t i a l Reinforcement + — T h i s e f f e c t was demonstrated. x — T h i s e f f e c t was t e s t e d but was not demonstrated. B l a n k s i n d i c a t e that the e f f e c t was not t e s t e d in the  study.  12  Contingent Tolerance In  the  and  previous  the A n t i c o n v u l s i v e E f f e c t o f section.  S i e g e l s i n t e r p r e t a t i o n of Although  there  is  now  the e x p e r i m e n t a l  alcohol  x  s t r o n g support  c l e a r from T a b l e I t h a t o n l y o f few have been  tolerance  research  about  another  some  of  administrations  on  seizure  Kristofferson.  1953)  one  Colborne*  by  Pinel.  crucial  to  the  the  effects  of  of  the  alcohol.  repeated  (Dember.  Greenberg & L e s t e r .  design  In  this its  Although t h e r e were  activity  Sigalet.  of  i t is  effects  o f t h i s theory.  effect  for  reviewed.  o f a l c o h o l s many  w i l l be described.  reports  mas  f o r such a view*  anticonvulsive effect, early  support  v  s t u d i e d w i t h i n the c o n t e x t  section.  Alcohol  alcohol  Ellen.  &  1953). a more r e c e n t  and  Renfrey  (1983)  experiments c o m p r i s i n g  was this  thesis. P i n e l e t a l . (1983) electrode i n stimulated  implanted  a  the amygdala o f each subject.  t w i c e a day  k i n d l e motor  f o r 16 c o n s e c u t i v e  seizures.  each s t i m u l a t i o n , elicited  first  and  but  At  first,  eventually  these  days motor  in  bipolar  Each r a t was  t h e r e was  mild  increased  single in  then  order  to  no response t o seizures  severity  until  were each  s t i m u l a t i o n r e l i a b l y e l i c i t e d a motor s e i z u r e c h a r a c t e r i z e d a sequence o f head clonus, of equilibrium.  The  r e a r i n g , f o r e l i m b clonus,  decrease i n the d u r a t i o n o f the  c l o n u s component o f the motor s e i z u r e was gauge the  anticonvulsive  effect  b a s e l i n e s were e s t a b l i s h e d , intubated and  with 4. 5 g/kg  of  the s u b j e c t s  ethanol  administered reverse  stimulations.  t o the r a t s i n  order.  that  is.  the  in  one  The control  to  After stable group  (303S s o l u t i o n ) 90 min after,  loss  forelimb  the measure used  alcohol.  an e q u i v a l e n t volume o f s a l i n e 90 min  b i d a i l y amygdaloid  and  by  were  before,  each o f  five  same substances were group  but  in  s a l i n e b e f o r e each s t i m u l a t i o n  the and  13  ethanol after. injected  On t h e t e s t day, s u b j e c t s i n both groups  intraperitoneally rats  with  that  ethanol  had  were  (1. 5 g/kg i n a 25%  solution).  The  been  stimulated  intoxicated  d u r i n g t h e t o l e r a n c e development t r i a l s  while  displayed  more f o r e l i m b c l o n u s than they had d u r i n g p r e t e s t i n g t h a t i s , they  had  effect.  become  tolerant  to  the  I n c o n t r a s t , t h e r e was  anticonvulsant  action  in  no  alcohol's anticonvulsant diminution  the  of  alcohol's  alcohol-after—stimulation  animals. Tolerance during  the term  study  has been  was f i r s t of  whereas  rats  amphetamine  a v a i l a b i l i t y developed effect,  termed  "contingent  who  each  tolerance  those  had  prior to  been  to  reported  by  given  who  eight  a period of food  amphetamine's  anorexic  g i v e n e i g h t i n j e c t i o n s o f amphetamine  each a f t e r a p e r i o d o f consumption d i d not. were  tolerance. "  c o i n e d by C a r l t o n and Wolgin (1971),  observed t h a t f o o d - d e p r i v e d injections  occurs  p e r i o d o f drug exposure, such as t h a t seen i n t h e  Pinel et al. This  t h a t d e v e l o p s f o r a response o n l y i f i t  Chen  (1968,  1972),  Similar who  results  showed  that  s i g n i f i c a n t l e v e l s o f t o l e r a n c e developed f o r t h e d i s r u p t i v e effects  of  o n l y those the maze  alcohol  on t h e performance o f a c i r c u l a r maze i n  s u b j e c t s t h a t had had an while  intoxicated.  opportunity  opportunity  motor and/or c o g n i t i v e s t r a t e g i e s t o c o u n t e r a c t learned  because  reinforcement  they  practice  He proposed t h a t t o l e r a n c e d i d  not develop u n l e s s t h e s u b j e c t s had an e f f e c t s of the alcohol.  to  E f f e c t i v e behaviours  to  learn  the d i s r u p t i v e  purportedly  were  increased the p r o b a b i l i t y of r e c e i v i n g  while intoxicated.  In h i s 1968 study.  Chen  employed  the  before-and-after  d e s i g n now r o u t i n e l y used i n many demonstrations o f c o n t i n g e n t tolerance.  I n Chen's v e r s i o n o f t h e b e f o r e - a n d - a f t e r  design,  s u b j e c t s i n one group r e c e i v e d t h e drug b e f o r e each t e s t  trial  14  and  s a l i n e a f t e r the test/  whereas s u b j e c t s i n t h e o t h e r  received s a l i n e before the t r i a l the  final  the t e s t  test  group  and t h e drug afterwards.  On  day. a l l s u b j e c t s r e c e i v e d t h e drug p r i o r t o  trial.  That  drug-before—test  there  subjects  was  more  provided  tolerance  strong  importance o f t h e response c o n t i n g e n c y  i n the  evidence  i n the  f o r the  development  of  tolerance. Since  Chen s(1968. 1972) s t u d i e s / f i v e o t h e r examples o f x  contingent a l c o h o l  tolerance  tolerance  d i s r u p t i v e e f f e c t s o f a l c o h o l on t r e a d m i l l  to  the  have  r u n n i n g has been shown t o develop had  been  reported.  more r a p i d l y when r a t s  t h e o p p o r t u n i t y t o r e p e a t e d l y practice  w h i l e i n t o x i c a t e d (LeBlanc.  Gibbins.  et  Benedict/  al. ,  1976i  Mansfield.  t o l e r a n c e develops a slower Berlin.  Woods*  & Kalant.  1973;  LeBlanc  & Woods. 1983).  Whether  i n the alcohol-after-treadmill condition at at  a l l (Wenger.  1980) has been a matter o f debate.  Chen (1979) showed t h a t opportunity  have  t h e t r e a d m i l l task  r a t e (LeBlanc e t a l . . 1976) o r n o t &  First,  on  the  test  day.  rats  Second.  given  t o b a r p r e s s f o r food reward d u r i n g t h e t o l e r a n c e  a c q u i s i t i o n phase had s h o r t e r l a t e n c i e s t o b a r p r e s s than control  subjects.  given  saline  during t h i s tolerance a c q u i s i t i o n Schlapler* potentiation o n l y when t h e  acceleration i n  in  the  Hjeresen. exposed  administration  abdominal  presynaptic  presence o f a l c o h o l . animals  before  the  Third.  task,  Traynor*  that tolerance to the  decay  of  postsynaptic  Alkana*  was  stimulated  Finn,  i n the  and Malcolm  <1983)  Reed. Nakazono. and Woods (1983) r e p o r t e d t h a t to did  a  warm not  environment  develop  tolerance  after  alcohol  to  alcohol s  hypothermic e f f e c t u n l i k e mice who were allowed t o the f u l l  the  ganglion of Aplysia occurred  terminal  Fourth*  the b a r p r e s s  period.  and Barondes (1980) observed  alcohol-produced  and  the  hypothermic  effect  v  experience  of alcohol administration.  The  15  fifth  and  tolerance  last to  example  alcohol*s  mas  the  aforementioned  anticonvulsant e f f e c t  study  of  (Pinel et al. »  1983). Although much o f t h e r e s e a r c h on c o n t i n g e n t  t o l e r a n c e has  i n v o l v e d a l c o h o l , t h e r e have been s e v e r a l n o t a b l e examples contingent  tolerance  t o o t h e r drugs.  Rats t h a t mere i n j e c t e d  with d—amphetamine a f t e r a c c e s s t o milk much  tolerance  to  anorexic  d i d not  1983;  drugged  (Carlton  reported while  that  under  tolerance  rats the  to  anorexic  as those  to drink  and  Schuster  who had had an o p p o r t u n i t y of  required  cocaine  effects  to drink  developed  of  cocaine  tolerance  to  run  on  effects  than  those  Commissaris before  a r o t a t i n g r o d developed  i t s disruptive  milk  greater than  a c c e s s t o milk w h i l e i n t o x i c a t e d . to  milk (1978)  Rech (1983) r e p o r t e d t h a t r a t s g i v e n p e n t o b a r b i t a l  being  as  1971* Demellweek & Goudie*  Woolverton  influence  the  s u b j e c t s denied and  & Wolgin*  Poulos e t a l . * 1981).  develop  e f f e c t s o f amphetamine*  s u b j e c t s g i v e n d-amphetamine and an o p p o r t u n i t y while  of  greater  those  given  p e n t o b a r b i t a l a f t e r t h e task. Like  Chen (1968)*  demonstrations  of  animals  coping  learn  most r e s e a r c h e r s have a t t r i b u t e d t h e i r  contingent or  adapting  t h e i r chances o f reinforcement* differential repeated and  in  level  of  tolerance  seen  giving  not  given  this  opportunity.  as  a  possible  explanation*  e x p l a n a t i o n has a l s o been suggested. need  t o appeal  of contingent could  rise  o p p o r t u n i t i e s t o perform t h e task i n t h e those  that  the  to the  i n the animals given  c o n d i t i o n i n g i n t e r p r e t a t i o n i s however n o t t h e forth  idea  s t r a t e g i e s that increase  thereby*  tolerance  to  drug  This only  state operant  one put  a Pavlovian conditioning In fact*  one  does  not  t o a l e a r n i n g t h e o r y t o e x p l a i n many i n s t a n c e s  tolerance.  A stress  or  habituation  mechanism  r e a d i l y e x p l a i n some i n s t a n c e s o f c o n t i n g e n t  tolerance.  16  However.  researchers  explanation  -typically  of contingent  offer  an  operant  learning  tolererance.  Wenger e t a l . (1980) suggested a P a v l o v i a n i n t e r p r e t a t i o n of* c o n t i n g e n t  tolerance.  saline-before-task they  receive  associated  subjects i s the  the  with t h i s drug  Because  drug  before  administration  with  before  administrations.  The  would  predict  therefore  the first  and that  not  t h e cues the  during view one  day  f o r the  occasion  t h e task, are  Pavlovian  test  on  associated  same  the  as  those  previous  drug  of  learned  should  not  tolerance s e e as much  t o l e r a n c e i n t h e s u b j e c t s who had r e c e i v e d a l c o h o l  after  task than i n t h e s u b j e c t s who r e c e i v e d a l c o h o l b e f o r e (Wenger e t  al. *  of a t e s t before test  i s not  resultant  1980).  According  which  t h e task  t o t h i s view, t h e presence  t h e i n j e c t i o n i s p a r t o f t h e CS and when  presented  decline  in  prior the  the  to  the i n j e c t i o n ,  magnitude  of  the  the  there i s a conditioned  compensatory response e l i c i t e d by t h e t e s t environment.  Rationale Three  experiments  were  conducted  with  the  of  fulfilling  one o b j e c t i v e .  tolerance  t o t h e a n t i c o n v u l s i v e e f f e c t o f a l c o h o l can develop  in  The o b j e c t i v e was t o  aim  t h e absence o f P a v l o v i a n  experiments would  have  two  t e s t i n g a h i t h e r t o untested of  Siegel's  model.  conditioning.  the  determine i f  The r e s u l t s o f t h e  implications.  One  e f f e c t of alcohol i n generality  of  the  i s t h a t by the  context  model would be  extended o r l i m i t e d . The test  of  second i m p l i c a t i o n i s t h a t t h e s e the  anticonvulsant  theory  that  contingent  experiments  tolerance  e f f e c t can be viewed as a s p e c i a l  are a  to alcohol's instance  of  17  Pavlovian  conditioning.  •Prom the f a c t t h a t on subjects  receive  preceded by  the  test  day  the  a l c o h o l f o r the f i r s t  the  interpretation  As j u s t o u t l i n e d *  test.  Evidence  would  be  t h i s claim a r i s e s alcohol-after-test  time without i t being for  supplied  by  this  demonstrations  r e s p o n s e s t h a t are the s u b j e c t of c o n t i n g e n t purpose  whether  of  the  Pavlovian  development F a i l u r e to  of  present  is  was  t o determine  necessary  for  effects  employed by P i n e l e t  under  al.  control  alcohol s %  c o n d i t i o n s comparable t o t h o s e  (1983)  to  demonstrate  t o l e r a n c e would c o n s t i t u t e a d i r e c t c h a l l e n g e i n t e r p r e t a t i o n of contingent  of  the  effect.  