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Ethanol effects on the olivocerebellar system Harris, David Platt 1983

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c. / ETHANOL E F F E C T S ON  THE  OLIVOCEREBELLAR  SYSTEM  By DAVID  PLATT  Ph.D., The U n i v e r s i t y  A T H E S I S SUBMITTED THE  HARRIS  of British  Columbia,  I N P A R T I A L F U L F I L L M E N T OF  R E Q U I R E M E N T S FOR DOCTOR OF  THE  DEGREE  OF  PHILOSOPHY  in THE  FACULTY  (Faculty (Division  We  to  THE  OF GRADUATE  o f Pharmacology  this  thesis  the required  U N I V E R S I T Y OF June 0  STUDIES  of Pharmaceutical  accept  David  1983  Sciences)  and  as  Toxicology)  conforming  standard  BRITISH  COLUMBIA  1983  Piatt Harris,  1983  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 o f 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 granted by the head of  department or by h i s or her  representatives.  my  It is  understood t h a t copying or p u b l i c a t i o n o f 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 without my  permission.  Department of The U n i v e r s i t y of B r i t i s h 1956 Main Mall Vancouver, Canada V6T 1Y3 Date  DE-6  (3/81)  <^L<-  IP,  /  ?/  Columbia  I  written  ii ABSTRACT  The  detrimental  effect of ethanol  movement and t h e s i m i l a r i t y cal  damage  to the cerebellum  that  ethanol  Each  cerebellar Purkinje  potential  profoundly  responses:  and  v i a the parallel  via  a solitary  that  fibres,  (PC) d i s p l a y s  locally  of  inferior  (1.5  an  action  direct  (10)  of ethanol  was  evoked  cortex  spike  found  both  t o t h e 10  nucleus,  CS a c t i v i t y  i s dependant  spike  However,  i . v . d i d produce  increase  upon  part  or i . v .  ethanol.  occurring systemically activity suggest  by a  by t h e e l e c t r o significantly  subsequent  a significant  of ethanol-evoked  the reduction  r e g u l a r i t y was n o t s i g n i f i c a n t l y  lesioning  signifi-  themselves.  rate.  only  t h e 10.  in parallel,  perhaps  spontaneous  i n d i c a t i n g that  from  the spontaneous  alter  SS r a t e ,  ( C S ) , evoked  These r e s u l t s s t r o n g l y  o f spontaneous  SS f i r i n g  intrinsicly  and t h a t  applied  reduced  action  electrical  reduced,  l e s i o n i n g o f t h e c o n t r a l a t e r a l 10 d i d n o t  of ethanol  suggests  t o h a v e no  by d i r e c t  stimulation  neurones.  local  evoked  lytic  istration  pathologi-  (10)  originates  i tsignificantly  o n t h e 10 n e u r o n e s  Elimination  of  two d i s t i n c t  (SS),  (CF) which  g/kg, i.v.)  by m i c r o p r e s s u r e ,  action  spike  In a d d i t i o n , ethanol,  olive  olive  and t h e complex  fibre  by c e r e b r a l  spontaneously. and  cell  the simple  o f CFs, while  evoked  effect to that  or the i n f e r i o r  e f f e c t o n t h e CS a c t i v i t y  activation  coordinated  e f f e c t s the o l i v o c e r e b e l l a r system.  climbing  Ethanol cant  of this  on  admin-  increase SS  o f CS a c t i v i t y .  altered  by e i t h e r  of  rate Simple 10  i i i Ethanol found  to reduce  lation  This  effects  PC's  and  locally  agreement,  by  applied  locally  are contrary  evoked  by l o c a l  ethanol  ethanol  on  stimucells  with  the p r e v i o u s l y r e p o r t -  this  inhibition,  acid  (GABA) .  antagonized  a p p l i e d GABA.  was  These  to the reported  thought  to  Both i n t r a v e n the i n h i b i t i o n  results,  effects  while  in  of ethanol  in  of  systems.  alter  ficantly evoked  by m i c r o p r e s s u r e  i n the m a j o r i t y of the  i s i n agreement  Intravenously cantly  t o PC's  of inhibition  by g a m m a - a m i n o b u t y r i c  evoked  other  result  of intravenous  be m e d i a t e d ously  the period  locally  of the c e r e b e l l a r cortex  tested. ed  applied  by  Golgi  reduce  cell  administered spontaneous  the period  ethanol firing,  of i n h i b i t i o n  d i d not while  of Golgi  signifi-  i t did cell  signi-  firing  10 s t i m u l a t i o n .  John  G.  Sinclair,  Ph.D.  iv T A B L E OF  CONTENTS  ABSTRACT L I S T OF A B B R E V I A T I O N S L I S T OF F I G U R E S L I S T OF T A B L E S ACKNOWLEDGEMENT I.  INTRODUCTION  1  I I . BACKGOUND I I . A . A n a t o m y , P h a r m a c o l o g y , and P h y s i o l o g y II.A.1. General Overview I I . A . 2 . The P u r k i n j e C e l l I I . A . 2 . a . Anatomy II.A.2.D. Motor L e a r n i n g II.A.2.C. Ionic Basis for E l e c t r o g e n i c i t y I I . A . 3 . The I n f e r i o r O l i v e I I . A . 2 . a . Anatomy II.A.2.D. I o n i c Basis for E l e c t r o g e n i c i t y I I . A . 4 . The G o l g i C e l l I I . B . Gamma-aminobutyric Acid II.C. Ethanol I I . D. E t h a n o l E f f e c t s on GABA I I I . METHODS I I I . A . A n i m a l P r e p a r a t i o n and S u r g e r y I I I . B . E l e c t r o d e P r e p a r a t i o n and P o s i t i o n i n g I I I . C . Equipment III.D. Software III.E. Experimental Protocols I I I . E . 1 . E t h a n o l on C o m p l e x S p i k e s I I I . E . I . i . Climbing F i b r e - P u r k i n j e C e l l Synapse III.E.1 . i i . Cerebral Stimulation I I I . E . 1 . i i i . The I n f e r i o r O l i v e I I I . E . 2 . E t h a n o l on S i m p l e S p i k e s I I I . E . 3 . E t h a n o l on L o c a l I n h i b i t i o n I I I . E . 4 . E t h a n o l on GABA I n h i b i t i o n I I I . E . 5 . E t h a n o l on G o l g i C e l l I I I . E . 5 . a . Spontaneous F i r i n g Rate I I I . E . 5 . b . I n h i b i t i o n by I n f e r i o r O l i v e S t i m u l a t i o n I V . RESULTS I V . A . E t h a n o l on IV.A.1. Climbing IV.A.2. Cerebral I V . A . 3 . The I n f e I V . B . E t h a n o l on I V . C . E t h a n o l on IV.D. E t h a n o l on IV.D. E t h a n o l on  i i vi v i i ix x  Complex S p i k e s F i b r e - P u r k i n j e C e l l Synapse Stimulation rior Olive Simple Spikes Local Inhibition L o c a l GABA I n h i b i t i o n Golgi Cell  4 4 4 7 7 16 19 22 22 27 30 32 38 44 47 47 48 51 53 55 55 55 56 57 58 ...59 60 61 61 61 63 63 63 66 75 85 92 98 110  V  V. DISCUSSION V.A. E t h a n o l on V.B. E t h a n o l on V.C. E t h a n o l on V.D. E t h a n o l o n V. E. E t h a n o l on VI.  Complex S p i k e s Simple Spikes Local Inhibition l o c a l GABA I n h i b i t i o n Golgi Cell  CONCLUSIONS  VII. VIII.  BIBLIOGRAPHY APPENDIX  119 119 124 126 129 130 133 135 154  vi L I S T OF  ABBREVIATIONS  3-AP  - 3-acetylpyridine  AP  -  CF  - climbing  CS  - complex  DAO  - dorsal accessory  DV  - dorsoventral  GABA  - gamma-aminobutyric  GABA-T  - GABA  10  - inferior  i .p.  -  intraperitoneal  ISI  -  interspike  i.v.  -  intravenous  LC  -  locus  LH  -  latency  MAO  - medial  NA  -  mepps  - miniature endplate  PAG  - periaqueductal  PC  - Purkinje  cell  PF  - parallel  fibre  PO  - principal  PSTH  - p o s t s t i m u l u s time  SEM  - standard  SS  - simple  TTX  - tetrodotoxin  anterioposterior fibre spike olive  acid  transamidase olive  interval  histogram  coeruleus histogram accessory  olive  noradrenaline  grey  nucleus  error  spike  potentials  of inferior histogram  o f t h e mean  olive  vii L I S T OF  FIGURES  1 . An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n the e v o c a t i o n of complex s p i k e s i n a P u r k i n j e c e l l by j u x t a f a s t i g i a l s t i m u l a t i o n 2.  3.  4.  Examples of spontaneous Purkinje cell activity  and  evoked  extracellular 67  An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l on the e v o c a t i o n of complex s p i k e s i n a P u r k i n j e c e l l by s t i m u l a t i o n o f t h e c e r e b r a l c o r t e x  69  An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n the e v o c a t i o n of complex s p i k e s i n a P u r k i n j e c e l l by s t i m u l a t i o n o f t h e c e r e b r a l c o r t e x . . . . .  71  5 . The e f f e c t o f i n t r a v e n o u s e t h a n o l on s p o n t a n e o u s c o m p l e x s p i k e a c t i v i t y , a n d t h a t e v o k e d by c e r e b r a l electrical stimulation 6. 7.  8. 9. 10. 11.  12.  13.  14.  64  73  Three superimposed o s c i l l o s c o p e t r a c e s showing t y p i c a l a c t i o n p o t e n t i a l s f r o m an i n f e r i o r o l i v e c e l l  76  Micrograph showing a t r a n s v e r s e s e c t i o n of the c a u d a l i n f e r i o r o l i v e s h o w i n g an e x a m p l e o f an ior olive recording site  77  An e x a m p l e o f an i n f e r i o r o l i v e c e l l ' s i n t r a v e n o u s e t h a n o l and h a r m a l i n e The e f f e c t o f i n t r a v e n o u s neuronal f i r i n g rate  ethanol  An e x a m p l e o f t h e e f f e c t o f ior o l i v e neuronal f i r i n g  on  infer-  response  to 78  inferior  olive 80  local  ethanol  on  infer82  A micrograph of a transverse s e c t i o n through the i n f e r i o r o l i v e showing a u n i l a t e r a l e l e c t o l y t i c lesion  86  The r e s p o n s e o f a P u r k i n j e c e l l t o e l e c t r o l y t i c l e s i o n i n g o f t h e i n f e r i o r o l i v e and t o t h e i n t r a venous a d m i n i s t r a t i o n of e t h a n o l  88  The e f f e c t o f i n f e r i o r o l i v e l e s i o n i n g a n d intrav e n o u s e t h a n o l a d m i n i s t r a t i o n on t h e mean i n t e r s p i k e i n t e r v a l between P u r k i n j e c e l l s i m p l e s p i k e s  90  The e f f e c t o f i n f e r i o r o l i v e l e s i o n i n g v e n o u s e t h a n o l on P u r k i n j e c e l l s i m p l e u l a r i t y over time  93  and intraspike reg-  viii 15. The e f f e c t o f l o c a l e t h a n o l on t h e i n h i b i t i o n P u r k i n j e c e l l e v o k e d by l o c a l s t i m u l a t i o n  of a  1 6 . An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l on t h e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d b y GABA a p p l i e d l o c a l l y b y m i c r o p r e s s u r e 17. The e f f e c t o f i n t r a v e n o u s of P u r k i n j e c e l l s induced 1 8 . An e x a m p l e inhibition  e t h a n o l on t h e i n h i b i t i o n b y l o c a l GABA  95  99 101  o f t h e e f f e c t o f l o c a l e t h a n o l on t h e o f a P u r k i n j e c e l l i n d u c e d by l o c a l GABA....104  1 9 . The e f f e c t o f l o c a l l y a p p l i e d e t h a n o l on t h e a b s o l u t e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d by l o c a l l y a p p l i e d GABA  106  2 0 . The e f f e c t o f l o c a l e t h a n o l on t h e r e l a t i v e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d by l o c a l l y a p p l i e d GABA  108  21.  The e f f e c t o f i n t r a v e n o u s e t h a n o l neous f i r i n g r a t e o f G o l g i c e l l s  on t h e s p o n t a 112  2 2 . An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n t h e i n h i b i t i o n o f a G o l g i c e l l e v o k e d by s t i m u l a t i o n of the i n f e r i o r olive  114  2 3 . The e f f e c t o f i n t r a v e n o u s e t h a n o l on t h e i n h i b i t i o n o f G o l g i c e l l s e v o k e d by s t i m u l a t i o n o f t h e i n f e r i o r olive  117  ix LIST  I. II.  III.  OF T A B L E S  Summary o f t h e e f f e c t o f l o c a l aneous f i r i n g r a t e o f i n f e r i o r  e t h a n o l on t h e s p o n t o l i v e neurones  84  Summary o f t h e e f f e c t o f l o c a l e t h a n o l on t h e p e r i o d o f i n h i b i t i o n e v o k e d by l o c a l s t i m u l a t i o n o f t h e cerebellar cortex  97  Summary o f t h e e f f e c t o f l o c a l e t h a n o l on t h e i n h i b i t i o n o f P u r k i n j e c e l l s e v o k e d by l o c a l l y a d m i n i s t e r e d gamma-aminobutyric a c i d  111  X  ACKNOWLEDGEMENT  I guidance,  support I  committee: Dr.  also wish  my t h a n k s  and ed .  the other  help  collegues  patience  financial  the British  the University  for his  research.  m e m b e r s o f my  research  D r . J . H. M c N e i l l , a n d  and a d v i c e .  I also wish t o  f o rtheir  f o rtheir  valuable  knowledge,  ideas  t o my w i f e ,  Liza,  my s t u d i e s .  m u s t a c k n o w l e d g e my s p e c i a l  her undying  Canada,  during  this  L o a n d Amy T i e n  a n d t o my o t h e r  The of  throughout  D r . S. K a t z ,  f o rtheir  t o Grace  companionship I  t o D r . J . G. S i n c l a i r  t o thank  D r . J . Diamond;  assistance,  for  grateful  and p a t i e n c e  J . A. P e a r s o n ,  extend  and  am d e e p l y  thanks  and s t r e n g t h . support  Columbia  of British  of the Medical Health  Columbia  Care  Reseach  Council  Research  Foundation,  i sgratefully  acknowledg-  xi  To  Liza  and  Lydia  with  a l l my  love.  1 I.  