x  environmental  be  Accordingly*  tolerance to a l c o h o l s anticonvulsant  demonstrate  anticonvulsant  experiments  conditioning  that  t o l e r a n c e can  brought under the c o n t r o l o f e n v i r o n m e n t a l cues. the  Pavlovian  contingent  t o the  Pavlovian  tolerance.  G e n e r a l Methods Subjects The  s u b j e c t s i n each o f the experiments were male hooded*  300-400g  rats  s u p p l i e d by C h a r l e s  with ad l i b i t u m a c c e s s t o s t a n d a r d  R i v e r Canada housed s i n g l y l a b o r a t o r y chow and  water.  Surgery^ Xn  each  electrode  was  experiment*  a  implanted  in  p o s t e r i o r t o bregma. 5. 0 mm 9. 0 mm  ventral  to  the  single  bipolar  the amygdala o f each r a t 1. 2  l e f t o f the s a g g i t a l  dura  o f each r a t .  s p r i n k l e d on the i n c i s i o n f o l l o w i n g s u r g e r y d r i n k i n g water d u r i n g  the f i r s t  stimulation suture.  Tetracycline and  added  to  5 days o f convalescence.  mm and was the  18  Kindlincj The  kindling  least 5  days  stimulated  phase  of  consecutive  for  weeks.  stimulations.  chamber  experiment, began a f t e r a t  recovery. with  The  at  each  lined  with As  1978).  stimulation.  stimulations,  bedding.  expected  was  but  by  the  between  removed 25  i t to  each  cm  opaque  the  leads,  i t s home  (cf. Mucha & P i n e l .  the r a t s a t f i r s t last  did  not  of  cage 1977;  respond  the  45  to  kindling  most responded t o each s t i m u l a t i o n w i t h a c l o n i c  rearing.  and  a  loss  f o r e l i m b clonus.  clonus.  of equilibrium.  v a r i a b l e i n each experiment was to  rat hr  attached  s e i z u r e c h a r a c t e r i z e d i n sequence by f a c i a l clonus,  2  p l a c e d i t i n a 58 x 58 x  seizure.  P i n e l & Rovner.  least  experimenter  immediately s t i m u l a t e d i t . and r e t u r n e d a f t e r the  Each  «**.A r. m. s. . 60 Hz) t h r e e times per day.  3  animal from i t s cage, plastic  each  postsurgical  ( 1 s. 400  5 days a week  of*  The  forelimb dependent  the d u r a t i o n o f the p e r i o d  of  T h i s measure has been shown t o be s e n s i t i v e  experimental  maninpulations  decrease s e i z u r e s u s c e p t i b i l i t y  designed  to  increase  < e. g. . P i n e l .  1980.  or  1981 ).  Baseline Following was  t h e k i n d l i n g phase o f each experiment,  subjected  referred  to  s t a b i l i t y of s u b j e c t was  to as  a  series  baseline  last  of  the  kindled,  in  response  —  to  hereafter assess  to stimulation.  the f i r s t  intervals.  in  at  least  10  s  of  Each the  On  one  Any  forelimb  to four of s i x baseline stimulations  e x c l u d e d from the experiment a t t h i s point.  the  one o c c u r r i n g 48 h r  45 k i n d l i n g phase s t i m u l a t i o n s .  subject that f a i l e d to display clonus  response  —  s i x times a t 48-hr  chamber i n which i t was a f t e r the  stimulations  stimulations  i t s convulsive stimulated  of  each r a t  of  was the  b a s e l i n e days o f Experiment 2. two e x p e r i m e n t e r s i n d e p e n d e n t l y  19  r e c o r d e d a f o r e l i m b c l o n u s d u r a t i o n s c o r e f o r each s u b j e c t . Pearson  correlation  scores,  coefficient  calculated  r e v e a l e d h i g h between-experimenter  A  f o r the paired  reliability,  j^(56)  = . 993, _p < . 001. Treatment Although t h e treatment phases o f t h e experiments d i f f e r e d considerably,  t h e r e were s e v e r a l f e a t u r e s t h a t were common t o  a l l o f them.  First,  t h e 48-hr s t i m u l a t i o n s c h e d u l e  initiated  d u r i n g t h e s t a b i l i z a t i o n phase was m a i n t a i n e d u n t i l t h e end o f the  experiment.  A c c o r d i n g l y , the  treatment  experiments began 48 h r a f t e r t h e l a s t On  each  treatment  day,  intraperitoneal injection of  each  baseline subject  either  1. 5  employed  stimulation.  stimulation.  injection. returned  After to  the  chamber  5  receiving same  (7. 6 ml/kg) 60 min  min the  chamber  weighed  prior  to  injection,  chamber,  Each  and then p l a c e d receiving each  the  r a t was  f o r 1 h r b e f o r e r e c e i v i n g an  amygdaloid s t i m u l a t i o n and b e i n g r e t u r n e d t o i t s home min l a t e r .  an  e t h a n o l (25/i  on each o f t h e treatment days was as f o l l o w s .  t h e treatment  a l l  The drug a d m i n i s t r a t i o n procedure,  animal was removed from i t s home cage, in  of  received  g/kg  s o l u t i o n ) o r an e q u i v a l e n t volume o f s a l i n e before the  phase  cage  5  I n experiments i n v o l v i n g more than one treatment  treatment environments were c o u n t e r b a l a n c e d t o negate  any n o n a s s o c i a t i v e e f f e c t s t h a t might i n a d v e r t a n t l y a f f e c t t h e results.  F o r example i n Experiment 1, Environment A  alcohol-predictive  environment  f o r half  was t h e  o f t h e a n i m a l s and  Environment B, f o r t h e o t h e r h a l f . Blood Samples A t a i l b l o o d sample first  was taken from each  subject  on t h e  day o f a l c o h o l a d m i n i s t r a t i o n and on t h e t e s t day, j u s t  20  be-Fore i t was r e t u r n e d t o i t s home cage. blood  samples,  cardboard  tube,  each  r a t was  snipped.  micropipette.  restrained  in  to  obtain  a cylindrical  t h e t a i l was b r i e - f l y immersed i n warm water t o  i n c r e a s e b l o o d flow. was  In order  A f t e r the t i p of the t a i l  blood which  was  was  collected  immediately  in  sealed.  of a  each r a t  heparinized  labelled.  and  stored i n a freezer. Test During  the  stimulation, 25%  s o l u t i o n ) 1 h r p r i o r t o an  amygdaloid  the a n t i c o n v u l s i v e  were i n c l u d e d  effect  of  stimulation. was  in  subsequent t e s t s .  of  interest.  A s u b j e c t was c o n s i d e r e d anticonvulsive  a l c o h o l a d m i n i s t r a t i o n was l e s s than t h e mean  effect  of  of  day o f  i t s clonus  on t h e l a s t t h r e e a l c o h o l s e s s i o n s o f t h e t o l e r a n c e  development phase. that  on t o l e r a n c e  i f i t s f o r e l i m b c l o n u s d u r a t i o n on t h e f i r s t  durations  In  o n l y s u b j e c t s judged t o have developed t o l e r a n c e  have developed t o l e r a n c e t o t h e  alcohol  alcohol  treatment  (1. 5 g/kg o f a  1 and 2. t h e e f f e c t o f m a n i p u l a t i o n s  Consequently, to  s e s s i o n 48 h r a f t e r t h e l a s t  each r a t was i n j e c t e d with e t h a n o l  Experiments to  test  achieved  I n Experiment  3,  however.  t h e b a s e l i n e c r i t e r i o n were i n c l u d e d i n a l l o f  the subsequent phases o f t h e experiment.  I n Experiment 3. t h e  e f f e c t o f CS preexposure on t h e development o f of interest.  a l l subjects  Accordingly.  subjects i n the analyses  tolerance  was  i t was e s s e n t i a l t o i n c l u d e a l l  regardless o f the l e v e l of  tolerance  achieved. Histology At t h e end o f t h e experiments, a  C0^_  chamber,  guidelines,  according  a l l animals were k i l l e d i n  t o Canada C o u n c i l on Animal Care  and t h e i r b r a i n s were removed  and  stained  using  21  the  blue-dot  staining  technique  (Skinner*  F a c i l i t a t e h i s t o l o g i c a l c o n f i r m a t i o n of After  each  rat  ferrocyanide passed  was  perfused  formaldehyde  through  the  with  solution*  electrode*  blue  in  the  presence  of  the  the  i n order to  electrode  a  saturated  a  direct  driving  t i s s u e surrounding the e l e c t r o d e t i p .  1971)  site.  potassium  current  iron  i o n s i n t o the  These i o n s t u r n a  potassium  was dark  f e r r o c y a n i d e * thus  r e v e a l i n g t h e p o s i t i o n o f the e l e c t r o d e t i p . Blood A l c o h o l A n a l y s i s Blood  alcohol  levels  were  determined  chromatograph t e c h n i q u e o f Gibbins* and W a l l g r e n and B a r r y sample  was  ( 1970).  dissolved  in  a p p r o x i m a t e l y 63 C f o r blood-propanol  3  and LeBlanc  propanol  before  The  was  then  gas  from  injected  column  used  carbon b l a c k proportion  to  filter  coated of  with  ethyl  a  the  carbowax  (1968)  heated the  into  to  heated the  gas  carrier.  gas  gas sample was  Q. 2V.  gas  each b l o o d  being  chromatograph t o a l l o w mixing w i t h the n i t r o g e n The  the  In t h i s technique*  min.  solution  Kalant*  by  graphitised  coating.  The  a l c o h o l i n the b l o o d sample r e l a t i v e t o  t h a t o f the p r o p a n o l was  graphed  subsequent  with  comparisons  on a  recorder  allowing  standards i n order to  for  determine  alcohol concentration. S t a t i s t i c a l Analysis Gross v i o l a t i o n s i n variance  necessitated  the  assumption  of  homogeneity  the use o f l e s s p o w e r f u l  nonparametric  procedures i n the s t a t i s t i c a l a n a l y s i s o f the r e s u l t s o f experiment. each  evaluate  experiment*  duration days  To  was  of  the  forelimb  assessed  the  stability  significance  of  of each  of t h e b a s e l i n e s i n differences  in  the  c l o n u s between the l a s t t h r e e b a s e l i n e  with  Friedman"s  nonparametric  two-way  22  a n a l y s i s of*  v a r i a n c e f o r r e l a t e d samples  Wilcoxon Matched-Pairs Signed-Ranks the  Mann-Whitney  jJ. T e s t  (Siegel,  i n d i v i d u a l a p r i o r i comparisons respectively. alpha it  level,  Multiple  Test  (Siegel/  1956).  The  (Siegel,  1956)  and  1956)  between  comparisons  were used t o make  and  of  within  course increase the  but they a l s o l e a d t o g r e a t e r power.  This  more l i k e l y t o f a l s e l y r e j e c t t h e n u l l hypothesis,  l i k e l y to accepted  accept  it.  Accordingly,  the n u l l hypothesis,  more c r e d i b l e .  The  level  statistical  comparisons  probability  of  each  a v a i l a b l e t a b l e s ) was  our  in  cases  conclusions . 05,  difference  however  (within  the  makes  and  less  i n which  were  o f s i g n i f i c a n c e employed  was  groups,  we  a l l the for a l l  the  actual  l i m i t s of the  r e p o r t e d i n t h e text.  Experiment 1 One purpose o f Experiment tolerance  to  1  was  to  determine  whether  the a n t i c o n v u l s i v e e f f e c t o f a l c o h o l i s s u b j e c t  to environmental control, that i s ,  whether  or  not  subjects  d i s p l a y more t o l e r a n c e t o the a n t i c o n v u l s i v e e f f e c t o f a l c o h o l if  alcohol  is  administered  in  environment than i f i t i s a d m i n i s t e r e d environment.  The  not a compensatory  an  alcohol—predictive  i n a saline-predictive  second purpose was t o determine whether c o n d i t i o n e d response would be  elicited  subjects tolerant to alcohol's anticonvulsant effect, whether  or  not  an  injection  of  or in  that i s ,  s a l i n e administered  i n an  a l c o h o l - p r e d i c t i v e environment would i n c r e a s e t h e d u r a t i o n  of  f o r e l i m b c l o n u s e l i c i t e d by subsequent c o n v u l s i v e s t i m u l a t i o n . Methods  23  Subjects.  Of  t h e 60 r a t s t h a t began t h e experiment*  died of p o s t s u r g i c a l their  complications.  mere  excluded  after  e l e c t r o d e s mere r e j e c t e d . 2 d i d not reach t h e c r i t e r i o n  of baseline s t a b i l i t y , on  2  4  i . e. a t l e a s t 10 s o f  forelimb  clonus  a t l e a s t f o u r o f t h e s i x b a s e l i n e s t i m u l a t i o n s , and 9 d i e d  during the  treatment  phase.  leaving  a  total  of  43  that  completed t h e t r e a t m e n t phase o f t h e experiment. Treatment. subjects  Following  k i n d l i n g and b a s e l i n e t e s t i n g , a l l  meeting t h e c r i t e r i o n o f s t a b i l i t y were i n j e c t e d and  s t i m u l a t e d on  alternate  environments. A  or  days.  B.  in  This  chamber.  with  situated  c o l o n y room was i l l u m i n a t e d by light.  