Acute the  modulatory  including  alcohol intoxication  fetal  been  to result  by o t h e r  bellar  system Each  i s evoked  (CS), (CF)  olive  they  both  intrinsically  Purkinje  1958;  intoxication 1977) have Although  alcohol-induced that  the olivocere-  d i s p l a y s two  by a c t i v i t y  cell  a n d by p a r a l l e l  e t a l . , 1980,1982;  spike  on t h e s i n g l e c l i m b i n g  spike  cell  olive  that  firing  and  complex  spike  Sinclair  increased  regularity and L o ,  activity i s CS  and L o , 1 9 8 1 ) ,  increased  fibre  (10).  ethanol  i n f u s i o n reduced  injected ethanol  a l . , 1980).  fibre  e t a l . , 1980; S i n c l a i r  intravenous  spike (SS)  t h e complex  the inferior  simple  distinct  i s the simple  potential i s called  on P u r k i n j e  slow  intraperitoneally  cell  s t u d i e s have r e p o r t e d  I t seffect  (Rogerset  of  do s u g g e s t  o f these  e t a l . , 1980; S i n c l a i r  (Sinclair  damage t o t h e  1977; V o l k ,  mediation  The f i r s t  The s e c o n d  contraversial:  These  i n damage t o t h e c e r e b e l l u m .  cerebellar Purkinje  Previous  1981).  pathways;  (Dow a n d M o r a z z i ,  (Chernoff,  p r o j e c t i n g t o t h e PC f r o m  (Colin  after  in  i s involved.  and i s evoked  cerebellar  and motor  In a d d i t i o n , chronic  mechanisms,  potentials.  activity.  observed  do n o t p r e c l u d e  ataxia  and  1971).  a l c o h o l syndrome  studies  action  to those  or to the i n f e r i o r  reported  these  i n disturbances  symptoms o f i n c o o r d i n a t i o n and n y s t a g m u s .  Murphy and O ' L e a r y , and  results  control of proprioceptor  symptoms a r e s i m i l a r cerebellum  INTRODUCTION  CS-like  activity while bursting  2 The of action ior  nuclei.  end.  The f i r s t  CS a c t i v i t y  the  cerebral  Three  by s t i m u l a t i o n  e t h a n o l on t h e s e  intravenously  action  because of theapparent outlined  above.  on SS r a t e  To  end, complex  experiments  central  1981),  the  effect  local GABA  spike  other  since  GABA sets  These  between  spontaneous 10  neurones.  CS a n d SS  i n the absence  lesioning  activity  the effect of o f CS  was e l i m i n a t e d  activity.  i n these  o f t h e 10.  e t h a n o l h a s been  shown  to modify  at other sites i n  ( N e s t o r o s , 1979, 1980; N e w l i n  o f experiments  surface stimulation,  GABA.  the effect of  i s not clear  study examined  experiments  which  1971),  were  transmitter's  o f e t h a n o l on t h e i n h i b i t i o n  exogenous  from  The  et a l . ,  i s a ubiquitous neurotransmitter i nthe  included  (ftbodward e t a l . ,  studied.  at examining  (GABA) t r a n s m i s s i o n  system  w h i t e m a t t e r and  e t h a n o l on t h e  activity  o f e t h a n o l on t h i s  cerebellum. effect  interaction  to  the activation  was t h e n  directly  infer-  of intravenously  o f e t h a n o l o n SS a c t i v i t y  acid  nervous  The e f f e c t  by r e c o r d i n g  addition,  and because  cerebellum,  applied  and r e g u l a r i t y  gamma-aminobutyric  involved  activations  by t h e e l e c t r o l y t i c  In  the  the sites  were c o n d u c t e d  of the cerebellar  Therefore, this  ethanol this  o f these  were d i r e c t e d  and l o c a l l y  o f 10 n e u r o n e s The  o f experiments  respectively.  s e t o f experiments  firing  sets  and second  cortex,  administered last  at examining  o f e t h a n o l i n t h e c e r e b e l l u m and t h e a s s o c i a t e d  olivary  this of  p r e s e n t s t u d y was d i r e c t e d  performed actions  designed  of Purkinje  i s thought  as w e l l  to study i nthe  to study of the cells  evoked  t o be m e d i a t e d  as i n h i b i t i o n  evoked  by by  by  3 F i n a l l y , s i n c e G o l g i c e l l s are an i n t e g r a l part o f the c e r e b e l l a r c i r c u i t r y and have been reported  to be i n h i b i t e d  10 s t i m u l a t i o n , the e f f e c t o f ethanol  upon t h e i r spontaneous  firing  i n h i b i t i o n was  and upon 10 stimulation-evoked  studied .  also  by  4  II.  I I .A.  Anatomy, Pharmacology,  II.A.1. G e n e r a l The brain  which  modulating grated  individual  granular  The  molecular  fibres), cells,  dendrites  and  the  Golgi  granule  and  fibres  and  the  whereas  the  granular  the  which  directly  clusters cell  carry  of  to  The  cell  of  layer  cell  layer; .  parallel  stellate  basket  and  contains  a x o n s and  layer  inte-  three  (the  basket,and  stel-  mostly  dendrites  i s densely  climbing  fibres  ( c f . Gould,  a  large  travelling  cerebellum.  climbing  the  of  packed  cerebellum,  v a r i e t y of  systems.  e x c i t a t o r y synapses,  dendrites.  fibres  bodies  and  a l . , 1967)  to  joint-muscle  the  et  inputs  reticular  fibres  the and  into  Purkinje  axonal  vertical  smooth  major  o r i g i n a t e from  includes  tracts  Purkinje  of  with  bodies.  two  the  v e s t i b u l a r and  input  tion  cell  are  and  mossy f i b r e s  cell  bodies  There mossy  spaced  part  divided  Eccles  Purkinje, Golgi,  thin  Golgi  by  mainly  The  cell  cells,  of  into a  l a y e r ; the  ( c f . review  contains  large  for coordinating  anatomically  molecular  sparsely  neurones.  Purkinje  been  layer  layer  responsible  m u s c l e movements  I t has  l a y e r s : the  the  Physiology  is a relatively  i s generally  and  and  Overview  cerebellum  whole.  cellular  late  BACKGROUND  with  In the  sources,  on  The such  as  mossy  spinocerebellar movement  mossy f i b r e s  called  fibres,  1980).  a d d i t i o n , the  l o c a t i o n and The  the  end  informain  rosettes, with the  other  hand,  granule prob-  5 ably  originate  (Eccles cells Each  e t a l . , 1966)  and other Purkinje  fibre and  s o l e l y from  and each  Deiters'  cell  i sthought  cells  nucleus  , other  eventually  (Scheibel  Output  from  (Isreal  ascend  allel  to thefolium  as  contacts  with  arborizations Basket  cells  Purkinje and  granule  inhibitory  from  The Purkinje other  cell  a t these  1965;  layer,  synapses i s  1968).  Phillis,  These  a r er e f e r r e d t o excitatory  stellate,  while  axosomatic  stellate  connections  make i n h i b i t o r y  i sbelieved  et a l . ,  only  1971).  axons, which  brainstem  nuclei.  synaptic  connections  on  axosomatic cells.  with the a t these a l l  t o be g a m m a - a m i n o b u t y r i c  However, t h e p u t a t i v e  from  cells.  contacts  and G o l g i  The t r a n s m i t t e r  m a y be t a u r i n e output  dendritic  and basket  make i n h i b i t o r y  on P u r k i n j e  a t t h er o s e t t e s .  cells  cells  axons  b i f u r c a t e and r u n par-  direction.  Golgi,  folia  There i s  of Purkinje,  synapses  stellate  several  rosettes.  f i b r e s a n d t h e y make e x t e n s i v e  i n turn  (GABA, B i s t i  into  i s distributed v i atheir  i neither  make i n h i b i t o r y  cells  n u c l e i and  and c l o s e l y packed  cells,  cells  to Golgi  t h ep e r p e n d i c u l a r l y  axodendritic  Golgi  one c l i m b i n g  1954).  thetransmitter  cells  Purkinje  collaterals  may b r a n c h  to the molecular  t h ep a r a l l e l  exactly  and S c h e i b e l ,  hundred  olive  via collaterals.  t h ec e r e b e l l a r  and W h i t t a k e r ,  t h eg r a n u l e  which  cells  and t o send  fibre  that  to several  to receive  end a t s e v e r a l  t o suggest  acetylcholine  projects  folia,  A s i n g l e mossy  evidence  i ntheinferior  cerebellar cortical  on i t s d e n d r i t i c t r e e ,  basket  and  neurones  acid  transmitter  ( O k a m o t o e t a l . , 1983b).  t h ec e r e b e l l a r c o r t e x  innervate  i s via the  t h e c e n t r a l c e r e b e l l a r and  6 Extensive interconnections Kawamura, third of  1980;  Courville  the c o n t r a l a t e r a l afferents  the  contralateral  the  vermis  Dieters'  interpositus  dentate  nuclei .  have system  et a l . , 1980).  olive  projects  vermis,  while  hemisphere.  nuclei,  and  the  (see Brodal  and  Briefly,  the r o s t r a l and  In turn,  the  lateral  the l a t e r a l  cortex  regions  fastigial  the para-vermal  caudal  two-thirds  the Purkinje  i n the c o n t r a l a t e r a l  Similarly,  b e e n made o n  to the cerebellar  to the para-vermal  terminate  nuclei.  studies  of the o l i v o c e r e b e l l a r  of the i n f e r i o r  supplies  the  anatatomical  region  regions  of  cells  of  and projects  project  to  to the  7 I I . A . 2 . The  Purkinje  II.A.2.a.  Anatomy Purkinje  lar  cortex  (Eccles an  and  et  the  This  cerebellar  tree  pattern right  of  subdivision lar  was  projection  strong  (1974).  climbing  each  strip  the  1980;  the  Courville  twelve ally  the  and  Each module a  reflected found Each  in  in  the  cerebelpathway  Purkinje  of  of  into to  cell  the  has  granular  the  axis  proposed  of  and the  folia  at  strips.  This  that  a l . , 1980)  m o d u l e s on of:  each  strip  are  functional  olivocerebel-  studies  by  c o l l a t e r a l s to  to  the  output  localized anatomical  tracing  Brodal  suggest  that  i t i s divided  (Voogd  the  of  cortex;  interconnections.  and  Bigare,  the a  and  i.e. six  Kawamura, into  symetric1980).  inferior olive  central The  of  neurones  (see  modules,  of  widely  system  side  Arm-  l o c a l i z e d group  addition,  subdivision of  a  Extensive  functional  a  by  distributed  nuclei.  strips The  supplies In  the  others).  d i s t r i b u t i o n of  strip.  that  parasagittal  1980;  i s supplied  which  the  corresponding  narrow  these  the  olivocerebellar  consists  been  electrophysiological  strip  of  i t has  i s such  direction  parasagittal  their  Each  extending  Bigare,  folding  semi-independant  opposed  (10);  Voogd  et  of  efferent  perpendicularly  into  is topologically  of  1981).  function,  deep c e r e b e l l a r  studies  i t s only  arborization  i s divided  sections  cells  (PF).  f i b r e s , each  separated  largest  provide  is flattened  cerebellar to  the  Scheibel,  terms of  1974;  angles  are  axons  dendritic  cortex  (Armstrong,  and  their  parallel fibres In  of  cells  a l . , 1967;  extensive  layer.  Cell  nucleus;  modules  and  8 their  associated  C1 , C 2 , caudal (DAO)  C3,  and  medial and  D.  project  while  DAO  strip  receives  jects  project  C2,  which  the  the  cell  at  estimated et  1972)  .  ed  by  cell  et  the  MAO  projects  the  the  strip olive  olive  from  strips  (Chujo  the  synaptic  D  the  nucleus,  C1  and to  C3, the  receives  (PO)  et  and  at  and  pro-  contain  i s reduced  those  from  animals second  fibre.  innervation  .  1967;  can  be  Also,  fibres  the  Pur-  PC  Palkovits  directly the  (Young  1966).  i s believed  in granule  infected  and  glutamate  cell  et  to  activat-  molecular of  et  deficient (Roffler-  a l . , 1974),  or  a l . , 1979).  e x c i t a t o r y input  more  major  Szentogathai,  synapses  Immature P u r k i n j e from  to  genetically deficit  (Rohde e t major  and  two  These  concentrations  which  virally  cells.  Bernard,  dendrites  high  the  exceeds 200,000 per  these  a l . , 1975)  of  connections  (Hamori  Fox  cell  first  Purkinje  connections  Purkinje  climbing  transient  passage"  a l . , 1978),  The  inputs  interpositus  and  B,  nuclei,  between  of  are  to  transmitter  as  receive  from  A,  accessory  Dieters'  Finally,  nucleus  fibres  number o f  such  x-irradiated  is  both  rostral  systems  layers  and  fibres  dorsal  anterior  d e n d r i t i c spines  a l , 1977)  cerebella, Tarlov  "en  been d e s i g n a t e d  nucleus.  parallel  glutamate  et  the  principal  The  glutamate.  (Nadi  C3  the  a l . , 1966a,1967;  be  granule  to  from  afferent  and  i s interposed  dentate  make e x t e n s i v e  al.,  (MAO)  fastigial and  have  B recieve  interpositus nucleus.  excitatory  (Eccles  the  S t r i p s C1  The  The  olive  and  from to  kinje  to  i t inputs  posterior fibres  S t r i p s A and  accessory  respectively. rostral  parasagittal strips  than  one  to  cells  Purkinje receive  climbing  fibre  cells a (Kawa-  9 guchi,  1975;  B a r r a g a n and  innervation  D e l h a y e - B o u c h a u d , 1 9 8 0 ) , but  i s reduced to a s i n g l e c l i m b i n g  ( E c c l e s e t a l . , 1966a; P u r o and of climbing suggested  f i b r e s and  their  continued  and  i t s associated  continued  maintenance o f the  Purkinje c e l l  dendritic tree  ( K o r n g u t h and  1979;  These l a t t e r w o r k e r s r e p o r t e d  rapid  itself  3-acetylpyridine  lateral vestibulospinal tract cell  the  have be due  to the  PC.  at the  synapse.  