of  two  distinctive  Environment A was an 58 x 58 x 25 cm  opaque, p l a s t i c chamber, l i n e d paper.  one  almond-scented  shredded  i n a room u p s t a i r s from t h e  both  natural  and  artificial  The c o l o n y room housed chamber B. which was a chamber  s i m i l a r t o t h e one d e s c r i b e d above, however i t was l i n e d an  unscented  corn  cob bedding m a t e r i a l , and was i l l u m i n a t e d  e n t i r e l y by a r t i f i c a l were  responsible  with  light for  only.  the  Different  testing  in  experimenters  each  of  the  two  environments. On t h e f i r s t  treatment day. a l l s u b j e c t s  were  injected  with e i t h e r a l c o h o l o r s a l i n e and s t i m u l a t e d i n environment A. S u b j e c t s were removed from t h e i r home cages by Experimenter A. placed  in  groups  of  five  or  six  i n a c a r r y i n g cage, and  t r a n s p o r t e d t o t e s t chamber A. where each s u b j e c t remained the c a r r y i n g test  chamber  cage f o r 5 t o 20 min. for  5  min.  each  in  A f t e r being placed i n the subject  received  an  i n t r a p e r i t o n e a l i n j e c t i o n o f e i t h e r a l c o h o l (1. 5 g/kg o f a 25% solution)  or  an  equivalent  volume  Immediately a f t e r t h e i n j e c t i o n , the  test  chamber  for  1  hr  of  saline  (7. 6 ml/kg).  each s u b j e c t was r e t u r n e d there  b e f o r e having  to  i t s leads  24  attached  and being  stimulated.  Each s u b j e c t mas removed  the t e s t chamber 5 min a f t e r s t i m u l a t i o n , cage with f i v e o r s i x o t h e r  subjects,  From  placed i n a c a r r y i n g  and r e t u r n e d  t o i t s home  cage. On  t h e second  treatment day, 48 h r l a t e r ,  a l l subjects  were removed from t h e i r home cages, p l a c e d i n c a r r y i n g in  groups o f f i v e o r s i x by Experimenter 8 and t r a n s p o r t e d t o  t e s t chamber B.  As  before,  each  subject  remained  c a r r y i n g cage f o r 5 t o 20 min, b e f o r e being chamber, Once  i n j e c t e d 5 min l a t e r ,  again,  each  that  other rats,  i n the  placed i n the t e s t  and s t i m u l a t e d 1 h r a f t e r that.  a n i m a l was removed from t h e t e s t chamber 5  min a f t e r s t i m u l a t i o n , six  cages  p l a c e d i n a c a r r y i n g cage with f i v e  and r e t u r n e d  t o i t s home cage.  had r e c e i v e d a l c o h o l on t h e f i r s t  Those  or  subjects  day r e c e i v e d s a l i n e on  the second and v i c e versa. There were a t o t a l o f 10 treatment days such t h a t days 3, 5, 7, 9 were i d e n t i c a l t o day 1 and identical to injections,  day  2.  5 alcohol  environment  and  Thus, injections  days  each  2,  4,  subject  6,  8  were  received  10  i n the a l c o h o l - p r e d i c t i v e  5 s a l i n e i n j e c t i o n s i n the s a l i n e - p r e d i c t i v e  environment. A l c o h o l T e s t Day.  On t h e a l c o h o l t e s t day , each  subject  r e c e i v e d a l c o h o l i n one o f t h e two t e s t environments. subjects  receiving  alcohol  had p r e v i o u s l y r e c e i v e d whereas  those  i n t h e environment i n which t h e y  alcohol  receiving  comprised  alcohol  environment comprised t h e D i f f e r e n t divided  into  Those  t h e Same  Group,  i n their saline-predictive Subjects  were  t h e two groups p r i o r t o t e s t i n g such t h a t  their  mean f o r e l i m b c l o n u s  durations  Group.  on t h e f i f t h  alcohol  session  were a p p r o x i m a t e l y t h e same f o r both groups and such t h a t h a l f of  the subjects  i n each  group r e c e i v e d t h e i r a l c o h o l t e s t  25  i n j e c t i o n i n each o f t h e two t e s t environments. received  the  test  administration  injection  injections  environment p a r t i c i p a t e d i n subjects  were  the  in  t h e drug trials.  t h a t had  the  saline  injected  a l c o h o l - p r e d i c t i v e environment  with  t h e treatment  Only those s u b j e c t s  alcohol test  These  accordance  p r o c e d u r e s used d u r i n g  S a l i n e T e s t Day. their  in  A l l subjects  received  alcohol-predictive  test  with  48  hr  saline  (Environment  A  later.  in  the  f o r half  the  r a t s and 8 f o r t h e o t h e r s ) 1 h r p r i o r t o s t i m u l a t i o n . Results The  results  of P i n e l e t  o f Experiment 1 c o n f i r m  a l . <1983)  that  tolerance  the previous  develops  rapidly  a l c o h o l * s a n t i c o n v u l s i v e e f f e c t on k i n d l e d s e i z u r e s . duration of forelimb first  alcohol  clonus  trial  14. 40 s by t h e f i f t h  report to  The mean  e l i c i t e d i n t h e 43 s u b j e c t s on t h e  was o n l y 3. 09 s. and i t had i n c r e a s e d t o and  last  tolerance  development  trial.  X<43)= 5. j> < . 002. Because  t h e purpose o f t h e p r e s e n t  factors that influence those  subjects  the  development  phases  s u b j e c t s whose mean c l o n u s  durations  clonus  of  the  durations  of  tolerance.  treatment  phase  on t h e f i r s t  of  the  experiment  on t h e l a s t t h r e e  were  not higher  and  16 i n t h e Same Group.  subjects a r e presented  in  —  10  alcohol  than t h e i r  a l c o h o l s e s s i o n were n o t t e s t e d .  Thus, c o m p l e t i n g t h e experiment were 33 s u b j e c t s . D i f f e r e n t Group  only  t h a t had d i s p l a y e d some e v i d e n c e o f t o l e r a n c e  were i n c l u d e d i n t h e t e s t trials  study was t o i d e n t i f y  F i g u r e 1.  which  17  i n the  The data o f t h e s e illustrates  the  major f i n d i n g s o f t h i s study. Baseline.  It  is  clear  from  Figure 1  that  stable  26  b a s e l i n e s were a c h i e v e d  by t h e end  of  the  baseline  period.  There was no s i g n i f i c a n t change i n d u r a t i o n o f f o r e l i m b over  t h e l a s t 3 b a s e l i n e days i n e i t h e r t h e D i f f e r e n t Group,  XY-(2, N=17)= 1. 88, _p > . 30 o r t h e 1. 20, any _p s s  clonus  p > . 50,  Group, A~c (2,  Same  N=16) =  and t h e groups d i d not d i f f e r s i g n i f i c a n t l y on  o f t h e s e 3 days,  ( a l l t h r e e Mann-Whitney UJs >  121, a l l  > .10). Treatment.  During  the  r e c e i v e d 10 s t i m u l a t i o n s , five following comparison  alcohol  treatment  phase,  a l l subjects  f i v e f o l l o w i n g s a l i n e i n j e c t i o n s and injections  on  alternate  days.  A  o f t h e d u r a t i o n o f t h e f o r e l i m b c l o n u s e l i c i t e d on  the f i v e s a l i n e  trials  baseline  (see F i g u r e 1) e s t a b l i s h e d t h a t t h e i n j e c t i o n  phase  with  procedure p e r s e d i d n o t clonus.  the  affect  clonus  durations  the duration  of  of the forelimb  The a d d i t i o n o f a s a l i n e i n j e c t i o n 60 min b e f o r e t h e  c o n v u l s i v e s t i m u l a t i o n had no s i g n i f i c a n t e f f e c t i comparisons o f t h e c l o n u s e l i c i t e d on t h e l a s t b a s e l i n e day and saline  treatment day, both p r o b a b l y  significant  44. 0, shift  treatment days. day  T(17)=  p > . 10,  _p > . 12.  there  was  significant 46. 0,  subjects.  treatment  days  durations  on  the  differences  first  _p > . 10  Also,  and  both groups  clonus  ( a l l five  Same of  f o r the D i f f e r e n t Group, J_(16)= 42. 0, subjects  exhibited  d u r a t i o n s on each o f t h e s a l i n e Mann-Whitney  U_'s > 140, a l l  > . 40). The  no  day with those on t h e l a s t s a l i n e treatment  equivalent  _p s  in  i n t h e b a s e l i n e s o f e i t h e r group over t h e  virtually x  Moreover  Comparisons o f t h e  treatment  r e v e a l e d no  Group,  change  t h e D i f f e r e n t Group, _T(17) = 52.0, p > .13, o r t h e Same  Group, JT(16)=  saline  last  r e l e c t i n g t h e most s t a b l e  performance f o r t h a t phase r e v e a l e d no s i g n i f i c a n t either  the  performance o f t h e s u b j e c t s on t h e f i v e  alcohol  27  F i g u r e 1.  The effect- o f s a l i n e o r a l c o h o l i n j e c t i o n s on the d u r a t i o n o f f o r e l i m b  clonus  r a t s by amygdaloid s t i m u l a t i o n . b a s e l i n e days,  elicited  i n kindled  Following 6  t h e s u b j e c t s i n two groups r e c e i v e d  a l c o h o l i n j e c t i o n s p r i o r t o odd numbered  stimula-  t i o n s and s a l i n e i n a d i s t i n c t i v e l y d i f f e r e n t environment p r i o r t o even number s t i m u l a t i o n s . the a l c o h o l t e s t , t h e s u b j e c t s  During  i n t h e Same Group r e -  c e i v e d t h e a l c o h o l and t e s t s t i m u l a t i o n i n t h e same environment i n which they had p r e v i o u s l y r e c e i v e d i t . whereas those i n t h e D i f f e r e n t Group r e c e i v e d the a l c o h o l and t e s t s t i m u l a t i o n i n t h e environment i n which they had p r e v i o u s l y r e c e i v e d s a l i n e . On  t h e s a l i n e t e s t , t h e s u b j e c t s i n t h e Same Group  r e c e i v e d a s a l i n e i n j e c t i o n i n t h e environment i n which they had always r e c e i v e d a l c o h o l . l a t i o n s were a d m i n i s t e r e d throughout t h e experiment.  Stimu-  a t 48 h r i n t e r v a l s The s o l i d l i n e s  sent t h e performance o f t h e D i f f e r e n t Group  represubjects  whereas t h e dashed l i n e s represent, t h a t o f t h e Same Group s u b j e c t s .  The symbols i n d i c a t e which  treatment t h e s u b j e c t s  received before  The  and c i r c l e s i n d i c a t e t h a t no  diamonds, squares,  treatment,  stimulation.  a l c o h o l i n j e c t i o n s or s a l i n e i n j e c t i o n s ,  r e s p e c t i v e l y were g i v e n  p r i o r to stimulation.  28  40-  u CO  35-  C/3 O  <  30 -  saline sessions  25-  a CO  20-  O  u  SAME DIFFERENT  15-  CD  LU  10-  alcohol sessions  CC  o LL. 5-  i — r  i  r  — i — i — i — i — i — i  1 2 3 4 5 6 1 2 3 4 5 6 7 8 9  10 1 2  LBaselineJ ' — T r e a t m e n t — STIMULATIONS  1  Test^  L  29  trials was  i s noteworthy i n two respects.  a substantial  alcohol  over  decrease i n the  the  five  trials  The f i r s t i s t h a t  anticonvulsive  groups  d i d not  Alcohol injected  The second*  Test.  with  On t h e a l c o h o l  alcohol,  test*  both  groups  i n the Different  Group  displayed  clear  injection*  the f i f t h alcohol  environment*  subjects  were  forelimb  tolerance clonus  ; i n contrast  groups  t o the f i r s t  alcohol  substantially  i n both t h e D i f f e r e n t Group* JT(17) = 5*  the duration  significant difference the forelimb  JJ(16, 17)=  Test.  alcohol-predictive seizures  of  injection forelimb  However, i t  environment clonus.  had  There was no  between t h e two groups i n t h e  clonus  e l i c i t e d . , on  no  the alcohol  duration t e s t day*  133* p > . 10.  Saline forelimb  whereas  Both  i n j e c t i o n produced  i s c l e a r i n Figure 1 that the e f f e c t on  were  i n j e c t e d and  p < . 004 and t h e Same Group* J_(16) = 0* p < . 0002.  of  that  those i n t h e Same Croup were i n j e c t e d  s t i m u l a t e d i n t h e s a l i n e - p r e d i c t i v e environment.  more  is  d i f f e r s i g n i f i c a n t l y on any o f t h e f i v e  stimulated i n the alcohol-predictive  those  of  ( a l l f i v e Mann-Whitney U/s > 23. a l l p > .10).  trials*  and  effect  f o r each o f t h e two groups*  X<17)= 0 and T(16)= 0, b o t h j ^ s < .002. the  there  Injection  of  environment d i d not e l i c i t  clonus duration predicted elicited  saline  i n the  in  the increase i n  by S i e g e l s  theory.  x  saline  The  s u b j e c t s o f t h e Same Group on t h e  s a l i n e t e s t were not s i g n i f i c a n t l y l o n g e r than those following  the  injections  in  the  elicited  saline-predictive  environment d u r i n g t h e treatment phase o f t h e experiment.  For  example*  not  seizures  significantly day,  T^db)^  seen  longer  on  the s a l i n e  test  day  were  than those on t h e l a s t s a l i n e treatment  53, £ > . 