s t u d i e s are  the  a n o t h e r s t u d y ( S o t e l l o e t a l . , 1975)  w i t h 3-AP,  but  rather  were n o t increased  while  spine  spine  m a i n t e n a n c e does n o t  d e v e l o p m e n t may  Each c l i m b i n g connection  with  form o f a g r e a t  cell-  reported  i n number.  and  repeated the more  In a d d i t i o n , that  r e d u c e d a f t e r 10 This  Purkinje  destruction suggests  fibre  that,  innervation,  a p p e a r t o be d e p e n d e n t upon i t .  f i b r e makes an  intimate  Purkinje c e l l  mentioned above.  many "en  a  continued  therefore  situation.  require climbing  a t l e a s t one  a r r a n g e m e n t , as was  f o r the  However,  c o n f i r m e d and  d e n d r i t i c spines  Purkinje  However, t h i s e x p e r i m e n t was  to c l a r i f y  the  i n t e r u p t i o n of axonal flow  r e s u l t s o f I t o ' s g r o u p were n o t  cell  that  1978,  They s u g g e s t e d  by a n o t h e r g r o u p ( M o n t a r o l o e t a l . , 1 9 8 1 ) .  required  1972;  (3-AP) c a u s e d  c o n s e q u e n t l o s s o f a neurohumour r e q u i r e d  f u n c t i o n i n g of the  and  the  ( I t o et a l . ,  f a i l u r e of i n h i b i t o r y transmission  t h a t t h i s may  Scott,  Woodward e t a l . , 1 9 7 7 ) , and  10 w i t h  been  development  Purkinje c e l l  d e s t r u c t i o n of the  presence  f u n c t i o n i n g has  f u n c t i o n i n g of the I t o , 1981).  The  adult  embryological  d e n d r i t i c spines  K a w a g u c h i e t a l . , 1975;  i n the  Woodward, 1 9 7 7 ) .  t o be e s s e n t i a l t o t h e  the  fibre  this  This  and  robust  in a topological connection  i s in  p a s s a g e " s y n a p s e s o v e r t h e PC's  the  entire  10 dendritic at  this  tree  (Eccles  synapse  physiological  e t a l . , 1967)  h a s been  suggested  experiments  support  .  The p u t a t i v e  t o be a s p a r t a t e . this  idea  application of L-aspartate  dependent  i n the spontaneous  kinje  cells  tested  Autoradiographical of  tritiated  nuclei al.,  support  D-aspartate  resulted  1982).  into  These workers  in vitro  increased  potassium  destruction  release  also  reported  concentration,  and  acid  major  input  interneurones:  Basket  cells  cell  somata  (Eccles  gamma-aminobutyric  contrast, onto  1967).  taurine. cells  Purkinje  cells  and  connections  while  stellate  at these  •  gamma-  cell i s  stellate  on o r n e a r t h e  Autoradiographical  an i n v o l v e m e n t o f  cells  at this  s e l e c t i v e x-ray  make  (Eccles  synapses  to suggest  the cerebellar c o r t i c a l  the  II.B).  dendrites  i s some e v i d e n c e  For example,  reduced  the outer  by  unchanged.  suggests  see Section  caused  significantly  of the Purkinje  e t a l . , 1967)  The t r a n s m i t t e r  GABA, b u t t h e r e  calcium-  (GABA) a s a n e u r o t r a n s m i t t e r  ( f o r more d e t a i l  connections 1966b,  acid  was  the basket  make i n h i b i t o r y  e l e c t r o p h y s i o l o g i c a l evidence  In  a  o f endogenous L - g l u t a m a t e ,  inhibitory  the cerebellar  synapse  that  o r deep  (Wiklund et  o f t h e 1 0 b y 3-AP a d m i n i s t r a t i o n ,  (GABA), and g l y c i n e  Purkinje  injection  bodies  was r e d u c e d  aminobutyric  cells.  that  •  o f endogenous L-aspartate.,  release  from  •;  o f 10 c e l l  dose-  of a l l Pur-  _  the report  potassium-induced  The  rate  a  the r a t cerebellar cortex  i n the labelling  dependent  after  includes  f o r example,  produced  firing  ( K r n j e v i c , 1982).  Electro-  since,  microiontophoretic increase  transmitter  et a l . , also  i tmight  destruction content  inhibitory  may be be  of  stellate  of taurine  11 eta l . ,  (McBride be  inhibited  taurine  by the  also  addition  receive  noradrenergic Anatomical structural,  input  employing  biochemical,  by S c h e i b e l ' s  o f the  from  cerebellar  these  studies  o fPurkinje  cells  cortex  onto  o f neonates  fluorescent,  ultra-  characterized  ofthis  coeruleus  h a s been  supported  slows  spontaneous  1971),  while  preserving  fibres  (Freedman  cation  o fputative  fibres  Studies  6-hydroxydopamine, a  (Marwaha have  eta l . ,  indicated  cell  and  noradrenergic  1980). a source  A noradrenergic  t o t h eP u r k i n j e  pathway  h a s been  well  p h y s i o l o g i c a l , and p h a r m a c o l o g i c a l  e t a l . , 1973) .  system  1981).  support  cell  a  electronmicrographic  innervation.  by a n a t o m i c a l ,  (Hoffer  1976;  may h a v e r e f l e c t e d  (Scheibel,  electrophysiological studies  thelocus  noradren-  (Hokfelt and  eta l . ,  cells  i nher  also  the Purkinje  a t least part  1979) .  support.  description o fnoradrenergic-like  t oPurkinje  irradiation  studies  That  A  experimental  Melamed  application o fphencyclidine,  innervation  for  1981).  Purkinje  sources.  i n thecerebellum  e t a l . , 1975;  innervation  apposition  Finally,  other  has had t h estrongest  Alexander  noradrenergic  X-ray  from  above,  and immunochemical methods had suggested  eta l . ,  involving  application of  discussed  1969;  study  reported t o  t ot h einputs  Fuxe,  in  are  O k a m o t o e t a l . , 1983a,b,c).  t o be a n e u r o t r a n s m i t t e r  recently  cells  e t a l . , 1978;  aline  Amenta  Purkinje  microiontophoretic  extrinsic  input  studies  Also,  local  (Frederickson In  cells  1976).  Activity  Purkinje activity  e t a l . , 1977)  cell evoked  i nthis  activity  afferent (Hoffer  by mossy and c l i m b i n g  and m i c r o i o n t o p h o r e t i c  neurotransmitter  et a l . ,  amino a c i d s  appli-  (Moises  et a l . ,  12 The inhibitory nuclei  cerebellar cortex  innervation  (Strahlendorf  demonstrated bellum to  the microiontophoretic  reflect  from  receptors  The r e s p o n s e  and m i c r o p r e s s u r e suggest  innervation  an  the raphe studies  i n the.  have  cere-  of Purkinje  cells  application of these  of Purkinje  receptors cells  may  (Marwaha  a l . , 1981).  the  only  output  axons o f t h e P u r k i n j e  connections such  as D e i t e r s '  been w e l l al.,  nucleus  of Purkinje  established  1971).  from  spinal  sites.  cord  over  cells,  cell  presumably entering  ( c f . Jansen  cell  and B r o d a l ,  axons onto (Obata  activity  centres  Deiters'  synaptic  but the exact  of the cerebellum  allowing  also  Purkinje  the cerebellum  innervate cells  1940)  cell  Otsuka e t  nuclei to  axonal on  (Bishop,  v i a t h e mossy f i b r e s  1982)  cells  t o modulate  The  neurones has  collater-  neighbouring  of distribution  granule  .  modulates  by t h e s e  connections  pattern  sites  e t a l . , 1967;  presumably  relayed  t o make i n h i b i t o r y  collaterals  to Golgi  may .  vary  Pur-  somata,  information  i n a manner  simi-  cells.  Purkinje two d i s t i n c t l y  climbing  i s through  w h i c h make i n h i b i t o r y  In addition, Purkinje  d i f f e r e n t areas  kinje  cells,  cell  higher  are reported  Purkinje  the cerebellar cortex  t o be GABA  Purkinje  information  als  from  on t h e c e r e b e l l a r n u c l e i and on b r a i n s t e m  transmitter  of  of histamine  and a n t a g o n i s t s  a histaminergic  The  lar  fibres  to receive  e t a l . , 1979) and b i o c h e m i c a l  the presence  agonists  i s reported  of serotonergic  ( P a l a c i o s e t a l . , 1981).  histamine  et  also  fibre  cells  are characterized  d i f f e r e n t spikes  inputs.  The f i r s t ,  by t h e i r  i n response called  generation  to parallel  the simple  spike  and  13 (SS),  i s evoked  parallel to  that  fibre of  3 0 - 5 0 Hz the  simple  and  called input  the  i s quite  second  the  rate  of  spikes:  an  spike  spike  about  course,  followed  initial  i s followed  by  1 Hz.  Roberts,  are et  related  by  1982).  the  of  an  by  cooling  injection  CS  with  climbing olive  recently the of  activity activity  or  10  CS  course  cell the  the the  usually  variability  by  cells  cell  the  of  is  powerful  have of  a a  shape  or  inhibition,  The  cell.  a normal  and  is  Purkinje  spikes  similar  neurones.  i s made up  with  by  et  the  spontanseries  and  which  has  Phillips,  of  time  wavelets.  Each  been  1956;  been r e p o r t e d  ( F e r i n et  named  Bloedel  greater  than  administration cessation  fibre  also  activity,  of  SS  caused  cell  SS  rate  by  about of  the  that  destruction was  reversably  h a l t i n g CS  (Montarolo  et  a l . , 1982)  and  and  Simpson,  et ces-  This  activity  local  1982).  of  associated  regularity.  by  Hz,  (Colin  Montarolo  by  (Leonard  8  et  harmaline,  confirmed  lidocaine  in-  activity  (3-AP), and  be  Colin  demonstrated  3-acetylpyridine  Purkinje  to  a l . , 1971;  T i l o k s c k u l c h a i , 1981;  a l . ( 1980)  with  has  rates  a complete  Rawson and  increased  s t u d y was  CS  (Granit  example,  Colin  inferior  with  to  stimulation  a l . , 1980;  sation  spike  For  associated  al.,  of  excitatory  1971).  Simple  evoked  of  to  Purkinje  smaller  period  and  1980).  time  I t i s evoked  Each  spike,  i n a c t i v a t i o n response  al.,  and  the  a Purkinje  inputs  fibre.  the  versely  by  most o t h e r  response  several  an  shape  of  (CS) .  large  by  or  irregular reflecting  climbing  e o u s CS  rate  inhibitory  complex  from  a  p o t e n t i a l s of  spike  e x c i t a t o r y and  activity  I t has  action  The  CS  intrinsic  input.  the  spontaneous  by  Indeed,  14 this  r e l a t i o n s h i p has  reduction of  of  ethanol  CS  was  activity also  and  regularity  The  increased  been  caused  associated  (Sinclair SS  rate  et  does  being  a r e d u c e d ,number o f  after  ethanol  An  report  spontaneous  for by  this  Ebner  firing  spike  only  evocation  i s a PC  one  climbing  fibre,  the  activity  of  cortical would  population ity  would  caused  others,  inhibitory  suggest  be  by  that  was  under  but  increased  only  the  for  beyond  by  the  a period period  Colin  et  1981,  1982).  to  due  be  of  a l . , 1980;  to  This the  of  increased I t o et  activation  activated climbing  has  little  CS  fibre  excitatory effect  of  of  see  total  that  that  activity  was  upon  the  the  were  affected suggests  influence  of  by  of  below).  This  climbing  fibre  then  which  evoked  SS  activ-  would  CS  which  be  activity  activity  is  extends  (Armstrong,  Rawson  10  a that  study  1974;  and T i l o k s k u l c h a i , does  cerebellar cortical  because  in  responses.  activity  SS  factor.  activation  ethanol,  above  a l . , 1981;  suppression  the  the  by  responses  i s modulated  the  (although  SS  one  This  there  cells  inhibitory  inactivation  reduced  of  1981).  to  They found  activity  reported  Lo,  only  Purkinje  through  level  and  suggested  rate  of  activity  some o t h e r  other.  example  a  lack of  was  direct  activity  Many w o r k e r s h a v e followed  i n the  probably  to  to  (1981).  firing  the  due  SS  inactivation  rate  i t s overall  i f the  be  rather  interneurones  reduced,  to  the  administration  increased  neighbouring the  laboratory:  Sinclair  appear  Bloedel  of  by  not  an  a l . , 1980; not  and  Specifically,  that  this  intravenous  with  increased  rates  by  CS-associated  correlated. a complex  by  a d m i n i s t r a t i o n , but  explanation  recent  reported  not  appear  neurones  by  stimulation generally  discharges  of  Golgi,  15 basket  and  stellate  Tilokskulchai, to has  recurrent no  1981).  PC  e f f e c t on  Similarly,  1981).  Rather, the  SS  which  Oscarsson,  or  evocation  these  observations  lying  membrane c o n d u c t a n c e s  In  contrast  SS  Bloedel  (1982)  or  flexure. and  rates  reported  spikes  SS  evoked  studies  the e f f e c t of  fibres,  as o c c u r s d u r i n g  asynchronous  could  that  also  be  be  due  PC  to the  calcium  spikes  to  cere-  shunting  responsible  (Ekerot  PC  and  extracellular ions  which  a modification  expected  are  1980). of the  seen Both  under-  f o r the e l e c t r o g e n i c i t y  by  bitory  action  activity, t o be  McDevitt  between  reported  reflects  or  juxtafastigial naturally.  