23.  In  fact*  there  was  a  small  but  30  i n s i g n i f i c a n t , d e c l i n e i n d u r a t i o n on t h e s a l i n e t e s t day. Dissussion The  [  two  major  findings  of  the present  experiment a r e  c l e a r l y a t odds with S i e g e l ^ s P a v l o v i a n i n t e r p r e t a t i o n o f drug tolerance. alcohol  First/  was  not  Animals t h a t had saline  in  found  to  received  another  same degree o f alcohol  tolerance t o the a n t i c o n v u l s i v e  tolerance  one  environment  to  the  anticonvulsive  Second/  cues  effects  there  repeatedly  of  compensatory reponse.  effect  alcohol  An  was  no  paired  forelimb  amygdaloid  of  elicit  injection  a  of  clonus  duration  elicited  stimulation —  in  fact/  two  contrast  a  in  evidence with  the  conditioned  saline  a l c o h o l - p r e d i c t i v e environment d i d n o t s i g n i f i c a n t l y the  and  o f which o f t h e two environments t h e t e s t  environmental  anticonvulsant  in  t h e treatment phase d i s p l a y e d t h e  i n j e c t i o n was administered. that  of  under e n v i r o n m e n t a l c o n t r o l .  alcohol  during  regardless  be  effect  i n the increase  k i n d l e d r a t s by  small  decrease  was  observed. These  findings  C r o w e l l e t a l . (1981)/ Cunningham  Le e t  with  al.  (1979)  previous reports of and  Mansfield  (1980) i n which c o n d i t i o n e d compensatory responses  as w e l l as s i t u a t i o n a l s p e c i f i c i t y were demonstrated tolerant to reason  the  hypothermic e f f e c t o f a l c o h o l .  for this  development  of  difference tolerance  in  to  results  only  some  may of  a l c o h o l i s dependent on P a v l o v i a n mechanisms. view i s t h a t methods o f the p r e s e n t the  and  in  One p o s s i b l e be  that  the  the e f f e c t s of Supporting  experiments  rats  unrelated  this to  measurement o f s e i z u r e d u r a t i o n were g e n e r a l l y comparable  t o those o f t h e  studies  supporting  other  Pavlovian  view  explanations  of  a l c o h o l tolerance.  Of  possible.  t h e i n j e c t i o n environment may have had  F o r example/  course/  the  are  31  no o b v i o u s effect, i n Experiment. saline  environments  discriminable.  may  1  because  not  have  Experiment  1  subjects —  they  in  the  should  chamber, room,  earlier  have  differed  et  light,  and  for  the  1981)  studies,  environments  been r e a d i l y d i s c r i m i n a b l e t o  the  respect  those  to  experimenter.  smell,  effects  phase  have  o f the  injection  Other r e s e a r c h e r s 1981)  have The  S i e g e l " s theory,  and  as  (Crowell important  p o i n t i s , however, t h a t a marked t o l e r a n c e e f f e c t d i d o f the p r e s e n t experiments,  not  used  or as many as 20  a l c o h o l t r i a l s i n t h e i r studies.  d u r i n g the course  testing  Another p o s s i b i l i t y  treatment  controlling  as 4 ( M e l c h i o r & Tabakoff, al. ,  sufficiently in  with  environment t o be r e a l i z e d . few  been  and  used  i s t h a t the 10 t r i a l s used i n the enough  alcohol  However, i n view o f the i n j e c t i o n  used s u c c e s s f u l l y  been  the  develop  according  to  so s h o u l d have any c o n d i t i o n i n g .  Experiment 2 If the  a  p a r t i c u l a r m a n i f e s t a t i o n o f a l c o h o l t o l e r a n c e were  result  possible  of to  Pavlovian accelerate  conditioning, the  dissipation  employing e x t i n c t i o n procedures. exposed tolerance trials. tolerance  to  the than  The  CS  without  tolerant  purpose o f  to  the  then of  it  would  be  tolerance  by  Tolerant subjects the  subjects  Experiment  anticonvulsant  UCS  should  not 2  repeatedly  display  less  g i v e n the e x t i n c t i o n was  effect  to of  determine  if  a l c o h o l can  be  extinguished. Methods Subjects.  Of the 29 s u b j e c t s t h a t s t a r t e d Experiment  2,  32  4  died  during  the  course  of  t h e experiment and 1 d i d not  a c h i e v e the c r i t e r i o n o f a t l e a s t 10 s o f f o r e l i m b c l o n u s  on 4  o f the 6 b a s e l i n e days.  rats  Accordingly,  completed t h e t o l e r a n c e development Baseline.  As  a  total  of  24  phase o f t h e experiment.  i n Experiment 1, each s u b j e c t r e c e i v e d s i x  baseline stimulations,  one e v e r y  48  hr,  thus  initiating  a  bidaily  s t i m u l a t i o n regimen t h a t was m a i n t a i n e d u n t i l t h e end  of the  experiment.  administered  five  Development.  tolerance  administered  baseline  stimulations  were  by Experimenter A (see Experiment 1).  Tolerance of  All  Each s u b j e c t underwent t h e  development  sessions  i n Experiment 1, 48 h r a f t e r  stimulation.  All  administered  in  tolerance  environment  A  i d e n t i c a l t o those the  last  development by  first  baseline  trials  Experimenter  were  A  (see  Experiment 1). Extinction.  Following  o f t h e experiment, groups  an  prior  to  one  Group o r a C o n t r o l Group,  comparable  duration  scores.  phase  of  or  a  control  Experimenter environment  each s u b j e c t r e c e i v e d e i t h e r  A A  injected as  she  days e x c e p t t h a t s a l i n e administered.  trial.  During  and  On  each  stimulated  Accordingly, the  extinction trial,  subject  in  had done on the t o l e r a n c e — d e v e l o p m e n t (7. 6 ml/kg) r a t h e r the  extinction  than phase,  s u b j e c t s r e c e i v e d f i v e b i d a i l y s t i m u l a t i o n s from B i n environment B.  an  extinction each  two  such t h a t  t o each o f the f i v e b i d a i l y s t i m u l a t i o n s c o m p r i s i n g  e x t i n c t i o n phase, trial  t h e s u b j e c t s were a s s i g n e d  Extinction  both groups had  the t o l e r a n c e development  ethanol the  was  control  Experimenter  33  T e s t Day.  A l l subjects  received  Environment A, 48 h r a f t e r t h e f i f t h control t r i a l .  a  test  and f i n a l  injection i n extinction  or  The i n j e c t i o n and s t i m u l a t i o n procedure used  on t h e t e s t day mas i d e n t i c a l t o t h a t  used  on  each  of the  t o l e r a n c e development s e s s i o n s . Results In  Experiment  2  as i n Experiment 1, s u b j e c t s developed  substantial tolerance to a l c o h o l s anticonvulsive effect  over  x  the f i v e  t o l e r a n c e development i n j e c t i o n s .  c l o n u s d u r a t i o n on t h e f i r s t  The mean f o r e l i m b  t o l e r a n c e development day f o r a l l  s u b j e c t s was 6. 97 s» whereas on t h e l a s t t o l e r a n c e day.  t h e mean was 44. 50 s. X<24)= 15/  only  those  the f i r s t the  < . 0002.  Once  t o l e r a n c e development day s m a l l e r than t h e on  that  Group/  underwent  this criterion.  subjects/  11  that  in  the  were  By  24  t h e t o l e r a n c e development phase/  22  It  22  was  the  Of  scores  of  to  statistical  analysis  three  the  baseline  ITs > 51/ a l l p**s > .10)/ Extinction  A*  (2/ N=ll)=  end  of  the  baseline  phase/  the  Not o n l y were t h e r e on  any  of  sessions  ( a l l t h r e e Mann-Whitney  but  scores  5. 5/  Ar(2/ N = l l ) = . 55/ p > . 70 s u b j e c t s these 3 b a s e l i n e days.  and  i n F i g u r e 2.  no s i g n i f i c a n t d i f f e r e n c e s between t h e two groups last  these  E x t i n c t i o n Group and 11 i n t h e C o n t r o l  d u r a t i o n s o f f o r e l i m b c l o n u s were s t a b l e . the  of  the  subjected  g r a p h i c a l l y represented Baseline.  mean  t h e l a s t 3 t o l e r a n c e development days were  i n c l u d e d i n subsequent phases o f t h e experiment. subjects  again/  s u b j e c t s d i s p l a y i n g a f o r e l i m b c l o n u s d u r a t i o n on  durations  achieved  development  the  p > . 55 varied  of nor  neither the  the  Control  significantly  over  34  F i g u r e 2.  The  e f f e c t of e x t i n c t i o n procedures on the  of Forelimb clonus  e l i c i t e d i n k i n d l e d r a t s by  amygdaloid s t i m u l a t i o n .  A f t e r the s u b j e c t s  oped t o l e r a n c e t o the a n t i c o n v u l s a n t a l c o h o l one  duration  e f f e c t s of  group o f s u b j e c t s r e c e i v e d s a l i n e i n -  j e c t i o n s before  s t i m u l a t i o n i n the environment t h a t  previously predicted alcohol administration another group o f s u b j e c t s r e c e i v e d the o n l y i n an environment t h a t was a l c o h o l administration. subjects  On  while  stimulation  not a s s o c i a t e d  the t e s t day.  with  all  r e c e i v e d a l c o h o l i n the a l c o h o l - p r e d i c t i v e  environment p r i o r t o being were a d m i n i s t e r e d l i n e s represent Group s u b j e c t s  stimulated.  Stimulations  at 48 hr i n t e r v a l s .  The  whereas the dashed l i n e s The  represent symbols i n -  c a t e which treatment the s u b j e c t s r e c e i v e d stimulation.  The  diamonds,  c a t e t h a t no treatment, injections,  solid  the performance o f the E x t i n c t i o n  t h a t o f the C o n t r o l Group s u b j e c t s .  ation.  devel-  squares and  before  circles in-  a l c o h o l i n j e c t i o n s or s a l i n e  r e s p e c t i v e l y were g i v e n p r i o r t o s t i m u l -  Although,  the C o n t r o l Group s u b j e c t s d i d  receive s a l i n e during  the e x t i n c t i o n phase,  their  performance d u r i n g the e x t i n c t i o n phase i s r e p r e s e n t e d by c i r c l e s f o r c l a r i t y .  not  35  52o  4844-  o r—  <  baseline sessions  4036-  EXTINCTION CONTROL  32O 00 ZD  o  extinction sessions  282420-  alcohol sessions  16_l LU  QC  o LU  1284-  1 2 3 L  i  4  r  —I—i—I—I—i—I—I—l—I—I—I  5 6 1 2 3 4 5 1 2 3 4 5 |  Baseline-  1  L  Tolerance J Development  L  STIMULATIONS  E x t i n c t i o n  J  T e s t  36  Tolerance  Development,.  As  i n d i c a t e d by F i g u r e 2,  groups of s u b j e c t s d i s p l a y e d  similar  development.  s u b j e c t s i n the E x t i n c t i o n Group  did  For  example.  patterns  not d i f f e r s i g n i f i c a n t l y from those i n the  on e i t h e r the f i r s t * JJ<3, 1) = 2, _p_ > .75  Extinction.  On  each  environment  given.  The  two  significantly U<11, 11)=  in  50,  o f the f i v e e x t i n c t i o n t r i a l s ,  the  day.  respectively.  of  each  57, _p > . 10,  clonus  regardless  subjects  other  or  the  did  on the f i r s t last,  not  differ  e x t i n c t i o n day,  L K l l , 11)=  63,  _E > • 10  a d d i t i o n , each group o f s u b j e c t s showed  no  s i g n i f i c a n t changes i n f o r e l i m b c l o n u s d u r a t i o n as a r e s u l t  of  the r e p e a t e d  In  Group  which the e x t i n c t i o n t r e a t m e n t s were  groups  from  Control  or l a s t ,  s u b j e c t s showed s i m i l a r l e v e l s of f o r e l i m b the  tolerance  U_(ll, 11)=  p > . 10 t o l e r a n c e development  of  of  both  extinction trials,  l a s t e x t i n c t i o n days, T e s t Day. Pavlovian  Contrary  model  significantly _y_(l, 3)=  the  t h a t i s , between the f i r s t > 24, p * s  > . 46.  tolerance, from  Neither test  the each  two  _T(4)=  group d i s p l a y e d any  day 2,  groups  ; neither  the  jp > . 13 were any  r e s p e c t i v e l e v e l s on the f i r s t  were  o t h e r on the t e s t  o f the E x t i n c t i o n Group, X*4)= 1, Group,  and  t o the p r e d i c t i o n s made from S i e g e l ^ s  different  on  durations Control  of  1, _g > . 25.  tolerance  both T s %  not trial,  evidence  forelimb _p > . 12  clonus nor  l o n g e r than  t o l e r a n c e development  of the  their  day.  