h a v e on  PC  firing  differences  activity.  s t i m u l a t i o n on  i n the  Golgi  as  their a  results  climbing and  modulatory  described  i n response  In a d d i t i o n , the cells  wrist  stimulation, The  CS  difference  a c t i v a t i o n o f many  occurring  CS  and  s t i m u l a t i o n such  above  de-  a f t e r spontaneous  the d i f f e r e n c e  10  found  increased  response  natural  to cause  versus spontaneous  s t u d i e s , which  activity  fibres  evoked  10  CS  synchronous  activity  climbing  of  above  inactivation  They suggested  those of the  effects  soma s i n c e i t  of the  ten Bruggengate,  reflect  evoked  between  the  and  to the  during  f o l l o w i n g the  complex  due  i t s dendrites.  creased  period  and/or  (Stockle could  be  the prolonged d e p o l a r i z a t i o n s of  of potassium  and  may  to  and T i l o k s k u l c h a i ,  to f l u c t u a t i o n s i n the  CS  t h e PC  (Rawson  suppression  after  of  responses  and  appear  at the  were r e c o r d e d a f t e r complex  1980),  concentrations  spike  by  Rawson  i t does not  to actions  stimulation  dendritic activity  dendrites  nor  antidromic  white matter  PC  ( I t o e t a l . , 1981;  collaterals  bellar  of  cells  (Schulman  above to inhiand  16 Bloom, rate  1981)  after  may a  provide  CS  seen  in  an  explanation  t h i s experiment.  Tiloksckulschai  (1981) r e p o r t e d  activated  stimulation.  CS  by  being  10  followed  by  Although significance signal  for  ultimate spikes  can  es  climbing  evoked  1967),  but  that  by  again  and  Purkinje  fibre input,  modified  by  the  PC  sensory  by  electrical cortex  stimulation  resulted  sponses,  caused  between  CS  and  SS  II.A.2.b. Motor The contraversial. functions  evoked  are  in  by  a as  i s not  Albus,  to  be  with  a  Complex  Rubia  is related However, and  shows  (1980) to  these  climbing  (Mariani  a l . , 1982).  enhancement or  have  complex respons-  neurones.  l i m b movement,  the  limbs  f i b r e and  of  the  whole  between  parallel  natural  of  to  1971), i t s  to  stimulation  a disruption  and  control  r e l i a b l e and  and  time  et  a  i s unclear.  a c t i v a t i o n of  the  SS  physiological  stimuli applied  responses  (3/12)  consistent  such  1969;  fibre activity  concurrent  cortical  or  function  v a r i a t i o n over  climbing  to  (Marr,  S i m i l a r l y , Kolb  cell  be  cells  have a s s i g n e d  intense  increased  rate.  movement p a r a m e t e r s .  show g r e a t  the  SS  t h i s response  climbing  position  would  fibre activity,  learning  acclimatization.  reported limb  some w o r k e r s  in cerebellar  be  This  the  However, Rawson  some G o l g i  a decreased  cerebellar  role  (Thatch, rapid  to  for  related were  fibre  input  corresponding The  cortical  reduction  established  the  re-  relationship  activity.  Learning  site  of  motor  learning  Many b e l i e v e performed  by  that  the  plasticity  is still learning changes  unknown and and to  is  retention the  parallel  17 fibre-Purkinje theories  have  cell  dendrite  been p u b l i s h e d  these  c h a n g e s may e f f e c t  1971;  Eccles,  fibre  acts  fibre  "context", o f the  1977).  motor  respond  t o a given  context.  These  by E c c l e s  (1977).  Albus'  crease  the  apses. the  Marr's  unit  similar capacity  theory  inputs. o f the  cerebellum  cerebellum t o damage  theory,  theories lar  imply  cortex  there  climbing  questioned t h a t once  retains  fibre  the  input.  con-  "learn" to  reiterated  more  active  PF-PC  by G i l b e r t  (1974)  arranged  i nunits,  are  muscle  to include  increasethe  a memory t r a c e arrangement  and others  with  and r e c e i v i n g  would  modular  syn-  appears  increase across  of the  t o support  superficially. i s some e x p e r i m e n t a l  t h e o r i e s , some o f w h i c h seriously  active  was e s s e n t i a l l y  conjointly  by " s p r e a d i n g " the  propos-  t h a t a CF i n p u t w o u l d d e -  that this  by Voogd  at least  More  tree i s  are  were  theory  parallel  t o l e a r n movements and a l s o  Obviously,  suggested  i n the  a PC w o u l d  ideas  was m o d i f i e d  He s u g g e s t e d  Although,  been  time,  projecting to a particular  many n e u r o n e s .  these  i t proposed  that Purkinje cells  robustness  this  that  e f f e c t i v e n e s s o f the  concept  each  its  except  Hence, over  Albus,  learned.  synapses which  with  identical  CF.  PF-PC  1969;  o f a PC d e n d r i t i c  jointly  recently  the  those  by w h i c h  that a climbing  results  s e l e c t e d PC's, b e i n g  a CF a c t i v a t i o n  t o strengthen  proposed  which  several  mechanisms  l e a r n i n g (Marr,  (1969)  Marr  and indeed,  proposing  as a l e a r n i n g s i g n a l  specifically, ed  synapse,  h a s been  quoted  support above,  b y some i n v e s t i g a t o r s . l e a r n i n g has taken  learned  responses  However, L l i n a s  eta l .  they  have  Some o f t h e s e  place,  i nthe  for  the  cerebel-  absence o f  (1975)  found  that  18 recovery  from  when t h e  10  cerebellar and  their  vestibular  was  lesioned  nerve not  learning  cerebellocortical their  cerebellar yield to  was  central  two  not  the  changes  may  which  Gilbert  of cerebellar (1974).  conjunctive long-lasting  selected and  Purkinje  cells.  o f motor  i t s h o u l d be  of  one  10  stimulation  vestibular  has  lent  proposed  spike  a t 20 but  extracompatithe  CF  and  Hz  that  1979) .  may  need  not  indicate  throughout  realized  the  that which  learning.  by  and  Marr have  fibre  by  (1969) reported  activity  evoked by  that  caused  o f t h e PF  depressed  evoked  used  learning  activity was  to  support to the  1982)  fibre-parallel  a t 4 Hz,  mecha-  in experimental conditions  function  nerve  by  learning  i m p o r t a n t to motor  Simple  Walton,  functioned  Llinas,  depression of the e f f e c t i v e n e s s  on  and  upon v i e w i n g PC  this  These  p l a c e a t an  experimental results  Also  that  a selection  i n which  are  I t o et a l . (1981,  climbing  took  based  views  A recent experiment theory  solely  (Pellionisz  occur  physiologically  nuclei  cortex.  (Llinas  o c c u r s a t many l o c a t i o n s  system.  Further,  A m a t h e m a t i c a l model  developed  opposing  plasticity  plasticity  were  sites.  movement r e s u l t s  nervous  paper  retention  functions  incompatible since that  or  (3AP).  indicating  the c e r e b e l l a r  as a t e n s o r s y s t e m  "lookahead"  predict  only  are  views  cortex  These be  site  CF's  and  reversed  brainstem, allowed the r e c o v e r y to  in a later  that  was  the c e r e b e l l a r  upon  They proposed  with  spared  dependent  were r e i t e r a t e d  ble  3-acetylpyridine  to take place,  findings  that  in rats  lesioning  was  and  lesions  which  connections to the  recovery  nism,  with  decortication,  vestibular  1979).  nerve  by  a  synapses  stimulation  conjunctive  stimulation  of  the  19 other  nerve  tion,  was  al.,  not effected  1981, 1982).  after slow of  alone, which  t h e 10  This depression recovered  s t i m u l a t i o n was  sensitivity  PF-PC s y n a p s e ,  to glutamate,  were a l s o  applied  glutamate  while  those  to aspartate  had  Furthermore,  a identical  fibre  since  activation Purkinje  cells  were  was  after  unaffected  course  and  changed.  sions  t h e PF-PC  was  I.A.2.C. I o n i c  t h e most  dependent  which  climbing  cells,  fibre  site  as w e l l  responsible  have unusual  mediate  to a  lesser  sensitivity parallel  activity  o f PC's  nor the  inhibition  studies  of  involving  f i b r e s and c l i m b i n g 1982).  of action  were  fibres  The  authors  f o r the  depres-  of Electrogenicity  conductances  electrogenicity,  stimulation,  synapse.  Basis  Purkinje  10  n o t a l l PF s y n a p s e s  Additional  likely  at the  iontophoretic-  or reduced  c o n f i r m a t o r y r e s u l t s ( I t o and Kano, that  by a  transmitter  the subsequent  stimulation of parallel  minutes  depressions  to the depression of the  the spontaneous  cells  ten  Similar  Responses to  depressed  ( I t o et  followed  the depression of glutamate  neither  concluded  ances  were  about  the putative  tested.  stimula-  rabbits  b u t was  an h o u r .  I t i s notable that  of basket  conjunctive found  time  responses.  effected  stopped,  f o r about  ally  extent.  conjunctive  i n PC's o f d e c e r e b r a t e  depression lasting  PC  d i d not receive  the unique  and p a r a l l e l  as t h e c l a s s i c a l f o r somatic  somatic  and  axonal  and d e n d r i t i c  responses  fibre  voltage-  inputs.  of these  conduct-  neurones  L l i n a s and  to  Sugimori  20 (1980a,b) bellar  in a series  tissue  strated  slice  The  spike  sodium  and  The  second  or  was  after of  between  guinea  was  two  main  a classical  by  conductance  have  demon-  f o r the  elec-  (TTX)  to the  sodium  had  been  of cobalt, was  electro-  sodium-depend-  voltage-dependent  This spike  was  blocked  by  b a t h i n g medium.  conductance, blocked with cadmium, or  evident the  per-  manganese  capable of generating prolonged  amplitudes probably determined  voltage-dependent  cere-  types of  fast  inactivating  a non-inactivating  This conductance  a  cells.  soma h a d  salts  pigs,  responsible  conductances.  the c h l o r i d e  with  from  of tetrodotoxin  calcium  D-600 .  plateaus  first  potassium  application  fusion  cell  probably generated  the  only  of Purkinje  The  experiments, using  conductances  Purkinje  responsiveness.  in vitro  preparation  the underlying  troresponsiveness  ent  of  non-inactivating  by  an  sodium  equilibrium and  potassium  conductances . Purkinje conductances  and  those  soma.  of the  spiking  which  blockers. and  were  The  and  Secondly, similar be  caused  and  PC  Firstly, TTX  behaviours d i s t i n c t  t h e y had  insensitive spikes  a set of  a  from  calcium-dependent  b u t was  were  ionic  b l o c k e d by  slow  rising,  calcium  fast  falling,  by a p r o l o n g e d a f t e r - h y p e r p o l a r i z a t i o n . after-hyperpolarization  dendrites sodium  o r may  potassium  displayed dependent  manifestation  spiking  demonstrated  electroresponsive  voltage-dependent  to the  another  dendrites  resulting  followed  inactivation calcium  was  cell  plateau  another  to  conductances.  a calcium-dependent  of the calcium  reflect  w e r e p r o b a b l y due  The  of the  soma.  conductance  distinct  plateau, This which  conductance.  may  21 It  i s possible  ity  may  the  PC, and n o t r e q u i r e  calcium ly,  be d u e s o l e l y  spiking  climbing  long  fibre  term  excitability type  potassium ionic ies  may  be e x p l a i n e d  of spike  be a r e f l e c t i o n  causing modification  i n these  since the Similar-  by c h a n g e s  i n the  i n the dendritic  of the prolonged  tree.  plateau-  o f membrane r e s i s t a n c e  be e x p l a i n e d studies  present i n  o f sodium.  T h e r e f o r e , given such  t o a b o v e may  activ-  g e n e r a t i o n and n e u r o n a l  c o n d u c t a n c e s , many o f t h e u n i q u e  1980a,b) .  spontaneous  o f sodium  conductances  modification  elucidated  cell  conductances  the presence  action  conductance.  alluded  ances  to the calcium  calcium  might  reponses  Purkinje  b e h a v i o u r was i n d e p e n d e n t  voltage-dependent The  that  a rich  interactions i n terms  (Llinas  and  set of and  theor-  o f the conduct-  and S u g i m o r i ,  22  I I . A . 3 . The  Inferior  The of  the  can  inferior  shape  (DAO);  pal  olive  the  10  .  medial  (PO).  The  nucleus  such  as  aqueductal  grey  cerebellar  cortex  the to  accessory  than  has  also  (Llinas  been  reverse  was  et  and  reported  named  have  differ  from  the  learning not  recuperation  The and  only  and  that  i t can  be  in  Kawamura, range  inferior  of  the  i t projects  motor  peri-  to  olive  retention.  from  as  nuclei,  prevent  princi-  another  a wide  and  the  indicated  one  raphe  cortex,  accessory  thought  from  because  Internally i t  dorsal  previously  nuclei.  