Discussion T o l e r a n t animals, not  differ  from  having  tolerant  undergone e x t i n c t i o n t r i a l s rats  that  had  not r e c e i v e d  e x t i n c t i o n procedure; t o l e r a n c e d i s s i p a t e d completely groups  between the end  in  of the t o l e r a n c e development phase  did the both and  37  the t e s t day. the  I n l o o k i n g a t F i g u r e 2, i t i s obvious  that  on  t e s t day, t h e e x t i n c t i o n group and c o n t r o l group s u b j e c t s  mere so c l o s e t o zero, differential  level  t h a t had  there  been  a  o f f o r e l i m b c l o n u s between t h e groups, i t  would n o t have been p o s s i b l e t o observe i t . of  tolerance  to  the  anticonvulsive  demonstrated i s c l e a r l y dissipation  in  extinction  o f a l c o h o l was  However,  the  o f t o l e r a n c e i n t h e s u b j e c t s not having i s a t odds with  t h r e e independent  laboratories.  (1979)  That  effect  doubt.  extinction t r i a l s al.  significantly  and  Mansfield  the  findings  rapid  undergone  reported  by  C r o w e l l e t a l . (1981), Le e t  and  Cunningham (1980)  have  a l l  r e p o r t e d a t t e n u a t i o n o f t o l e r a n c e t o t h e hypothermic e f f e c t o f alcohol to  i n o n l y those  t o l e r a n t s u b j e c t s t h a t had been exposed  t h e e n v i r o n m e n t a l cues (CS) without  the e x t i n c t i o n  phase.  In  t h e drug  (UCS),  during  each o f these s t u d i e s , a f t e r t h e  period of tolerance acquisition,  one  group  of  subjects  g i v e n s a l i n e i n t h e presence o f a l c o h o l - a s s o c i a t e d cues, the  other  group  undisturbed,  was  or  left  given  s a l i n e - a s s o c i a t e d cues.  i n t h e home saline  The  in  marked  the  Siegel's  model  suggest  while  relatively  presence  decrease  c l o n u s i n t h e c o n t r o l group c o n t r a r y t o from  cage,  was  of  of  forelimb  the p r e d i c t i o n  made  t h a t t h e r e was no c o n d i t i o n i n g  u n d e r l y i n g t h e development o f t o l e r a n c e t o t h e  anticonvulsive  e f f e c t of alcohol.  Experiment 3 The  purpose  preexposure, conditioning  of  Experiment  3  was  to  determine whether CS  a treatment t h a t has a major e f f e c t on would  Pavlovian  i n f l u e n c e t h e development o f t o l e r a n c e t o  alcohol's anticonvulsant effects.  Would repeated  exposure  to  38  the  alcohol-predictive  subsequent  cues  development  anticonvulsant  without  of  effects?  3c  Hughes,  Although  1979.  alcohol  tolerance  to  tolerance  a n a l g e s i c e f f e c t has been s u b j e c t e d (Bardo  the  to  such  Sherman, Proctor,  alcohol's  to a  retard  morphine's  manipulation  & Strub, 1982), i t  has never been a p p l i e d t o any example o f a l c o h o l t o l e r a n c e . Methods Subjects. experiment,  Of  the  30  subjects  that  started  this  1 s u b j e c t was e l i m i n a t e d a f t e r the b a s e l i n e  due t o an i r r e p a r a b l y c l o g g e d e l e c t r o d e , Accordingly,  phase  and 4 s u b j e c t s  died.  25 r a t s completed the t o l e r a n c e development  phase  o f the experiment. Baseline.  The  baseline  phase  of  the  i d e n t i c a l t o t h a t o f Experiments 1 and 2. that  started  the  experiment  met  experiment A l l 30  was  subjects  the c r i t e r i o n o f b a s e l i n e  stability. Preexposure. stimulations,  After  subjects  the  were  six  assigned  bidaily t o one o f two  which r e c e i v e d e i t h e r a CS preexposure treatment Group,  n=13)  p r i o r t o each  or  a  control  of  the  preexposure  subjects  Experimenter  A  described  using  earlier  r a t h e r than a l c o h o l was subject  was  stimulated  were  except  five  injected drug  (Preexposure n=12)  stimulations. and  The  stimulated  administration  by  procedure  o f course, t h a t s a l i n e (7.6 ml/kg)  injected  in  Environment  p l a c e d i n t h e t e s t chamber,  1 hr a f t e r w a r d s  groups,  treatment ( C o n t r o l Group,  succeeding the  baseline  and  chamber 5 min a f t e r s t i m u l a t i o n .  was  A.  i n j e c t e d 5 min  removed  Accordingly,  from  the  Each later, test  the Preexposure  39  subjects  were preexposed t o a l l o f the cues t h a t s u b s e q u e n t l y  p r e d i c t e d the a d m i n i s t r a t i o n o f a l c o h o l . subjects  The  were a l s o i n j e c t e d with s a l i n e and  Control  Group  stimulated  during  the preexposure phase but by Experimenter B and B —  a treatment i d e n t i c a l t o t h a t  given  to  i n Environment the  Extinction  Group s u b j e c t s d u r i n g the e x t i n c t i o n phase of Experiment 2. Tolerance  Development and  preexposure or c o n t r o l intraperitoneally i n Environment stimulations  trials,  with  A,  1  all  After  hr  according  prior  to  the  five  were  injected  o f a 25%  solution)  of  next  subjects  a l c o h o l ( 1. 5 g/kg  used i n Experiment 1 and test  Test.  each  the  to  the drug a d m i n i s t r a t i o n  2.  The  six  procedure  s i x t h session constituted  the  trial.  Results Preexposure associated  to  with  the  cues  subsequently  be  a l c o h o l a d m i n i s t r a t i o n d i d not a t t e n u a t e  the  r a t e o f t o l e r a n c e development. activity subjects  exhibited during  development, Figure  the  and  test  the  the  Subjects  Control  forelimb clonus  mean  Preexposure  baseline, phases  level and  of  seizure  Control  preexposure,  Group  tolerance  o f the experiment i s shown i n  Group  by  the  i n both the Preexposure Group (n=12) end  Preexposure, A*~(2, N=13)= 3.9, 0. 5,  The  would  3.  Baseline. and  by  that  _p > . 70,  of  displayed the  stable  baseline  j> > . 10 and  (n=13)  l e v e l s of  pha^se.  Control,  (2, N=12) =  Groups showed s t a b l e l e v e l s o f f o r e l i m b  by the l a s t t h r e e b a s e l i n e days.  In a d d i t i o n , the two  d i d not d i f f e r s i g n i f i c a n t l y from each o t h e r on any days ( a l l t h r e e Mann-Whitney IPs > 50,  a l l p's >  The clonus groups  of these 3  .10).  40  F i g u r e 3.  The  e f f e c t , of p r e e x p o s i n g s u b j e c t s t o the  only,  before  of forelimb  CS-UCS p a i r i n g , on the clonus  elicited  by an  s t i m u l a t i o n i n Kindled rats. phase, given  subjects  CS  duration  amygdaloid  In the  preexposure  i n the Preexposure Group were  s a l i n e i n the environment t h a t would sub-  sequently  predict alcohol administration,  C o n t r o l Group s u b j e c t s were g i v e n  while  s a l i n e i n the  environment t h a t would not s u b s e q u e n t l y be i a t e d with a l c o h o l . ment s e s s i o n s  and  During the t o l e r a n c e  on the t e s t s e s s i o n ,  r e c e i v e d a l c o h o l i n the a l c o h o l - c u e d  assocdevelop-  a l l subjects  environment  p r i o r t o r e c e i v i n g amygdaloid s t i m u l a t i o n .  The  s t i m u l a t i o n s were g i v e n a t 48 hr i n t e r v a l s .  The  s o l i d l i n e s represent  Pre-  the performance o f the  exposure Group s u b j e c t s whereas the dashed represent The  t h a t o f the C o n t r o l Group s u b j e c t s .  symbols i n d i c a t e which treatment the  received p r i o r to stimulation. c l e s and  lines  The  subjects  diamonds,  squares i n d i c a t e t h a t no treatment,  cirsaline  i n j e c t i o n s or a l c o h o l i n j e c t i o n s , r e s p e c t i v e l y were given p r i o r to stimulation.  STIMULATIONS  42  Preexposure.  Control  Group  subjects  did  not  s i g n i f i c a n t l y from t h e Preexposure Group s u b j e c t s the f i v e preexposure s e s s i o n s  on  differ any  ( a l l f i v e Mann-Whitney JJ_" s > 58,  a l l _ p " s > .10).  Repeated s e s s i o n s d i d not s i g n i f i c a n t l y  the  forelimb  levels  of  Xy(4. N=13)= p > . 30,  3.4,  £  subjects during  Tolerance  seizures  e x h i b i t e d by the Preexposure Control,  Xj- (4, N=12)=  and T e s t Day.  day,  in  and  alcohol  On  a l l subjects,  j> < . 0004,  3,  tolerance.  The  two  4.3,  of  first  completely  but by the t e s t day,  subjects  groups  the  administration  the Preexposure group, J_(13)= 3, £ <. 0002 and T(12)=  alter  t h e preexposure phase.  Development  t o l e r a n c e development blocked  clonus  > . 30  of  Control  exhibited subjects  both  group,  considerable  did  not  differ  s i g n i f c a n t l y on t h e t e s t day, _U(10» 11)= 67, £ > . 10. Discussion Contrary  to  the  prediction  (1977), e x p e r i e n c e w i t h  the  cues  alcohol  did  not  administration  development  or  the  final  anticonvulsive effect subjects phases.  the  Clearly, that  CS  the  been  very  preexposure on  few  manifestations  reports  preexposure t o r e t a r d  of  theory  later  signal  tolerance  of  to  both groups o f  seizure  activity  development,  from  the  5iegel s v  and  test  Pavlovian  would r e t a r d the development As d i s c u s s e d  assessing Thus,  preexposure s u g g e s t s t h a t P a v l o v i a n some  In f a c t ,  prediction  tolerance.  %  tolerance  tolerance  t o l e r a n c e has not been confirmed. have  would  of  alcohol.  preexposure  Siegel s  a l t e r the r a t e of  level  preexposure  on  that  demonstrated comparable l e v e l s  throughout theory  of  based  drug  tolerance  the  earlier, effect  of  there of  CS  a l t h o u g h t h e e f f e c t s o f CS c o n d i t i o n i n g may  tolerance, in  the  the  underlie  f a i l u r e o f CS  present  experiment  43  argues  against  the  role  development o f t o l e r a n c e  Histology  of  Pavlovian  i n the  to alcohol s anticonvulsive effect.  and Blood A l c o h o l  Blood a l c o h o l concentrations days,  conditioning  %  Analysis  between groups  and  between  i n each experiment were a n a l y z e d by a r e p e a t e d measures  ANOVA.  I n Experiments 1,  alcohol  2,  and  3,  differences  in  l e v e l s between t h e D i f f e r e n t and Same Group  F<1, 30) =  . 56,  £ > . 25,  subjects,  J z ( l , 20)=  the  1. 62,  Extinction  £ > . 22,  and  C o n t r o l Group s u b j e c t s , _F(1, 22) = . 027, In addition,  and  blood  subjects,  Control  Group  t h e Preexposure and  p > . 25 were n o t  found  t o be  significant.  no s i g n i f i c a n t d i f f e r e n c e s  across  days due t o m e t a b o l i c accumulation o f a l c o h o l were seen  i n Experiment 1, _F<1, 30) = . 07, _p > . 25, . 98,  p > . 34,  actual  blood  Experiment 2, £(1, 20) =  o r Experiment 3, JF(1, 22)= 1. 97, alcohol  _p > . 10.  The  l e v e l s f o r each sample taken from each  group f o r a l l t h r e e experiments a r e p r e s e n t e d i n T a b l e 2. Figures brains  of  4, 5, and 6 show t h e subjects  t i p s were s i t u a t e d i n t h e r i g h t  b a s o l a t e r a l and c o r t i c a l amygdaloid n u c l e i .  anteriorally  placed  electrode  amygdaloid n u c l e u s ; t h e caudal b a s o l a t e r a l one  most  amygdaloid  was i n t h e r o s t r a l  subject  electrode  caudate,  i n the  were  medial, The most  basolateral  posterior  was  nucleus.  Two e l e c t r o d e  b e l o n g i n g t o a D i f f e r e n t Group s u b j e c t  Same Group two  sites  i n Experiments 1, 2, and 3, r e s p e c t i v e l y .  Most o f t h e e l e c t r o d e lateral,  stimulation  bordering  the tips,  and t h e o t h e r t o a  l o c a t e d i n t h e claustrum.  Finally,  t i p s were s i t u a t e d i n t h e v e n t r a l p o r t i o n o f t h e  bordering  t h e l a t e r a l amygdaloid nucleus.  Table  2  Mean B l o o d in  A l c o h o l L e v e l s (q|1) of E x p e r i m e n t s 1, 2, a n d 3  Subjects  Day  Group  Experiment  3  1st  Treatment  Test  Same  3.098  2.957  Di f f e r e n t  2.667  2.314  Extinction  3.457  2.854  Control  3.314  3.400  Preexposure  3.248  3.1 38  Control  2.856  2.890  45  F i g u r e 4.  Electrode  placements o f r a t s i n t h e D i f f e r e n t  Same Groups from Experiment 1. taken from P e l l e g r i n o ,  Brain  Pellegrino*  sections  and were  and Cushman (1979).  47  F i g u r e 5.  Electrode Control  placements of* r a t s i n t h e E x t i n c t i o n  Groups from Experiment 2.  taken from P e l l e g r i n o .  Pellegrino.  Brain  and  sections  were  and Cushman (1979).  48  49  F i g u r e 6.  E l e c t r o d e placements o f r a t s i n the CS prexposure and C o n t r o l Groups from Experiment 3.  