to  so  (MAO); and  studies  inputs  the  deep  i n motor  a l . , 1975)  the  olive  s p i n a l cord,  and  the  was  afferentation (Brodal  (PAG)  implicated  10  subnuclei:  receives  the  (10)  v e n t r a l brainstem.  However, r e c e n t  s t r u c t u r e and  sources,  be  the  into three  the  nucleus  i n t o s u b d i v i s i o n s which  terms of  to  to  i s more complex  divided  1980)  olive  i t gives  been d i v i d e d  olive  Olive  the  appears  Lesioning learning  but  labyrinthine lesions  .  I I .A .3 .a . A n a t o m y Experiments tracing  techniques,  used  document  to  receive  times  synaptic  at  terminate MAO 1974;  and  mainly the  Martin  autoradiography,  the  neurones  involving retrograde  sources  these  inputs  clusters. on  on  input the  a l . , 1980).  to  The  the  from  i n the  (King,1980;  orthograde  degeneration  distal  Afferents  dendritic shafts  d o r s o l a t e r a l DAO et  of  and  and  10.  have  been  Olivary  dendrites,  some-  the  cord  spinal  caudal  Nicholson  part and  deep c e r e b e l l a r n u c l e i  of  the  Gwyn, project  23 to  the  whole  1976, 1978; al  o f the Angaut  a f f e r e n t s are  1975;  10 e x c e p t  parts  and C i c i r a t a ,  limited  Souso-Pintal inputs  nucleus,  a n d v e n t r a l PAG, a n d f r o m  nucleus  al.,  1978;  the  1969),  midbrain,  and M a r t i n ,  et a l . ,  1982).  MAO ( M a r t i n  whereas  the  Cortic-  et a l . ,  w h o l e 10  i n c l u d i n g the  tegmentum,  the  specifically  s u b p a r a f a s c i c u l a r i s (Brown Linauts  MAO ( K i n g  Haroian,  o f the  receives  the  from  1982;  to parts  and B r o d a l ,  o f the  1978;  thalamus,  e t a l . , 1977;  Saint-Cyr  red  King e t  and C o u r v i l l e ,  1978) . A reported Wiklund caudal  catecholaminergic  (Fuxe,  1965;  (Garver  lesions  (King  present  thoughout  neuropil  which  10 b u t  mainly  receives  DAO i n t h e  rat  substance-P  genously  thoughout  enkephalin spontaneous  i n the  PO.  (Ljungdahl have  a f t e r PAG  An i n t e n s e i n the  etal.,  n o t been  1978),  1978)  i s suggestive Schulman  (1981)  leu-enkephalin-like immunoreactivity the  10.  by i o n t o p h o r e s i s and f i r i n g  but  i d e n t i f i e d as  and a l p h a - b u n g a r o t o x i n  a cholinergic input.  reported  degenerate  tract  of acetylcholinesterase i n the  e t a l . , 1977)  recently  optic  h a s been r e p o r t e d  i n t h e 10 ( H u n t a n d S c h m i d t ,  nucleus  o f the  grey  a n d w h i c h may be m o n o a m i n e r g i c a r e  The p r e s e n c e  (Marani  1977;  attributed to the  periaqueductal  nucleus  Terminals  immunoreactivity  containing  i n t h e 10.  sites  the  t i p o f the  terminals  and the  the  10 h a s b e e n  Chan-Palay,  h a s been  1977),  e t a l . , 1978)  substance-P-like lateral  1975),  1973).  et al.,  e t a l . , 1973;  whose o r i g i n  (Chan-Palay,  and Sladek,  (Hoffman  yet  Hoffman  e t a l . , 1977) medulla  i n n e r v a t i o n o f the  Additionally, local or micropressure  evoked  binding that the has hetero-  applicationof  depressed  both  by i o n t o p h o r e t i c a l l y a p p l i e d  24 DL-homocysteic The aminergic  acid  10 a l s o  input  h a s been r e p o r t e d  i nthe cat,  Palay,  1977;  fibres  may be t h e  1981).  (Schulman,  raphe  r a t and monkey  et a l . ,  and Wiklund  nuclei  the  Electrophysiological  evidence  activity  Harmaline  firing 1973;  e t a l . , 1976)  tonergic  i n n e r v a t i o n o f the  suggested  (Sjolund  that  to o l i v a r y  harmaline  cells  antagonized  iontophoretically of  olivary  cells  oscillatory (Llinas idea, late  (Llinas  firing  by u n m a s k i n g  phase o f o l i v a r y modifies  climbing  (Desclin, projection  firing  inferior fibres  1974;  cell  Batini  or local  Destruction  o f sero-  neurotoxic reduced  only  drugs  the effects  e t a l . ( 1976)  Headley  a t o n i c 5-HT  substance  tried  I t i s known  1980)  which  t h esomatic  calcium  Consistent  t o cause  a marked  (Headley i s the  that  conductance  with  main,  1976;  i f not  i n the  i t only  1976). sole,source  and deep n u c l e i  Chan-Palay,  i s topographically arranged, with  this  reduction  and Lodge,  cerebellar cortex  et a l . ,  that  may c a u s e t h e  action p o t e n t i a l s , although  olive  input  causes a h y p e r p o l a r i z a t i o n  see below).  rate  t o the  (5-HT)  synchronous  e t a l . , 1973)  by h a r m a l i n e .  and Yarom,  1981a,  serotonin  by s u p p r e s s i n g  harmaline  5-HT h a s b e e n r e p o r t e d  The  1977).  induced  applied  and Yarom,  slightly  for  Biscoe  b e c a u s e 5-HT w a s t h e  thef i r i n g  or  (de Montigny and Lamarre,  10 b y s p e c i f i c  acts  Chan-  e t a l . , 1976)  rhythmic,  administration.  et a l . ,  1965;  Sources o f these  o r 5,7-dihydroxytryptamine) markedly  harmaline  (Fuxe,  suggests  causes  1973;  (Headley  of  also  an i n d o l -  10 ( C h a n - P a l a y , 1977).  i n t h e 10 a f t e r i n t r a v e n o u s L l i n a s and V o l k i n d ,  (5,6-  1977)'.  (Bobillier  neurones w i t h i n o r surrounding  i n t h e 10.  to receive  the  1977).  The  caudal  third  25 of  the  nucleus  thirds  projecting  projecting  hemispheres,  et  from  the  and  only  Puro  and  one  fibre  may  innervate  ragan  and  Delhaye-Bouchaud,  and  essential 1972;  immature  their to  continued  the  Kawaguchi  et  dendritic  tree,  and  However, c o n t r a r y  to  reported  that  Purkinje  after  destruction  However,  another  Purkinje  cell  that  inhibitory  with  of  transmission  at  the  to  i n t e r u p t i o n of  the  attempt arolo  et  whether its  designed  synapse.  to  not  function.  the  of of  as  et  the  flow.  this  caused  Purkinje  cell  requires  to  and  Scott,  and  the  cell.  a l . ( 1975)  were not  reduced in  climbing  number.  fibre  1979)  reported  a rapid  failure  that  this a"  the  on  may  be  to  due  recent (Mont-  therefore, 10  of  vestibulo-  unsuccessful ,  be  cell  cell-lateral  seen  Bar-  suggested  Unfortunately,  be  the  climbing  increased  f i n d i n g was to  of  Purkinje  for  (Eccles  climbing  a l . , 1977)  rather  Purkinje  to  (Kornguth  the  the  a l . , 1975;  been  a l . ( 1978,  3-AP  adult  one  presence has  of  receive  opposed  et  two-  1980).  to  i n the  S o t e l l o et  a role  et  I t remains  Purkinje  appears  They suggested  axonal  repeat  a l . , 1981). or  Ito with  cell  but  indicated  10  tract  Kawamura,  d e n d r i t i c spines  the  spinal  1973)  3-AP,  functioning:  destruction  Woodward  reports,  cell  study  The  functioning  these  regions  development  (Hamori,  the  lateral  (Kawaguchi  functioning  a l . , 1975;  maintenance  rostral  where more t h a n  1980).  embryological  continued  10  s i n g l e PC  the  fibre  1977),  animal  and  and  cell  climbing  Woodward,  i n the  and  Brodal  Purkinje  situation  a  vermis  paravermal  cerebellar  one  a l . , 1966;  fibres  the  r e s p e c t i v e l y (see  • Each input  to  to  maintain  26 In ing  addition  to innervation  f i b r e s are reported  nuclei cells  (Chan-Palay, (Eccles  to have  1977;  reported  not to project  (Desclin  and  Colin,  studies  have  inhibit  molecular  and  Desclin  climb-  and  Golgi  1980).  They  are  interneurones  However, e l e c t r o p h y s i o l o g i c a l  electrical  layer  1980)  Colin,  layer  cells,  to the c e r e b e l l a r  Colin,  and  to molecular  1980).  reported  collaterals  Desclin  e t a l . , 1967;  of Purkinje  stimulation  interneurones  o f t h e 10  (Bloedel  and  to  Roberts,  1971) . The to  have a f i r i n g  Harvey, in  constituent  1966;  chronous  firing  between  the  e l e c t r o t o n i c spead  neighbouring  an  and  microscopic  experiments  i n h i b i t o r y input  cells. terminal tion  also  preferentially  due  1980)  recurrent  that  to tend caused  and  Colin  i n t h e 10  10  been  1981a)  by t h e of  elec-  The  syn-  would  of  allow  between  published  studies.  o l i v a r y neurones  firing  (3-AP), They  which  rates  or i t s periphery  neurones.  fire  from  and e l e c t r o p h y s i o l o g i c a l  (1980) found  3-acteylpyridine  destroys  to  to the presence  collaterals,  of the slow  reported  and  1981a,b).  f o r these has  indicated  from  Desclin  with  and  synapses which  L l i n a s and Yarom,  degeneration  o f t h e 10  (Armstrong  i o n i c mechanisms  i s likely  (King,  t o be t h e c a u s e  However,  been  o f membrane d e p o l a r i z a t i o n s  Evidence  e t a l . , 1974;  suggested  cells  have  i s probably  dendrodendritic  cells.  electron  latter  1979)  ( s e e below, L l i n a s and Yarom,  junctions  (Llinas  Rawson,  of the underlying  gap  both  and  0.3-1.5 Hz  Spontaneous f i r i n g  activity  trogenicity  o f about  Armstrong  synchrony.  pacemaker  rate  n e u r o n e s o f t h e 10  no  of  receive  was these  axonal  after  a drug  The  destruc-  which  concluded  that  this  27 ruled  out the existence  of recurrent  o l i v a r y axons a t these  locations . II.A.3.D. I o n i c  Basis  of  Extracellular strate  the a t y p i c a l  ones.  Initially,  the  potentials  prolonged 1976)  .  converts  action  an a p p e a r a n c e v e r y  recordings 1974)  .  In addition  arization which  described  firing  As s h a l l  that  conductance,  tetrodotoxin  (TTX) .  since  be  and t h e seen  i n the  electrode  intracellularly extracellular et a l . ,  f a s t - r i s e and t h e l a t e a late slice  experiments  have  conductances potentials character  1980, 1981a,b).  the i n i t i a l voltage  depol-  hyperpolarization  o f the rhythmic  fast  was  underlyand have of  These  portion  dependent  t h i s conductance  In contrast  initial  position.  of the ionic  i s due t o t h e f a m i l i a r  by a  and L o d g e ,  potential  recorded  Tissue  and Yarom,  have demonstrated  potential sodium  (Llinas  cell,  the  1970 and L l i n a s  i s also  the elucidation  the  followed  to the c e l l ,  components o f t h e o l i v a r y a c t i o n  allowed  iments  to the early  f o r up t o 2 5 0 ms.  neur-  to the dendritic  (Crill,  the characterization  these  olivary  above  components, there  lasts  allowed  similar  by t h e s e  (Headley  r e f l e c t a change  potentials  demon-  deflection  to a diphasic  to a somatic  neurones  approaches  i n amplitude.  probably  a dendritic  Olivary  generated  t o a b o u t 5 ms  moves c l o s e r  reduced  changes  from  potentials  extending  i s usually  position  from o l i v a r y  as t h e m i c r o e l e c t r o d e  deflection  below, these  also  action  As t h e e l e c t r o d e  plateau  ing  recordings  have a sharp monophasic  plateau  monophasic  have  Electrogenicity  exper-  of the  increase i n  blocked  the late-depolarization  by and  28 late  hyperpolarizations  intact  following  components c o u l d tions to  are  these  late  which  triggers  i n turn  be  from  dendrites  of olivary  olivary neuronal  Llinas  w e r e due  somata,  another  which  i s only  hyperpolarizing  ionic and  somatic calcium;  latory nally  produced and  the  subsequent latory  do  loop  i s clear  synaptic  by  inputs  the  cells  the  neurone's  to originate  known that  current  i n the  conductances,  conductance  o b s e r v a b l e when t h e c e l l  is  1980,  current  1981a). will  A small  trigger  p r o v i d e an  ionic  cells.  late  This calcium  modifications,  membrane p o t e n t i a l  would  and  For  in  turn, and  the  the  oscil-  potential.  f o r example  through  i n a modulation example,  by  hyper-  neuronal environment,  result  of o s c i l l a t i o n .  followed  closes  action  oscil-  exter-  conductance  spike  dendritic  to the  a  depolarization,  somatic calcium  the changes  These  slow  spike  depolarization  late  another  f o r the  a sodium  inter-  calcium  In p r o g r e s s i o n ,  causes  The  basis  the  calcium  p o t a s s i u m , and  spike.  the to  sodium,  of the  period  are  potentials  dendritic  external or  action  refractoriness.  triggering  that  solu-  concluded  display  respectively.  calcium  which  not  depolarization  unmasking  of  spike  limited  Yarom,  potassium mediated  polarization, causes  and  behaviour of o l i v a r y  calcium  It  which  conductances:  The  appear  calcium  nally  spikes  Yarom  remain  late  inward calcium  to these d e n d r i t i c  (Llinas  dependent  and  conductance.  hyperpolarized injected  they  neurones.  addition has  as  these  chloride  t o an  these conductances  neurone  However,  or magnesium  a potassium  resulting  TTX.  dependent  b l o c k e d by a p p l i c a t i o n s  conductance.  polarizations  In  sodium  treatment with  o f cadmium, c o b a l t ,  block calcium  not  the  to  of  mecha-  29 nism of  of harmaline's  the  tory  excitatory  action  may  somatic  calcium  conductance  and  behaviour  (Llinas  and  1981b).  Yarom,  the  be  due  the  subsequent  unmasking oscilla-  30 II.A.4.  The  Golgi  Golgi the of  granular 4-31  ive  Hz  and  trees  that  and  Stimulation fibre  However,  they  of  found  them  cerebellar  cortex  having  and  Bloom,  of  be  In  also  Palay  and  to  cells  Bloom  (Rawson  (1980)  electrical  as  on  and  cells  neurotransmitter et  at  GABA  (Bisti  this  transmitter  includes  evoked  activation  of  PC's  but  not  climbing  significant  increase  Tilokskulchai, find  stimulation  of  the  studies  1981).  excitation 10,  but  strychnine  on  et  mossy  fibre  a l . , 1967)  s y n a p s e s has  Experimental the  the  antagonism  large  (Bisti  orthodromic doses of et  .  been  p o t e n t i a l s , produced  and  relatively  indicate Golgi  post-synaptically  (Eccles  a l . , 1971).  of  by  both  these  depression  cells,  1974).  activates  to  pre-synaptically  Purkinje  and  axons  of  rather  inhibited.  i n h i b i t o r y actions  dendrites  a  (Hamori  cell  failed  Electrophysiological have  produce  a  synapses  Chan-Palay,  which  extens-  studies  axosomatic Purkinje  and  cortex,  fibres  in  rates  from  anatomical  f i b r e s and  1954;  have  input  from mossy  receive  situated firing  cells  excitatory  addition,  found  Golgi  an  f i b r e s and  climbing  was  1981). Golgi  receive  cerebellar  during to  the  probably  the  Schulrnan  cells  neurones  Scheibel,  rate  Golgi  large  1966).  collaterals,  firing  relatively  and  c o l l a t e r a l s of  (Scheibel  are  parallel  Szentagothai,  from  of  (Schulrnan  number o f  indicate  in  cells  layer  dendritic  large  Cell  on  by  granule  terminals The  suggested  Golgi the  well  to  be  cell-induced antidromic  p i c r o t o x i n and Golgi  as  supporting  a c t i v a t i o n of  a l . , 1971).  cell  putative  evidence of  cells  granule  bicuculline,  cells  are  also  31 reported  to take In  cell-Golgi cell level  ( H o k f e l t and  inhibitory  at a constant  i s t h e one  efficiently.  GABA  terms of c l a s s i c a l  cell  activity  up  loop  Ljungdahl,  control would  level.  theory  tend  One  at which the c e r e b e l l a r  can  1972).  the  t o keep  granule the  speculate  circuitry  granule that  works  this  most  32 II.B.  Garama-aminobutyric  acid  Gamma-aminobutyric a  neurotransmitter  Exogenously causes  (Krnjevic studies al.,  cycle.  reaction  (GAD, R o b e r t s thesis  may  Although  synaptosomes  terminals,  reuptake  acid  a n d GABA may that  from  to that  space  acid  route  in  o f GABA  the tricarb-  limiting  h a s been  non-vesicle  the synaptic  from  step  of  decarboxylase o f GABA  and R o b e r t s ,  be s t o r e d  i s calcium-dependant.  as t h e  1980).  and r a t e  binding  similarly  relaxant  substances  derived  A secondary  d e p e n d e n t GABA  well  sedative-hynotic  as w e l l  by L - g l u t a m i c  (Yoneda  been  f o r the manufacture  i s the f i n a l  ornithine  H o w e v e r , GABA r e l e a s e ,  via  route  of L-glutamic  i ti s likely  transmitters,  the  1981; Simmonds,  synthetic  This  have  (Curtis et  t o m e d i a t e many o f  o f p i c r o t o x i n and r e l a t e d  e t a l . , 1979) .  sodium  and a l s o  by t h e  pharmacological  and muscle  of barbituates,  and i s c a t a l y z e d  be f r o m  suggested  which  cortex  t o be s p e c i f i c  and d e a c t i v a t i o n  e t a l . , 1978; O l s e n ,  decarboxylation  produced  and  as  1982).  change  i n the cerebral  anticonvulsive,  actions  actions  acid  to that  Biochemical  of the benzodiazepines,  anticonvulsant  oxylic  in  1967).  anxiolytic,  The m a j o r  the  transmitter  I t i s i n c r e a s i n g l y being  convulsant  is  a conductance  s h o w n t h e GABA r e c e p t o r  sedative,  established  e t a l . , 1976; O l s e n ,  identical  1971) and i t s s y n t h e s i s  (Haefely  (GABA) i s w e l l  GABA p r o d u c e s  inhibitory  have  actions and  applied  and S c h w a r t z ,  studied. the  (see Roberts  a hyperpolarization  endogenous  acid  syn-  1981).  show t o o c c u r  v e s i c l e s i n some release  o f other  Deactivation by a h i g h l y  also  occurs.  putative o f GABA i s specific  33 transport  system  into  (Snyder  e t a l . , 1973;  systems  appear  entially  1981). is  both  Balcar  and non-neuronal  and Johnston,  t o be d i f f e r e n t i a b l e  inhibited  by d i f f e r e n t  Subsequently,  i n theinner  1973)  since  blockers  the major  v i aGABA-transaminase  located  neuronal  they  These two  c a n be p r e f e r -  (Schousboe  enzymatic  et a l . ,  d e a c t i v a t i o n o f GABA  1979),  (GABA-T, M e t c a l f ,  mitochondrial  •  cells  which i s  membrane ( S c h o u s b o e  et a l . ,  1977) . Biochemical to  be a c o m p l e x  The  agonists  well  studies  have  of interrelated,  GABA a n d m u s c i m o l  as the antagonist  revealed  but independent,  both  one  binds  action  h a s been  exists  evidence  between  studies  et al., have  which  binds  antagonists  well established that  the benzodiazepines  1978;  had suggested  Olsen, this  1981;  interaction  t o be a m o d u l a t o r  reduces  reported  (Costa, increase  (Enna  t o be d i s p l a c e d  1979).  Conversely,  thea f f i n i t y  which  and Snyder,  GABA  o f these  binding  of  above,  there  This  modulator  benzodiazepines  h a s been  benzodiazepine  1980).  thea f f i n i t y o f  1977).  by t h e b i n d i n g  f o r many  a t the receptor  appears  subunit  this  Simmonds,  mentioned  is  Indirect  c o r r e l a t i o n s b e t w e e n GABA a g o n i s t s a n d  supported  site  an i n t e r -  a n d GABA.  I n a d d i t i o n t o t h e two s u b u n i t s  GABA r e c e p t o r  charact-  states o f the receptor:  level.  the  1977).  and Snyder,  and p h a r m a c o l o g i c a l  and t h e benzodiazepines  (Haefely  Recent  quite  o f behavioural  antagonists  another  subunits.  1978).  and Okada, It  years  agonists,  receptor  a t t h e same s i t e , a s  (Enna  i n d i c a t e two c o n f o r m a t i o n a l  which  (Mohler  bind  bicuculline  However, d i f f e r e n c e s i n b i o l o g i c a l eristics  t h e GABA  shown t o  receptor  sites  34 (Tallman appears  e t a l . , 1978). t o be l i m i t e d  receptors,  However,  resulting  i n at least  affinities  two,  the low a f f i n i t y  epines  (Braestrup Another  act  with  portion  the  since  sites  group  show b i n d i n g  complex  by b i n d i n g (Olsen,  by a l s o  binding  major  site  cord,  event  suggested nerve to  e t a l . , 1980).  to label  the chloride  of the interaction i s the rapid  This  of chloride ions.  of spinal  to reduce  terminal  e t a l . , 1978)  may r e s u l t  cord  upon  In the case reported  because  This  of the spinal  t o cause  membrane  t h e amount o f t r a n s m i t t e r r e l e a s e d  i s thought  This  h a s been  t o be g r e a t e r  than  f a c i n g c h l o r i d e pump  h a s been by t h e  referred inhibi-  t o be d u e t o c h l o r i d e i o n e f f l u x ,  the chloride concentration  suggested inward  effect  i n either  the trans-  as p r i m a r y a f f e r e n t d e p o l a r i z a t i o n o r p r e s y n a p t i c  tion.  and  primary a f f e r e n t s , which  (Eccles e t a l . , 1963).  of  increase  t o c h l o r i d e i o n (McBurney  GABA a d m i n i s t r a t i o n h a s b e e n  depolarization  the opening o f  (Ticku  or h y p e r p o l a r i z a t i o n depending  membrane g r a d i e n t  inter-  Similarly, the  to block  to this  postsynaptic  1978; N i s t r i  depolarization  to the benzodiaz-  1981).  t h e membrane c o n d u c t a n c e  Barker,  Of t h e  to the ionophore  1981).  GABA a n d t h e r e c e p t o r - i o n o p h o r e c o m p l e x in  1979).  o f a g e n t s , t h e b a r b i t u a t e s , may  p i c r o t o x i n i s thought  (Olsen, The  subtypes o f  (Costa,  d i h y d r o p i c r o t o x i n h a s been r e p o r t e d  ionophore  n u m b e r o f GABA  e t a l . , 1980).  o f t h e GABA r e c e p t o r  ionophore  two r e c e p t o r  and d i s t r i b u t i o n s  the receptor  GABA a n t a g o n i s t  of the subunit  to a portion of the t o t a l  different only  the presence  that (Nishi  intracellularly extracellularly e t a l . , 1974) .  h a s been due t o a I t may be  35 also  due i n p a r t  cellular (Curtis  space  t o a b u i l d up o f p o t a s s i u m  due t o t h e d i s c h a r g e  e t a l . , 1971).  pre-synaptic Fischbach calcium  Recently,  inhibition  (1978). mediated  of neighbouring  found  proposed  GABA w a s a b l e  component o f d o r s a l - r o o t  t o block  ganglion  antagonism  was i n s e n s i t i v e t o b i c u c u l l i n e a n d o t h e r  the antagonism GABA r e c e p t o r .  interfered  directly  inhibition  b y GABA  with  inward  involves  calcium  cellular  chloride  (Krnjevic,  Gamma-aminobutyric erized be  a s an i n h i b i t o r y  the inhibitory  acid  transmitter  basket,  and G o l g i  synapse  h a s been most e x t e n s i v e l y  been  shown  mitter al.,  t o mimic  evoked  o f the postthe extra-  neurones  GABA h a s b e e n  shown  i n the cerebellum.  I t may  by P u r k i n j e ,  stellate,  c e l l - D e i t e r s ' neurone  studied.  E x o g e n o u s GABA h a s  of synaptically released  Bruggencate  found  GABA w a s r e l e a s e d  (Obata e t inhi-  by e x o g e n o u s a n d s y n a p t i c a l l y t o be b l o c k e d  and E n g b e r g , into  trans-  For example,  b y t h e GABA  p i c r o t o x i n and b i c u c u l l i n e ( C u r t i s , Duggan, and  1970;  t o be  charact-  by s t i m u l a t i o n o f t h e c e r e b e l l a r c o r t e x  of Deiters'  released  t h e GABA  well  The P u r k i n j e  the action  postsyn-  i s believed  quite  1 9 6 7 ; ten Bruggencate and E n g b e r g , 1 9 7 1 ) .  bition  ists  cells.  used  antag-  1982).  h a s been  transmitter  GABA  Postsynaptic  since  generally  action  that  current.  ion influx  ion concentration  intracellularly  therefore,  slow-  Because t h e  the  the hyperpolarization  membrane due t o c h l o r i d e  than  to involve  I t was p r o p o s e d ,  synaptic  higher  depolarization.  does n o t appear  a  cell  without  aptic  any s i g n i f i c a n t  by D u n l a p a n d  potentials  onists  afferents  a more d i r e c t mechanism f o r  b y GABA h a s b e e n  They  i o n i n the extra-  1971).  the fourth  Obata  antagon-  Felix,  and Takeda  (1969)  ventricle after  stimu-  36 lation  of the cerebellar cortex.  individual the  Deiters'  c e r e b e l l a r vermis  shown  to associated  membranes is  nucleus  the transmitter Although  Deiters'  nucleus,  cerebellar mediate and  cell  been  neurones.  and b a s k e t  to block  may  cell  inhibition  of granule  blocked al.,  1971; C u r t i s  addition, of  endings  Ljungdahl,  o f other  by M o i s e s  Purkinje  GABA  cells  antagonists cells  by s t i m u l a t i o n o f  i s due t o t h e a c t i v a -  and t h e i r  subsequent have  also  produced  by i o n t o p h o r e s e d  GABA  (Bisti  1 9 7 1 ; Woodward  studies basket,  have  et a l . , 1971).  demonstrated  and P u r k i n j e  on P u r k i n j e  In  accumulation  cells  cells  et  and a l s o a t  ( H o k f e l t and  1972) .  modification  study  of the  of Purkinje  GABA e v o k e d  cells  from  GABA a n t a g o n i s t s  terminating  There action  GABA  cells.  and F e l i x ,  H-GABA a t s t e l l a t e ,  nerve  by  and b a s k e t  histological  as t h a t  of Purkinje  (LOC s t i m u l a t i o n ) , w h i c h  the inhibition  suggest  I t appears t o  cells.  the inhibition  fibres  of Purkinje  again  interneurones.  parallel  of the s t e l l a t e  the neuronal  be t h e t r a n s m i t t e r  by s y n a p t i c a l l y r e l e a s e d  inhibition  data  i s n o t as good  produced  tion  with  synapse.  