B r a i n s e c t i o n s were  taken from P e l l e g r i n o , P e l l e g r i n o , and Cushman (1979).  50  51  General The  purpose  whether  of  Pavlovian  the  Discussion  present  thesis  conditioning contributed  o f t o l e r a n c e t o the a n t i c o n v u l s i v e e f f e c t three  studies  predictions tolerance any the  comprising  made  mas  from  ; however.  t o the of  effect.  In  of  Siegel s  Pavlovian  x  tolerance 1.  to  in  the  administered  environment  theory  found  effect  to t o l e r a n t subjects  of  would  of  in  Experiment 2 was  accelerate  provided  to  tested be  alcohol  the  drug  in  a  just as  as  those  and  saline  alcohol-predictive  compensatory  increase  an attempt t o show t h a t  the d e c l i n e i n t o l e r a n c e t o  a n t i c o n v u l s i v e e f f e c t of alcohol.  in  anticonvulsive  environment.  environment d i d not e l i c i t a c o n d i t i o n e d extinction  The  conditioning  subjects  were  alcohol-predictive  in seizure activity.  alcohol.  alcohol's  tolerant  t o l e r a n t t o the a n t i c o n v u l s i v e tested  development  none o f t h e s e t h r e e experiments  Experiment  saline-predictive  determine  t h i s t h e s i s attempted t o t e s t f o u r  e v i d e n c e o f the involvement o f P a v l o v i a n , development  to  However, because  the  tolerance  t o the a n t i c o n v u l s i v e e f f e c t o f a l c o h o l d e c l i n e d c o m p l e t e l y i n untreated it  was  control  subjects  over the 10-day e x t i n c t i o n phase,  not c l e a r whether e x t i n c t i o n  procedures  are  in  c a p a b l e o f c o n t r i b u t i n g t o the d e c l i n e o f t h i s type o f tolerance.  However.  the  rapid  decline  anticonvulsive e f f e c t of a l c o h o l i n suggests  that  t h i s example o f t o l e r a n c e was  product of learning,  which has  preexposure  of  1977).  alcohol.  of  the  subjects  not o r i g i n a l l y  a in  In Experiment 3. ,  the s u b j e c t s t o the environment i n which  they s u b s e q u e n t l y r e c e i v e d a l c o h o l d i d not a f f e c t the development  to  been h y p o t h e s i z e d t o r e s u l t  a more e n d u r i n g change ( S i e g e l . 1975. the  alcohol  i n tolerance  nonextinguished  fact  tolerance  to  the  anticonvulsive  ensuing e f f e c t of  52  I n t e r p r e t a t i o n o f the The  present  Results  r e s u l t s are r e l e v a n t t o  ostensibly similar.  questions.  The  two  first  different.  but  i s whether o r  not  t o l e r a n c e t o the a n t i c o n v u l s i v e e f f e c t o f a l c o h o l can  develop  i n the  present  absence  of  experiments p r o v i d e experiment.  Pavlovian  conditioning.  The  a c l e a r answer t o t h i s question.  a s u b s t a n t i a l degree o f t o l e r a n c e was  In  each  observed i n  the absence o f the u s u a l i n d i c a t o r s of P a v l o v i a n  conditioning.  Thus.  the  considered  experiments  together.  provide  the  strong  results  evidence  a n t i c o n v u l s i v e e f f e c t o f a l c o h o l can the c o n t r i b u t i o n o f P a v l o v i a n The the  present  instance  experiment  particular Pavlovian  is  develop  conditioning.  generation  of  and  tolerance,  criticism  f o r the i n d u c t i o n o f  investigation The  certainly  tolerance  appropriate  to  i f Pavlovian  —  parameters  the  in  this  of  the  for  the  anticonvulsant  of the  case. present reliable  effect  of  c o n d i t i o n i n g were the b a s i s f o r t h i s  these parameters should  the r e l i a b l e  conditioning i n  not s u b j e c t t o the u s u a l  conditioning.  the  without  r e s u l t s , t h a t i s . t h a t the parameters under  were  present  tolerance to  indeed  were not a p p r o p r i a t e  effect  experiments alcohol,  that  f a i l u r e t o f i n d evidence of P a v l o v i a n  d i r e c t e d at negative the  of  generation  have been  of conditioning.  appropriate  for  C l e a r l y , they were  not. It  is  conditioning was  possible, did  albeit  unlikely,  that  o c c u r i n a l l o f the p r e s e n t  in  Experiment 2 i n which the d i s s i p a t i o n o f t o l e r a n c e e f f e c t s  was  complete  extinction augmentation  in  control  procedures of  This  this  is  a  very  subjects  would decline  have even  real  experiments but possibility  so  somehow masked.  Pavlovian  t h a t i t was produced if  they  a  u n l i k e l y that demonstrable were  present.  53  However, the f a c t t h a t t o l e r a n c e t o effect  alcohol's  anticonvulsive  d i s s i p a t e d so r a p i d l y i n n o n e x t i n g u i s h e d c o n t r o l s  suggest t h a t P a v l o v i a n underlying argued  conditioning  t h e o r i g i n a l development  that the conditioned  effects,  i s enduring  example.  he  describes  morphine's  analgesic  12  and  days.  in  was  the  S i e g e l has  l i k e other  absence  of  conditioned  extinction.  For  a case i n which r a t s made t o l e r a n t t o  e f f e c t were l e f t  i n t h e i r home cages f o r  were s u b s e q u e n t l y found t o s t i l l  t o l e r a n t t o morphine's  mechanism  of the effect.  tolerance,  the  not  does  analgesic  effect,  be c o m p l e t e l y  unlike subjects  that  had been exposed t o e x t i n c t i o n procedures. Can and 3?  t h e same c r i t i c i s m I s i t l i k e l y that  these  two  experiments  a l s o be d i r e c t e d a t Experiments 1  the was  a  tolerance  that  conditioned  developed  in  response t o some  f e a t u r e o f t h e i n j e c t i o n environment t h a t was somehow  masked?  The problem i n experiments l i k e Experiments 1 and 3 i s t h a t i t is  never  clear  exactly  what  feature  or  i n j e c t i o n environment a r e s e r v i n g as t h e  features  of the  Thus.  i t is  CS.  never c l e a r t h a t i n j e c t i n g s u b j e c t s i n another environment has removed  t h e c r i t i c a l CS u n l e s s  there i s a s u b s t a n t i a l d e c l i n e  i n t o l e r a n c e as a r e s u l t .  However i n Experiments 1 and 3. t h e  differences  between  injection  alternative  environment were as g r e a t o r g r e a t e r  the  environment  and  the  than i n most  demonstrations o f the s i t u a t i o n a l s p e c i f i c i t y o f other  alcohol  t o l e r a n c e e f f e c t s , o r f o r t h a t matter t h e t o l e r a n c e e f f e c t s o f other  drugs.  differed  The two environments  in  terms  characteristics, environments  of  light,  in  in  experimenter.  l o c a t i o n , and  some  other  and  location  (e. g. . M e l c h i o r  (e. g. .  Siegel.  & Tabakoff, 1981).  testing  smell.  studies  s i t u a t i o n a l s p e c i f i c i t y of tolerance noise  Experiments  have  and  differed  3  chamber contrast,  demonstrating  1977) This  In  1  only  the in  or j u s t l o c a t i o n  indirect  evidence  54  suggests  that  conditioned  it  is  unlikely  e f f e c t s u»as due  that  the f a i l u r e t o observe  t o a masking of  extant  Pavlovian  influences. More d i r e c t e v i d e n c e a g a i n s t by the  results  of  the  presence  of  administration. it  was  theory  all  the  during  saline  compensatory CR.  were i n j e c t e d  the  cues  This provides  On  the  saline  in  of  whatever the c r i t i c a l  injection  should  s a l i n e given  cues  with  predictive  t h i s t e s t , and  Instead,  alcohol-predictive activity.  of  Accordingly,  present  provided  s a l i n e t e s t i n Experiment 1.  s a l i n e test, tolerant subjects the  such an argument i s  produced  according have  alcohol cue  was,  to Siegel's elicited  a  i n the presence o f  the  a small decline i n seizure  u n e q u i v o c a l evidence  that  Pavlovian  c o n d i t i o n i n g does not u n d e r l i e the development of t o l e r a n c e alcohol's anticonvulsant The  second  the p r e s e n t can  but  s l i g h t l y d i f f e r e n t question  the  development  anticonvulsive effect. Pavlovian  effect.  f i n d i n g s i s whether or not P a v l o v i a n  influence  of  Although  e f f e c t s i n the p r e s e n t  tolerance  there  is  experiments,  relevant  rule  be i n v o l v e d  to  no  alcohol's  evidence  under other  conditions.  the p r e s e n t  experiments  routes  of  studies tolerance  (e. g.  and  have  etc. )  demonstrated  because t h e r e was  c o n d i t i o n i n g i n the present to  assume t h a t P a v l o v i a n  injection  were  similar  environmental  effect  experiments,  it  seems  of  schedules,  to  those of  control  not even a h i n t o f  of  Pavlovian reasonable  c o n d i t i o n i n g would not i n f l u e n c e  development o f t o l e r a n c e t o a l c o h o l ' s regardless of  anticonvulsant  doses,  one  e f f e c t s might  However, because the c o n d i t i o n s  administration  that  alcohol's  of  because the same  out the p o s s i b i l i t y t h a t P a v l o v i a n i n tolerance to  to  conditioning  methods were used i n each experiment t o produce t o l e r a n c e , cannot  to  anticonvulsive  the method employed i n t h e i r generation.  the  effects Thus,  55  i t appears t h a t types  of  Pavlovian  alcohol  hypothermic  and  conditioning  tolerance hypnotic  (e. g. ,  effects)  but  tolerance to a l c o h o l s anticonvulsant  One  o f the two  conditioned  x  others  (e. g. ,  effect).  i m p l i c a t i o n s o f the f a i l u r e t o demonstrate  Although  there  the  has been q u i t e recent, confined  to  only  drugs (see T a b l e I ) . obtained  support  press)  himself,  and  model  tolerance,  this  a few  To date,  most  of  these  studies  f o r S i e g e l s t h e o r y of t o l e r a n c e . acknowledges  refers  to  a  to  that  not  all  For example, Pavlovian  instances  acute  than  descending p o r t i o n .  at  the  same  tolerance  all  training  same  session.  Acute  t o l e r a n c e i s an i n s t a n c e i n which t o l e r a n c e  develops  and  testing  absence  are  of  done  absence  d e s c r i b e d by S i e g e l .  of  within the  that types  of  and  Acute ascending  In acute  the drug i s adminstered o n l y once,  of  tolerance i s  conditioning.  curve  have  Siegel (in  g r e a t e r drug e f f e c t on the  p o r t i o n o f the b l o o d c o n c e n t r a t i o n the  has  e f f e c t s of a l i m i t e d number o f  x  not e a s i l y a t t r i b u t a b l e  of  trend  the r e s e a r c h t h a t has been done  t o l e r a n c e can be c o n d i t i o n e d .  c o n c e n t r a t i o n on  Pavlovian  have been a number o f r e p o r t s o f  r e s e a r c h on P a v l o v i a n c o n d i t i o n i n g and  designs,  to a l c o h o l s  t o l e r a n c e t o the a n t i c o n v u l s i v e e f f e c t of a l c o h o l  tolerance.  tolerance  not  some  Conclusions  i s t h a t i t l i m i t s the g e n e r a l i t y o f  been  influence  tolerance  x  Major I m p l i c a t i o n s of the  can  in  conditioning effects  Whether a l l i n s t a n c e s o f long-term  t o l e r a n c e can be c o n d i t i o n e d or not i s a q u e s t i o n t h a t has received a have  great deal of scrutiny.  claimed  (Cappell,  that  Roach,  the &  Pavlovian  Poulos,  1981;  S i e g e l and model  the  his  applies  Siegel,  1977,  drug not  supporters to  many  i n press;  56  Siegel,  Hinson,  Mansfield Krank,  & Krank,  1979) or a l l ( C r o w e l l e t  make  a  considerable simply  specific  point  the  Instead,  tolerance  that. does  The p r e s e n t  "There i s  not  t o l e r a n c e r e s u l t s from r e p e a t e d  pharmacological  p. 189)  stating  Siegel et al. result  organism s u f f e r i n g r e p e a t e d p h a r m a c o l o g i c a l  o f t h e drug i n t h e c o n t e x t signal  In fact.  of  evidence . . . t h a t  from  insult.  1981;  & Cunningham. 1980; S i e g e l . 1977; S i e g e l . Hinson. &  1978) c a s e s o f drug t o l e r a n c e .  (1978)  al. ,  o f e n v i r o n m e n t a l cues t h a t  stimulation. "(Siegel  study  application  clearly  does  not  et  reliably  al.,  support  1978, such  a  claim. There  have  was c l a i m e d Pavlovian  o n l y two p u b l i s h e d  t h a t an i n s t a n c e  conditioning  serious design the  been  first  flaws  r e p o r t s i n which i t  o f t o l e r a n c e was n o t  control.  In  subject  both, t h e s t u d i e s have  t h a t c a s t doubt on t h e c o n c l u s i o n s .  study.  Sklar  and  Amit  (1978)  On  each  of  In  attempted  demonstrate t h a t t h e e x t i n c t i o n procedure d e s c r i b e d (1975) would a t t e n u a t e  by  t h e l e t h a l e f f e c t s o f morphine i n r a t s .  t h e seven t o l e r a n c e i n d u c t i o n s e s s i o n s ,  subjects  subjects  On each o f t h e subsequent 8  received  environment, home cages. and  saline  and t h e o t h e r  in  the  days.  half  Amit  h a l f remained u n d i s t u r b e d  in  their  On t h e t e s t day. a l l s u b j e c t s were i n j e c t e d w i t h (1978)  to  be  twice  that  m o r p h i n e - a s s o c i a t e d environment. the  two  groups  e x t i n c t i o n group r a t s died,  were  of  the  The number o f  was used as t h e dependent measure.  group died.  the  morphine-associated  mg/kg o f m o r p h i n e — a dose p r e v i o u s l y determined  between  they  15 mg/kg o f morphine and on Day 7, they r e c e i v e d 105  mg/kg morphine.  100  to  Siegel  r e c e i v e d i n c r e a s i n g doses o f morphine such t h a t on Day 1 received  to  5 out o f 16 r a t s  in  Sklar  LD50—in dead  No s i g n i f i c a n t  found ; whereas  by  the  animals  differences 6  out o f 16  the  control  The a u t h o r s concluded t h a t they had demonstrated  57  t h a t c o n d i t i o n i n g e f f e c t s d i d not lethal effects is  that  of  morphine.  tolerance  to  demonstrated; i t was  affect lethal  effects  entirely  induction  phase.  study  was n o t  assumed t o have developed.  e n t i r e l y p o s s i b l e t h a t no t o l e r a n c e had developed tolerance  to the  A grave problem with t h i s  morphine*s  only  tolerance  thereby  making  It i s  during  the  the  experiment  irrelevant.  In a r e p l i c a t i o n o f t h i s study.  S i e g e l . Hinson.  and Krank  (1979) demonstrated t h a t e x t i n c t i o n procedures c o u l d i n f l u e n c e t o l e r a n c e t o morphine''s l e t h a l e f f e c t s a f t e r they  demonstrated  the  effects  development  morphine.  of  tolerance  to  the  lethal  E s p e c i a l l y i n view o f t h i s r e p o r t ,  of  the s i g n i f i c a n c e  o f S k l a r and Amit*s experiment i s q u e s t i o n a b l e . In a second study.  Demellweek and  amphetamine-injected  and  Goudie  saline-injected  and a d i s t i n c t i v e odour, once. 20 min b e f o r e a 30  received  eight  such  20  min  noise. after.  red  Subjects  sessions before the t e s t session during  which a l l s u b j e c t s were i n j e c t e d with amphetamine f o r milk  dim  an  illumination  p e r i o d and again.  white  in  made  milk-access  by  rats  placed  environment. min  distinctive  (1983)  consumption  i n t h e home  demonstrate c o n d i t i o n e d hyperphagia.  cages.  and In  tested  order  these same s u b j e c t s  to were  g i v e n 12 days o f ad l i b i t u m a c c e s s t o f o o d and water a f t e r t h e first  test  access  t o milk i n t h e amphetamine-predictive environment.  Demellweek  session. and  b e f o r e r e c e i v i n g a s a l i n e i n j e c t i o n and  Goudie  (1983)  situational specificity concluded  nor  were  able  compensatory  to  t h a t t o l e r a n c e t o amphetamine s a n o r e x i c  a s e r i o u s methodological conclusion.  distinctive  problem  Although  environment  during  i n this they the  neither  hyperphagia.  %  not i n f l u e n c e d by e n v i r o n m e n t a l manipulations. such a  show  tolerance  they  e f f e c t was  Unfortunately,  experiment  exposed  As  subjects  belies to a  development  58  sessions.  the  amphetamine  home cage b e f o r e environment.  i n j e c t i o n was always g i v e n  t h e r a t was t r a n s f e r r e d  Consequently  a  very  to  the  i n the  distinctive  s a l i e n t predictor of the  e f f e c t s o f amphetamine was d i s s o c i a t e d from t h e environment i n which t h e  effects  hyperphagia  were  experienced.  was n o t e l i c i t e d  That  conditioned  i s not s u r p r i s i n g i n view o f t h e  confounding i n f l u e n c e s o f t h e 12 day i n t e r - t e s t p e r i o d i because  i t had  some  features  i n common w i t h t h e t o l e r a n c e  a q u i s i t i o n phase, may have a c t e d It  i s clear  that  i n t e r p r e t a t e d with There  of  Sherman<1979)  as an  extinction  procedure.  particular  experiment  should  be  caution.  a r e two  conditioning instance  this  which  published  effects  were  tolerance, showed  reports  in  which  some  n o t demonstrable f o r a p a r t i c u l a r while  other  effects  were.  t h a t whereas he was a b l e t o demonstrate  e x t i n c t i o n o f and a compensatory CR t o morphine's hyperthermic effect,  he was n o t a b l e t o show  the same  effect  situational  o f morphine.  In addition,  specificity for he showed t h a t o f  these t h r e e c o n d i t i o n i n g e f f e c t s o n l y s i t u a t i o n a l c o u l d be demonstrated f o r morphine's a n a l g e s i c other  hand,  able  to  effect. Amit's  effect.  On t h e  Eikelboom and Stewart(1981) found t h a t they were  show  compensatory  specificity  situational CR  or  Accordingly,  specificity  extinction these  of  reports  effects  morphine's differ  but  not a  hyperthermic  from  Sklar  and  (1978) and Demellweek and Goudie's (1983) i n t h a t some  s u p p o r t f o r S i e g e l ' s model found. different Pavlovian  effects  of  drugs  The a u t h o r s concluded  are d i f f e r e n t i a l l y s e n s i t i v e to  conditioning influences.  I n n e i t h e r r e p o r t however,  did the authors claim that Pavlovian not i n f l u e n c e Negative  that  conditioning  effects  do  tolerance. results  experiments c r e a t e a  such dilemma  as  those  found  f o r researchers.  i n the present Generally,  59  negative  f i n d i n g s a r e not pursued f o r two reasons (a) they a r e  more e a s i l y a t t r i b u t a b l e t o s p u r i o u s consequently difficult state  (b) they  are  not  readily  t o determine i f t h e n e g a t i v e  of  affairs  or  are  simply,  of  the negative  this  because  of  the  the  o f time,  tendency  problem o f p u b l i s h i n g n e g a t i v e  are r e l u c t a n t t o p u b l i s h r e p o r t s have not  undergone  Pavlovian  c o n d i t i o n i n g and  There  extensive  further  of  negative  tolerance  is  studies,  reports  has  d e f i n i n g the l i m i t s  of  seriously the  a  case  in  The  absence  the  model  of  not a f f e c t drug t o l e r a n c e , the  cannot  first  be  clear  issue  of of  tolerance.  conditioning  are  point.  r e p o r t i n g the lack o f  about t h e c o n d i t i o n s under which  the g e n e r a l i t y o f S i e g e l * s model  that  The r e s e a r c h on  Without i n f o r m a t i o n does  do  publishers  findings  undermined  Pavlovian  to  complicates  r e s u l t s because  c o n d i t i o n i n g e f f e c t s i n tolerance.  negative  the  e f f o r t and money  examination.  a r e o n l y a few p u b l i s h e d  Pavlovian  t o determine  Investigators are reluctant This  true  further careful analysis of  expenditure  i n v o l v e d i n such a task.  It i s  results reflect a  In order  findings,  the problem i s e s s e n t i a l .  published.  as o f t e n i s t h e case, t h e  r e s u l t o f m e t h o d o l o g i c a l problems. source  or anomolous f a c t o r s , and  Pavlovian  the question of answered.  present  studies  obtained  i n t h e absence o f c o n d i t i o n i n g e f f e c t s .  The  account o f t o l e r a n c e By being so,  they add i n an i m p o r t a n t way t o the i s s u e o f the g e n e r a l i t y o f the model. The  second i m p l i c a t i o n o f t h e f a i l u r e t o demonstrate t h a t  tolerance  to  influenced provide  by  the  anticonvulsive  Pavlovian  in  which  tolerance  subjects  of  is  alcohol  that  was  i t does not  i n t e r p r e t a t i o n of  As p r e v i o u s l y d e s c r i b e d ,  t o demonstrate c o n t i n g e n t design,  conditioning  support f o r the Pavlovian  tolerance.  effect  contingent  t h e t y p i c a l paradigm used is  the  before-and-after  e i t h e r r e c e i v e t h e drug b e f o r e a  60  task  or  the  drug  after  development t r i a l s . drug b e f o r e  the  the  task,  the  test  the  tolerance  On the t e s t day, a l l s u b j e c t s r e c e i v e t h e  task.  According  subjects r e c e i v i n g a l c o h o l before on  during  day  t o Wenger e t a l .  t h e task  (1981),  f o r the f i r s t  time  do not show t o l e r a n c e because they a r e n o t  e n c o u n t e r i n g t h e same cues on t h i s day t o l e r a n c e a c q u i s i t i o n days.  as  they  had  For the d r u g - a f t e r - t e s t  on  the  subjects,  the exposure t o t h e t e s t apparatus and performance o f t h e task reliably  preceded  the  drug  administration  t o l e r a n c e development s e s s i o n s . subjects that  do  had  not  signalled  drug-after-test  D i f f e r e n t Group s u b j e c t s receive  cues  On t h e t e s t  not  for  study  associated  the  is  administration. in  that  they a l l  w i t h t h e drug on t h e t e s t day. experiments do not  environmental  control  of  a Pavlovian  t o l e r a n c e such as t h a t seen i n  (1983)  these  a r e comparable t o t h e  o f Experiment 1,  alcohol's anticonvulsive effect, contingent  sessions,  drug  subjects  Because t h e r e s u l t s o f t h e p r e s e n t support  each o f t h e  r e c e i v e t h e same cues ( t e s t apparatus etc. )  previously  Accordingly,  on  quite unlikely.  provide  tolerance  interpretation of  the  Pinel  Consequently,  et a l .  a theory  as t h a t proposed by Eikelboom and Stewart (1982), which refinment  of  S i e g e l ' s theory,  an e x p l a n a t i o n been  no  of  assessing  tolerance,  the  three  the  Pavlovian  as suggested by Wenger Wenger  et  m e t h o d o l o g i c a l problems  that  limit  t h i r d study,  is a  there  have  t o l e r a n c e can be Three  studies  interpretation et  al.  of  (1980).  experiments t h a t have t e s t e d t h e o r i g i n a l  h y p o t h e s i s proposed by  test  To date,  by any v a r i a t i o n o f S i e g e l s theory.  contingent Two  tolerance. v  reported  such  would a l s o not be supported as  attempts t o determine i f c o n t i n g e n t  explained have  of contingent  to  however i s a w e l l  of the Pavlovian  al.  (1980)  their  controlled  have  serious  conclusions. and  The  comprehensive  i n t e r p r e t a t i o n of contingent  tolerance.  61  The  three  studies  and  the  contribution  of  the  present  experiments t o t h e q u e s t i o n o f the P a v l o v i a n i n t e r p r e t a t i o n o f c o n t i n g e n t t o l e r a n c e a r e reviewed below. Demellweek amphetamine's  and  Goudie  anorexic  <1983)  effect  showed t h a t t o l e r a n c e t o  was  e n v i r o n m e n t a l manipulations.  In  not  influenced  addition,  they  b e f o r e - a n d - a f t e r paradigm t o demonstrate c o n t i n g e n t to the  same  effect  o f amphetamine.  contingent tolerance,  rats  were  used  I n o r d e r t o demonstrate  injected  intraperitoneally  20 min b e f o r e a c c e s s t o milk.  equivalents  Those s u b j e c t s t h a t  had r e c e i v e d amphetamine b e f o r e milk a c c e s s were g i v e n 20  min  afterwards, were  three  each o t h e r o n l y supplement  amphetamine-before  in  milk  the  intake;  d i f f e r i n g i n t h e amount Subjects to  the  number  of  groups, food  amphetamine b e f o r e three  food  during  pellets  which  milk access.  