inhibitory  inhibition  shown  These  the evidence  cortical  by r e m o v a l o f  e t a l . , 1 9 7 1 ) a n d GABA h a s b e e n  concentrations  GABA a l s o  stellate  Golgi  have  i n high  at this  t h e GABA c o n t e n t o f  n e u r o n e s was r e d u c e d  (Otsuka  of Deiters'  Also,  cell  electrical  i s also  some e v i d e n c e  transmitters  to suggest  i n the cerebellum  o f GABA t r a n s m i s s i o n .  stimulation  of the locus  may  be m e d i a t e d  For example,  e t a l . (1979) demonstrated  by s y n a p t i c a l l y r e l e a s e d  that the  that  GABA  coeruleus  a  recent  inhibition  i s enhanced and  by  of both  iontophoretic  37 noradrenaline. modulate of was  blocked  from  guinea  by b i c u c u l l i n e .  or, tentatively,  a n d h e n c e GABA  (1983)  calcium  pig cerebellar slices. They  u p o n GABA a u t o r e c e p t o r s  receptors, calcium  Namima e t a l .  the d e p o l a r i z a t i o n produced,  3H-GABA  acting  Further,  may  release.  suggested  or other  found  dependant This  that  release  modulation  t a u r i n e may be  bicuculline  be b l o c k i n g  taurine to  sensitive  the influx  of  38 II.C.  Ethanol  It of  ethanol  mediated no  i s u n l i k e l y that  on n e u r o n a l  firing  and s y n a p t i c  by a r e c e p t o r  since,  other  macromolecule  degree  i s known w h i c h  of specificity.  explain  ethanol's  more t h a n mutually  exclusive,  even  mechanism  theories  alcohol  have  of action.  some  basic  dehydrogenase,  ethanol been  t o any  postulated to  I ti s conceivable as they  that  that  are not  d i f f e r e n t mecha-  i nd i f f e r e n t neuronal  o f ethanol's  of action  transmission i s  with  and i t i s probable  beginning  directly  o f the f i r s t  f o r ethanol  anaesthetic  of this  systems.  physical  Unfor-  e f f e c t sa r e  They  found  holds  to i t s lipid  anaesthetic  action  o f a c r i t i c a l concentration concept  was e x t e n d e d  molecular  volume:  bulkier molecules  molecules.  Seeman  lowers  the density  crease  i nbiological  membranes  membranes  changes  (Meyer,  o f anaesthetic  1937).  a r e more  i n t h e membrane  than  ethanol  that that  suggesting  proteins  to include  e f f e c t i v e than  that  and f u r t h e r  strongly  i n cell  (1954)  by M u l l i n s  was g r e a t e r  no p r o t e i n ,  t o be  i s due t o t h e  demonstrated  o f synaptosomes  containing  conformational  (1974)  o f an  o f the Overton-Meyer  This  small  a n d Meyer a t  ethanol,  solubitility  t o the formation  that  suggested a  the potency  o r s i m i l a r compound, i n c l u d i n g  which  lipids.  which  w a s made b y O v e r t o n  century.  proportional  attainment  observations  action  c o r r e l a t i o n lead  concept  the  reacts  mechanism  contraversial. One  This  than  o n e m e c h a n i s m may be i m p o r t a n t  tunately,  the  Many  mechanism  n i s m s may be i m p o r t a n t  still  the molecular  the def o r model that  contributed to  39 the  membrane e x p a n s i o n .  tics  c a n be r e v e r s e d  (Trudell suggest as  t h ec e l l  disrupting  ethanol  Kendig acts  their  ethanol  t o produce  However,  i t i sprobable  resonance groups  ethanol,  produce  of thelipids  only mild  t o produce  reported  were  important  sites  within the  was shown  probably  para-magnetic  (1977)  marker  have  a s l o w a s 10 mM, This  recaused  concentration o f  t o moderate  intoxica-  to spatial  membrane  bound  enzymes  f u n c t i o n i n g (Barondes e t a l . ,  includes  complexes.  ionophores, F o r example,  a concentration-dependent  sodium-potassium-ATPase inhibition  o f those  as i n e b r i a t i o n .  o f membrane  and changes  surrounding  class of proteins  been  which  non-specific  i s an  and G o l d s t e i n  to their  and r e c e p t o r  This  spectroscopy  o f s y n a p t o s o m a l membranes.  k n o w n t o be c r i t i c a l This  such  biomembranes and  such  and s p e c i a l i z e d  Chin  pumps, g a t e s ,  of  such  fluidization  In addition, fluidization  1979).  site,  t o be f a r i n e x c e s s  at concentrations  i n v i v o would  arrangements  findings  a q u a n t i t a t i v e m e a s u r e m e n t o f membrane  F o r example,  fluidization  is  t o produce  appear  that  and f l u o r e s c e n c e  that  tion.  by e x p a n d i n g  More r e c e n t l y , t h e m e t h o d s o f e l e c t r o n  disruption.  ethanol  These  a t a hydrophobic  physiological effects,  a t more s e n s i t i v e  has allowed  ported  .  pressures  c a u s e s membrane f l u i d i z a t i o n , t h e  required  required  membrane.  e t a l . , 1975)  primarily  a s membrane l e a k a g e  mechanism  o f high  o f anaesthe-  structure.  concentrations  effects  application  membrane, a n d may a c t  Although local  by the  e t a l . , 1973; that  In addition, theeffects  activity  (Schwartz  t o be c a u s e d  due t o a l t e r a t i o n s  ionic ethanol has inhibition  et al.,  by a l l o s t e r i c  1975). effects  o f t h e enzyme-phospho-  40 lipid  interaction. As  tions  would  be p r e d i c t e d  o f e t h a n o l have  electrical potential squid  stimuli i n an  giant  1964).  isolated  axon  Higher  o f t h e membrane  concentrations sodium  channels,  resulting  action  linated (Quevedo  are  et a l . ,  and  displacement vitro  1971;  reported and  (1981),  a reflection tion  binding,  the  the  1964;  isolated  Moore e t a l . ,  a further  depolarization,  1972).  larger  depol-  conductance.  inactivation  (Seeman,  more t h a n  and  been r e p o r t e d  from  Myers,  and  found  1979).  calcium  1979).  no  tissues,  synaptosomes  in vitro  Ferko  of  coworkers  Ross e t a l . ,  of  sodium and  a  Small  unmye-  myelinated  fibres  effect  Bobjock,  of differences uptake.  systems,  such  the data  are  e t h a n o l to cause both  i n vivo  e t h a n o l may as  the  and  in  have  binding  (Seeman  et a l . ,  other groups  in vivo 1980) . that  to  K a l a n t and  potassium, to  (Hood Woo  these r e s u l t s  affecting  cause  found  have  membranes  i n membrane p r e p a r a t i o n  In a d d i t i o n  and  calcium  workers  Still on  to a l t e r  Other  recent review, suggest  anaesthetics  permeability  and  in a variety  Ross and  1979;  of calcium  cause  amplitude  e t h a n o l t o have  in their  Binstock,  mM)  e t h a n o l has  to increase  Harris,  to a c t i v a t e  action  i n a slower propagation v e l o c i t y  of calcium  Michaelis  a compound  the  1978) .  (Ross,1977;  ethanol  amplitude of  by d e c r e a s i n g p o t a s s i u m  affected  binding  contradictory.  the  low c o n c e n t r a -  to ethanol producing a s l i g h t  (>100  potential  fibres  above,  to reduce  or  and  conductance,  Although content  nerve  i s due  the  to a c t i v a t e  (Armstrong  decreased  lower  found  required  This result  arization  been  from  and  are  defini-  calcium  calcium-dependent be m o r e  sensitive  41 to  intracellular  the  ionized calcium,  concentration  of calcium  Modification predicted reported tials  to modify to increase  cortex  al.,  1980; Sunahara  reduced.  from  These  noradrenaline, effected Lee  also  ed  creased  calcium  Similarly, reported  ion concentration  to increase  calcium-dependent potential mepps of  (Carlen  of  and C o r r i g a n ,  to this  dopamine  latter  result,  and g l u t a m a t e ,  least  Seeman a n d by  ethanol. ethanol  ileum  induc-  e t a l . , 1962, 1967; by i n -  e t a l . , 1980b). h a s been  spontaneous and miniature  e t a l . , 1971),  to  and t o i n c r e a s e  (Bradley  be  I t h a s been r e -  junction ethanol  1980),  the acetylcholine receptor  contrary  (Mayer  depolarization-evoked (Quastel  to also  be r e v e r s e d  calcium-independent  (mepp) number  o f other  being  of guinea-pig  could  et  dopamine,  However,  (Hurwitz  effect  i n the neuromuscular  GABA  events.  the contracture  This  the cere-  transmitter release,  on p o s t - s y n a p t i c  e t a l . , 1980a) .  serotonin,  t o be i n c r e a s e d  addition to affecting  poten-  1965; Okada,  was r e p o r t e d  1975).  by a c e t y l c h o l i n e o r p o t a s s i u m  Mayer  (Gage,  be  h a s been  endplate  The r e l e a s e  a n d GABA, w i t h  dopamine r e l e a s e  to antagonize  would  and L o , 1978; P h i l l i s  the cerebral cortex  has an e f f e c t  ported  junction  1980).  and I s r a e l ,  affecting  Ethanol  of miniature  transmitters included  found In  release.  1968; S i n c l a i r  glutamate,  or content  o f a c e t y l c h o l i n e from  and K a l a n t ,  (Carmichael  (1974)  release  necessarily  e t a l . , 1980) .  binding  nerve-muscle  (Phillis,  transmitters  of calcium  the frequency  but t o i n h i b i t  bral  (Baker  neurotransmitter  i n the isolated  1967),  without  end-plate prolong the a f f i n i t y  e t a l . , 1980).  However,  acetylcholine binding,  was i n c r e a s e d ,  decreased,  and t h a t  or not  42 affected ent  unpredictably  parts  of  glutamate vitro  to  brain  binding  ethanol  Carlen CA1  the  et  to  ethanol  (Ciofalo,  brain  from  involved  hippocampal  slices,  augment c a l c i u m - m e d i a t e d p o s s i b l y by  tration  effectiveness.  or  Ethanol and  binding  ethanol  on  be  single unit  early report  ous  of  ethanol  while  to  found  to  a l . , 1971).  have  been  have  larity,  even  1977).  Similar results  low  to  rate  Lo,  moderate  of  belli  (Rogers  increase  i n the  higher  doses  SS  activity  latter  the  a  decreased  also  was  activity  depressed  was  observed  given  (Rogers  et  post-syn-  in  release effects For  decerebrate  (Seil  in vivo: simple  spike  explants  and  a  regu-  et a l . , ethanol  spike  intact  These  of  intraven-  firing  reported  at  firing  rat  cere-  Sinclair  and  concurrent effects  activity  more r a p i d l y o r and  concen-  Purkinje  a l . , 1980;  firing.  complex  and  be  of  appears  cerebellar  from  et  recording  calcium  to  input  in situ  SS  by  firing.  spontaneous  Sinclair  of  report  infused  presumed  increased  workers  in  i n the  evoked  been r e p o r t e d an  by  transmitter  slowly  When e t h a n o l  was  pre-  reflected  synaptic  recorded  regularity  to  ethanol.  have  a l . , 1980;  These  b e e n due  after  burst  et  of  caused  cells  both  Conversely,  increased  absence  doses  Purkinje  1981).  have  i n the  that  report,  ethanol  excite interneurones,  ( E i d e l b e r g et to  be  cells  cats  found  recent  that  a l t e r a t i o n s to  depressed  tending  another  differ-  decreased  A  found  s p o n t a n e o u s and  an  cells,  In  from  intracellular  mechanisms  expected  example, dose  .  increasing intracellular  induced  would  1980)  a l . , 1980).  which  aptically,  in preparations  s y n a p t o s o m e s was  ( M i c h a e l i s et  a l . (1982),  cells  by  complex  a l . , 1980) .  may  reported in  spike-like  43 A variety reported  f o r other areas of the  the  spontaneous  was  depressed  berg  and  onal  firing  ized  discharge of  by  slow  Wooley,  ethanol study  of neuronal responses  was  and  1970) .  enhanced 1981).  inhibited Brick,  by  low  of  cholinergic  and  i n the  of  For  intraperitoneally  of ethanol  (Eidel-  hippocampal  intravenously  (Grupp, firing  could and  c o e r u l e u s were  be  neurinfused  1980).  agonists  injected  example,  horn i n t e r n e u r o n e s  adrenergic antagonists locus  been  A  later  antagon-  unaffected  or  (Grupp,  found  to  be  ethanol (Pohorecky  and  1977).  pressure  Ethanol  applied  depressed  their  locally firing  thetic-like  manner  application  of e t h a n o l onto  about  doses  inhibition  and  by G A B A - e r g i c Most c e l l s  by  by h i g h e r d o s e s  this  by d o p a m i n e r g i c  dorsal  Conversely, dorsal  excited  that  spinal  system.  intravenous infusion  inhibited  showed  nervous  t o e t h a n o l have  half  inhibited reported  o f them (Siggins  that  (Siggins  to  be  and  onto  Purkinje  in a non-specific, French,  hippocampal  excited,  while  1979) .  1980).  ethanol,  either  perfused or  a decreased  ones r e c o r d e d i n t r a c e l l u l a r l y  micro-  local  anaes-  Similar  the other h a l f  Bloom,  caused  by  pyramidal cells  and  microelectrode,  cells  Carlen  firing  caused were  e t a l . ( 1982)  applied  focally  i n most o f the  i n hippocampal  slices.  