from  given  to  given  were  used.  exposures p r i o r  a l l subjects  received  A l l t h r e e amphetamine-before  amphetamine-after  Goudie(1983) concluded  milk.  differing  groups developed s i g n i f i c a n t l e v e l s o f t o l e r a n c e , i n to the  milk  t h r e e amphetamine-after groups a l s o of  session  to  pellets  were g i v e n 21 drug-milk o r milk-drug test  saline  whereas s u b j e c t s g i v e n s a l i n e b e f o r e  a c c e s s were g i v e n d-amphetamine 20 min a f t e r a c c e s s There  a  tolerance  with e i t h e r 2 ml/kg o f d-amphetamine o r v o l u m e t r i c of s a l i n e ,  by  groups.  contrast  Demellweek  that the opportunity t o experience  and the  a n o r e x i c e f f e c t s o f amphetamine was c r u c i a l t o t h e development of tolerance described, that  t o amphetamine's a n o r e x i c e f f e c t .  the authors  Pavlovian  claimed that  conditioning  their  attempts  influenced  amphetamine's a n o r e x i c e f f e c t were u n s u c c e s s f u l . p r e v i o u s l y d i s c u s s e d problems l e f t considerable  doubt  t h e i r claims that the  with  the  do  not  to  support  show  tolerance  to  However, t h e  experimental  about t h i s c o n c l u s i o n .  results  As p r e v i o u s l y  design  Accordingly, a  Pavlovian  62  i n t e r p r e t a t i o n of contingent Mansfield,  Benedict*  tolerance are equivocal. and  Woods(1983) attempted t o show  environmental c o n t r o l o f t o l e r a n c e to the of  alcohol  and  contingent  caused by  alcohol.  problems,  the  concerns  In  most  tolerance  addition  serious  t h e i r conclusions.  interpretation  of  hypothermic  t o t h e motor d e f i c i t s  to  some  criticism  methodological  of  Conclusions  contingent  effect  t h e i r experiment  about  the  t o l e r a n c e based on  Pavlovian  observations  from two d i f f e r e n t e f f e c t s o f a l c o h o l a r e i n v a l i d . In t h e t h i r d study,  Poulos,  Wilkinson,  t e s t e d the Pavlovian i n t e r p r e t a t i o n using  amphetamine's  interest.  anorexic  as  the  tolerance  behaviour  of  They i n j e c t e d r a t s i n t r a p e r i t o n e a l l y with 4. 0 mg/kg  bidaily tolerance  induction  access  days.  conducted 48 hr a f t e r t h e l a s t of  contingent  effect  d-amphetamine 20 min p r i o r t o milk  half  of  and C a p p e l l (1981)  on  each  of  five  On  the,. t e s t  session,  tolerance  induction  session,  t h e s u b j e c t s r e c e i v e d an i n j e c t i o n o f amphetamine i n  the amphetamine-associated environment, received i t i n a  novel  whereas t h e o t h e r h a l f  environment.  Rats  tested  in  the  f a m i l i a r environment showed g r e a t e r t o l e r a n c e t o amphetamine's anorexic  effect  than  rats  t e s t e d i n t h e n o v e l environment.  Having shown t h a t a s s o c i a t i v e i n f l u e n c e s they  attempted  to  a f f e c t contingent seven  bidaily  determine  tolerance.  ip  affected  tolerance,  i f Pavlovian influences could S u b j e c t s i n two groups  received  amphetamine i n j e c t i o n s and s u b j e c t s i n two  o t h e r groups r e c e i v e d seven b i d a i l y i p s a l i n e i n j e c t i o n s .  One  of t h e groups o f s u b j e c t s r e c e i v i n g amphetamine was allowed 30-min  milk  access  20  o t h e r group was allowed  min access  a  a f t e r the i n j e c t i o n whereas t h e to the  milk  on  the  days  in  between i n j e c t i o n s .  A l l o f t h e s u b j e c t s r e c e i v i n g s a l i n e were  allowed  milk  access  to  t o l e r a n c e i n d u c t i o n phase.  20  min  a f t e r i n j e c t i o n during the  On t h e t e s t day, s u b j e c t s i n  both  63  the  amphetamine  groups  and  i n one  i n j e c t e d with amphetamine 20 min subjects and  in  allowed  the  t o milk.  The  the o t h e r s a l i n e group were i n j e c t e d with  saline  milk  access,  subjects  were  20 min  tested  b e f o r e access later.  in  In  the  environment whereas the o t h e r h a l f environment.  of the s a l i n e groups mere  each  group,  half  amphetamine-associated  were  tested  in  a  novel  Poulos e t a l . (1981) argued t h a t i f t o l e r a n c e t o  amphetamine s  anorexic  x  effect  morphine s analgesic e f f e c t , K  were  similar  to  that  to  then exposure or non-exposure  to  the t o l e r a n c e measuring task s h o u l d not a f f e c t the development of tolerance.  The  having  amphetamine  received  results  developed t o l e r a n c e . familiar there  a  was  contingent  evidence  development  greater  some  to  the  milk  not j u s t the systemic  the  homeostatic  those t e s t e d i n the  tolerance  than  They noted t h a t  associative  a  group  revision  instigating  Certainly, and  the  could  developed  of  Pavlovian  the  stimulus  for  mechanism,  that  is,  adaptation  the  i t is  a  the Once  to  the  influenced  Although t h i s r e v i s i o n i s  reasonable  one,  and  it  maybe  tolerance  tolerance. the r e s u l t s o f the p r e s e n t  experiments do  i d e a o f a common mechanism u n d e r l y i n g K  e t a l . (1983) demonstrated t h a t r a t s t h a t had  not  contingent  conditioned tolerance to a l c o h o l s anticonvulsive  Pinel  on  animals  s t u d y i n g the r e l a t i o n between c o n t i n g e n t  and c o n d i t i o n e d support  although  presence of i t i n the body.  conditioning effects.  l o o s e l y formulated, in  those  influence  drug-induced change i s a c t i v a t e d , t o l e r a n c e can be  useful  access  of t o l e r a n c e i s the f u n c t i o n a l consequence of  drug,  by P a v l o v i a n  subjects  an unamended P a v l o v i a n h y p o t h e s i s  proposed  which  o n l y the  prior  o n l y the c o n t i n g e n t  They in  min  n o v e l one.  for  tolerance,  tolerance. hypothesis  showed  completely  not e x p l a i n why  20  that  Of these s u b j e c t s ,  environment  tested i n  showed  effect. undergone  64  amygdaloid greater  seizures  during  alcohol  t o l e r a n c e than r a t s t h a t had  seizures while intoxicated. development was  intoxication  of  tolerance  not undergone amygdaloid  In the p r e s e n t  i t is  mechanism  unlikely  underlies  r e v e a l any  Pavlovian  hypothesis  of  that  a  contingent  a n t i c o n v u l s i v e e f f e c t when  the  conditioning effects.  Pavlovian tolerance  specific  effects  contingent  experiments,  to alcohol's anticonvulsive e f f e c t  not shown t o be a l t e r e d by P a v l o v i a n  Accordingly,  developed  to  procedures  did  not  tolerance  do  alcohol's  designed  to  Indeed,  any  so.  involving  mechanism i s not s u p p o r t e d by the p r e s e n t  conditioning  a  Pavlovian  experiments.  C o n c l u d i n g Remarks Studies tolerance,  i n v e s t i g a t i n g c l a s s i c a l c o n d i t i o n i n g e f f e c t s and  such as the p r e s e n t  t h e o r e t i c a l and  practical  p e r t i n a n t i n t h a t i t has that  a  Pavlovian  one  are important from  standpoint.  They are  been suggested by S i e g e l  the  clinical  studies.  with  regimen. after (CS's).  certain  If  aspects  drug  addict  e l i c i t e d and  be counteracted, abuser h a v i n g  studies  are in a  o f the drug environment and  drug  in  compensatory CR's  develop  response t o the drug cues  receives  in  the  would  not  c o n s e q u e n t l y the e f f e c t o f the drug would  not  thereby i n c r e a s i n g  the  n o n - d r u g - a s s o c i a t e d environment, be  and  the  administration  a  press)  associates  As i n the a n i m a l s t u d i e s ,  repeated  (in  Accordingly,  c l i n i c a l s i t u a t i o n , the drug a d d i c t g e n e r a l l y drug  clinically  S i e g e l argues t h a t the same  elements r e s p o n s i b l e f o r t o l e r a n c e i n the animal in  a  mechanism c o u l d u n d e r l i e drug overdose  withdrawal r e a c t i o n s from a drug. also present  both  an overdose.  the  drug  the compensatory CR the  According  probability  of  to S i e g e l ( i n press),  a  65  drug abuser c o u l d undergo withdrawal r e a c t i o n s exposure t o  the  drug  environment.  support f o r h i s p r o p o s a l .  just  by  There i s some c l i n i c a l  Siegel cites  the  case  of  a d d i c t s r e c e i v i n g treatment i n a h o s p i t a l s i t u a t i o n . they  are  sucessfully  hospital,  some  hospital. the  soon  treated become  for  their  readdicted  Although  addiction after  which  were  Accordingly,  leaving  subsequently  elicited  the  relieved  compensatory  by t a k i n g the drug.  the supposedly "cured" a d d i c t s become r e a d d i c t e d .  Siegel contrasted t h i s s i t u a t i o n  with  vetrans  t o h e r i o n i n Vietnam  who  although  s u f f e r the problem much.  i n the  i n which they were f i r s t a d d i c t e d t o the drug,  S i e g e l s p e c u l a t e d t h a t the environment CR s  heroin  Noting that o f t e n these relapsed a d d i c t s return to  environment x  mere  He  of  noted  addicted  readdiction  after  the  Vietnam d i d not  rehabilitation  environment  ( U n i t e d S t a t e s ) c o m p l e t e l y d i f f e r e n t from t h a t  in  which they  were i n i t i a l l y a d d i c t e d .  clinical  examples  observations  of  drug  addicts,  s u f f e r i n g from drug overdose, did  also  was  no  suggest t h a t  Siegel who  the  Siegel s v  press)  drug t o l e r a n c e i s i n v e s t i g a t e d . those  mechanisms  involving  although  the  t h i s p a r t i c u l a r time,  u n d e r s t a n d i n g human  Clearly  infra-humans,  underlying drug  drug  not  that  tolerance cases  dose they There  conditioning  though,  studies,  shed l i g h t on t h e might  dependence and abuse.  p r e s e n t s t u d i e s suggest t h a t as i n  tolerance,  cites  brought i n t o a h o s p i t a l  report that  g r e a t e r than usual,  (in  v e r y few c l i n i c a l s t u d i e s i n which c l a s s i c a l  even  the  difference  not take the drug i n t h e i r u s u a l drug environment.  are of  T h i s complete  g r e a t l y a t t e n u a t e d t h e chance o f e l i c i t i n g  model might e x p l a i n drug overdose.  taken  returned  t h e r e b y r e d u c i n g the chance o f r e a d d i c t i o n . Some  the  vetrans  as an  CR's,  reformed  of  to  i n environment  that  that  of  aid  in  Accordingly, infra-human  a l l i n s t a n c e s o f human drug dependence can  be  66  explained The  by a P a v l o v i a n present  mechanism.  s t u d i e s have  shown  that  a n t i c o n v u l s i v e e f f e c t of* a l c o h o l can c l a s s i c a l conditioning effects. the g e n e r a l i t y  of  tolerance  to  the  develop i n the absence of*  T h i s suggests a l i m i t a t i o n  the P a v l o v i a n  model o f t o l e r a n c e .  on  Without  examples o f c o n d i t i o n s under which a p a r t i c u l a r model does not apply*  one  In f a c t *  obtains  a very b i a s e d and  no c o n c l u s i o n s  be made.  The  Pavlovian  r e s u l t s of the p r e s e n t  case  of  does  tolerance  study*  not  speculate effect  and  weight*  that  of  in  alcohol  conditioning*  cannot  although  studies  the P a v l o v i a n an  no  data  c o n d i t i o n i n g does likely  contribute  tolerance.  that  is*  the  rats* etc.  of  a  X would  anticonvulsive by  classical  have been p r e s e n t e d i n t h i s In  any  case*  the  do suggest a l i m i t a t i o n on the g e n e r a l i t y o f  model o f t o l e r a n c e .  understanding  very  hooded  influenced  t h e s i s t o c o n c l u s i v e l y prove t h i s claim. present  this  t o l e r a n c e t o the be  the  to  at a c e r t a i n laboratory*  general*  can  i n d i c a t e that  apply  studied*  a n t i c o n v u l s i v e e f f e c t o f a l c o h o l i n male c e r t a i n age  picture.  about the g e n e r a l i t y o f the model  model of t o l e r a n c e  specific  often inaccurate  of and  the does  I t i s c l e a r * however,  situations not  in  influence  which  that  Pavlovian  tolerance  would  s u b s t a n t i a l l y t o our u n d e r s t a n d i n g of drug  67  Re-Terences  Alkana, R. 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