by neur-  44 I I .D. E t h a n o l  E f f e c t s o n GABA  Although showing been  an e f f e c t  quite  ioural  n o t much d i r e c t of ethanol  ethanol epines  on G A B A - e r g i c  a lot of indirect  s t u d i e s have and t h a t  evidence  evidence  substances,  and b a r b i t u a t e s , whose e f f e c t s  between  have  been  studies  been d i r e c t e d a t GABA's r o l e  tion. the  For example,  GABA  rats,  antagonist  as measured  Hakkinen  bicuculline  by t h e t i l t i n g - p l a n e  inhibitor  o f GABA c a t a b o l i s m ,  increased  the level Ethanol which  (cf.  1977).  that  enhanced  presynaptic  or l i g h t  produce  (1973)  enhanced  primary  amphibian  GABA.  to modify  Esplin,  inhibition  spinal  enhances  acid  an  (AOAA),  that  cord  preparation.  the spinal  presynaptic b y GABA  and Z a b l o c k a  (1966)  anaesthetic  agents  Conversely,  reported  spinal  produced  system,  ethanol  potential.  ethanol  d i d not However,  ( 1 5 0 - 4 5 0 mg/100 m l )  Therefore,  presynaptic  seda-  E i d e l b e r g and Wooley  a f f e r e n t d e p o l a r i z a t i o n , but i n a cord  that  Conversely,  a t a dose which  that, i n a similar  also  intoxica-  intoxication in  t o be m e d i a t e d  any p o t e n t i a t i o n o f d o r s a l root  Davidoff  ethanol  test.  as w e l l as other  anaesthesia.  (1969) r e p o r t e d  behavioural  (1976) r e p o r t e d ethanol  to  intoxication.  Miyahara,  ethanol  attributed  i n ethanol  amino-oxyacetic  i s g e n e r a l l y agreed  reported  tion  of  i s reported  inhibition, Levy,  reduced  Behav-  benzodiaz-  I n a d d i t i o n , a few  and Kulonen  has  the effects of  as t h e  o f GABA p a t h w a y s .  have  this.  such  modification  published  f u n c t i o n , there  suggesting  shown a s i m i l a r i t y  of other  h a s been  perfused  i tappears  inhibition  that  produced  by  45 Unfortunately, on  GABA's a c t i o n s  spinal  cord  reported the  actions  line,  ally  or  contradictory.  produced  but not that  or intravenously, cells  electrical  cortex. ably  stimulation  I t i s notable  that  ethanol  modifies  i.p.) CA3  neuronal  mossy  fibre  have  by m i c r o p r e s s u r e  instance,  ethanol  Backstrom  conventional  while  not a f f e c t i n g the ribbon  the  inhibition  garded  this  GABA-ergic  shown  thought to  Carlen  to  ethanol  Other  antagonism  workers  ( 1 1 - 4 5 mM)  i n isolated  synapses.  Siggins  by GABA.  t o be a n o n - s p e c i f i c  et a l .  GABA .. a p p l i e d  t h e e f f e c t s o f GABA.  synapses  cells  (3 g/kg  of the dentate  frog  For inhiretina,  and F r e n c h  d i r e c t application of ethanol  of Purkinje  that  d i d n o t augment  (0.1-10mM).  that  by  o f r a t hippocampal  Conversely,  responses  a t remark-  ethanol  by s t i m u l a t i o n  to antagonize  GABA  experiments  inhibition  a t low doses,  found  seen  Recent  the duration  ejection  (1977)  that  feline  of the cerebral  experiments,  cell  bited  (1979) r e p o r t e d  microosmotic-  (1981) have  pathways.  ethanol,  CA1 p y r a m i d a l  reported  hand,  of single  e f f e c t s were  neuronal  produced  or commissural  GABA-induced focally  increased  that  noradrena-  On t h e o t h e r  inhibition  and Bloom  In these  inhibition  (1982) r e p o r t e d  these  a hippocampal  significantly  antagonized  administered  (0.2-2 mg/Kg).  Mancillas-Trevino,  by GABA.  ethanol  acetylcholine,  of the surface  low doses o f ethanol  mediated  of the  by m i c r o i o n t o p h o r e t i c a l l y a p p l i e d  Newlin,  be  ethanol,  ethanol  e t a l . (1973)  o f GABA.  potentiated  produced  the level  Lake  by i o n t o p h o r e t i c  (1980a,b) reported  cortical  above  electro-osmotically applied  and s e r o t o n i n ,  Nestoros  on t h e e f f e c t o f  on s i n g l e n e u r o n e s  are often  that  the studies  However,  antagonized they r e -  effect since  i t was  46 often  accompanied  ening  of spike  that of  ethanol  be  duration.  mediated  onism  cells  cortical  of spike  Finally,  ( 1 . 5 g/kg i . v . )  r a t Purkinje  cerebellar  by r e d u c t i o n s  surface.  As t h i s  o f GABA  and  of  found  inhibition  stimulation of the  inhibition  i s thought t o  were i n t e r p r e t e d a s an  inhibition.  length-  and Lo (1981)  the period  by l o c a l  b y GABA, t h e r e s u l t s  by e t h a n o l  Sinclair  reduced  produced  amplitude  antag-  47  III.A.  Animal The  Wistar the  animals  rats weighing  animal,  pad.  175 a n d 250 g o b t a i n e d  Columbia  water.  Animal  the right  ylene  tubing  those  experiments  Rectal  Quebec.  temperature  intravenous  was c a n n u l a t e d with  a tracheal cannulation a small  or  animal  of  s o l u t i o n by  was m o n i t o r e d  by  within physiological current  injections  with  normal  involving the e l e c t r o l y t i c  respired using  either  In each  controlled direct  ( C l a y Adams) p r e f i l l e d  olive,  Facility  a s a 20%  and m a i n t a i n e d  vein  from  albino  by i n t r a p e r i t o n e a l i n j e c t i o n  subsequent  femoral  Care  La P r a i r i e ,  by a f e e d b a c k  To a l l o w  made,  animal  e x p e r i m e n t s were male  (1.4 g/kg, Sigma) a d m i n i s t e r e d  automatically  inferior  i n these  between  e l e c t r o n i c thermometer  heating  Surgery.  was i n d u c e d  in distilled  limits  and  Laboratories,  anaesthesia  urethane weight  Breeding  METHODS  used  University of British  Canadian  an  Preparation  III.  N o . 10 saline.  t o be polyethIn  lesioning of the  was p e r f o r m e d  and t h e  r e s p i r a t o r (Harvard  Instru-  ment 680) . The frame  (Narashige)  (1979).  cm  Manufacturing stimulating  with  dura  head  according  The s k i n o v e r  ( a b o u t 0.3  The  animal's  was t h e n  t o t h e method  the s k u l l  i n diameter)  were  Company) t o a l l o w electrodes  was t h e n  into  reflected  two p a i r s o f f o r c e p s .  positioned  i n a stereotaxic  of Pelligrino  was r e t r a c t e d a n d drilled  with  (Dremel  of recording  and  brain locations.  and t h e p i a m a t t e r Exposed  burrholes  a Moto-tool  the placement  the appropriate  et a l .  gently  t i s s u e was c o v e r e d  ripped with  48 normal  s a l i n e o r agar  III.B.  Electrode  Preparation,  Single in  (4% i n saline)  Placement,  barrel recording  a conventional  manner  from  1.5 mm  (Glass  strand  of fibreglass to facilitate  cial  electrode  glass with in  Company o f A m e r i c a ,  The p i p e t t e s were puller  r o d under  histological tion  (Narashige)  a microscope  a Pontamine  0.5 M s o d i u m  pulled  Sky Blue acetate,  marking  of the dye.  drying.  and Methods  microelectrodes  pettes  action.  to prevent  diameter  were  glass  their  filling  conventionally and t h e t i p s 1 um.  by  The e l e c t r o d e s  both sites  capillary  broken  against  They were  recording  a single  on an commer-  dye ( I C N P h a r m a c e u t i c a l s ,  of recording  micropi-  Omega D o t ) c o n t a i n i n g  t o about  allowing  prepared  filled  Inc.,  and  a  6BX)  later  by i o n t o p h o r e t i c  ejec-  h a d DC i m p e d a n c e s o f 1 5 - 2 5  megohms . Multibarrel by  glueing  around  a number o f s h o r t  a central full-length  (Lepage) . to  The f o r m e r  the micropressure  interaction curing, the  between  individual electrode  while  hockey  stick  pipette with  so shaped  pipettes was p u l l e d  barrel,  five  heated,  together.  After  conventionally  filled  pipette  their  equipment  and g i v e n  blanks  epoxy connection  and t o p r e v e n t leakage.  After  was i n s e r t e d  a half turn  a period  constructed  minute  b a r r e l s due t o i n t e r - b a r r e l  electrode  the surrounding  were  shaped  to allow  or iontophoresis  puller,  barreled  central  were  microelectrodes  t h e r e s u l t i n g m u l t i b a r r e l assemblage  electrode  three  recording  into  t o bond t h e  f o rcooling, the  and t h e t i p b r o k e n .  For a  t h e r e s u l t i n g t i p s i z e w a s 3-4 um.  as above,  served  barrels, filled  as t h e recording  with  drug  The  barrel,  solutions,  49 served  as drug The  to  1.5  0.25, min)  drugs  g / k g , 20%  M i n 1 4 5 mM Two  effects;  minimize  were  cortex  four  1.0 mm  and c o n n e c t e d  a l . , 1979) and used  calibrated  zero  point.  Kopf  Inst.,  and because o f t h e s p a t i a l  micro-  ( 6 7 0 mM i n equias a  Ejection  NE-100).  together  array  positioned  The c o o r d i n a t e s  of the  (Pelligrino  relative  to the cranial  requirements  The  electrically.  the electrode  damage  by a  constructed  i n an p l a n a r  a stereotaxic atlas  To a v o i d  by  was u s e d  effects.  in parallel  to position  with  channel  s t i m u l a t i o n was e v o k e d  by s t e r e o t a x i c t e c h n i q u e s . from  pH  to test f o r  to obtain  and s t i m u l a t i n g e l e c t r o d e s were  were o b t a i n e d  ethanol  balancing  by a c o m b - e l e c t r o d e  glued  solu-  psi.  and j u x t a f a s t i g i a l  was s t i m u l a t e d  10  Ejection currents  Sucrose  o f 0-20  over  filled  administered  were chosen  (David  (up  ( G A B A , 2 M,  i n s a l i n e ) and s u c r o s e  e t a l . , 1981).  i n the range  centers,  site  The d r u g s  ( 7 5 0 mM  bipolar electrodes  the brain  1982).  f o r non-specific pressure  Recording  tion  nA.  concentric electrode  cerebral  et  acid  as a c u r r e n t  (Palmer,  concentrations  Olivary  target  effects  o f 0-40  (Sorensen  to test  pressures  in  drugs were:  and g a m m a - a m i n o b u t y r i c  ethanol  These  osmolarity  on  a s a 10 mg/ml  administered  and t h e second  current  were  saline) .  bipolar  o r a s one dose  for control applications of saline  i n the range  pressure  from  22 m i n u t e s  a d d i t i o n b a r r e l s o f t h e same e l e c t r o d e w e r e  current  control  ethanol  i n d i v i d e d doses o f 0.25,  ( u p t o 5 mg/kg, g i v e n  NaCl)  the f i r s t  were  i n t r a v e n o u s l y were:  either  The i o n t o p h o r e t i c a l l y  saline:  to  given  g/kg over  and h a r m a l i n e  4) .  barrels.  administered  w/v,  0 . 5 , a n d 0.5  tion) . (1  application  to i t s  circula-  of the electrode  50 carriers,  n o n - v e r t i c a l approaches t o b r a i n  sites  were  sometimes  used. Recording direct  negative  barrel.  This  site.  brain  been  lesioning  30  ventricle  was  40 um  a t -20  using  conventional microscope and  2415), tion  then  an  ethanol) .  black  of  the l e f t slit  f o r at least  Division)  40%  subsequently  through  The  filled  three  32x.  and  The  preserved  a  and mounted  procedures.  were  stained  with  cresyl  M i c r o g r a p h s were  v a r i a b l e contrast  illumination,  I I I , 2.5x film  a green  taken  was  The with  right the s a l i n e with  a  formaldehyde b r a i n was  onto  glass i n 2 1 of  violet  using  with  light  a  o b j e c t i v e , ASA  and  then  (Damon/IEC  (Kodak, T e c h n i c a l  filter,  of  needle,  a f r e e z i n g microtome  Centigrade  by  A t t h e end  decapitated i n 10%  the  current  saline,  perfused  stored  after  marked  direct  of the heart.  days.  (Zeiss Photomicroscope  Kohler  were  normal  then  at the  e t h a n o l - g e l a t i n s o l u t i o n (2 g g e l a t i n Sections  white  with  was  and  sections with degrees  opened  the animal  animal  dye  a  recording  located  t i p with  was  ventricle and  sites  the  the e l e c t r o d e .  chest  t h e b r a i n removed  into  slides  were  by p a s s i n g  through  of the blue  Stimulation  syringe  2 min) .  guillotine,  sliced  were marked  f o r 10 m i n ) a spot  spots  the animal's  into  ml over  solution  uA  left  s) p a s s e d  t o a 50 m l  introduced  (30  (6  sectioned.  experiment  attached  These  of interest  the t i s s u e at the electrode  (0.3-0.9 mA, the  current  procedure  recording had  sites  at a  6.3),  Pan  magnifica-  51 III.C.  Equipment Single  10x  gain  voltage  filtered, R5030).  and The of  3  a  and  kHz.  This  durations action low  displayed  a high low  was of  about  filter's  The  signal  record with  with  a 3 dB  a 3  a duration  of  c u t o f f frequency  as  dB  required.  inferior  be  Typically,  delay  output  of  latter  centre  The based and  upon  was  input  allowed  the  signal  the  be  monitored  ed  to  standard  (constructed system.  by  pulses the The  lying  within a  visually.  cells  cutoff  c u t o f f of  of 1  neuronal  required at  1 to  the 10  Hz  by  author,  input  would  the  author),  the  author) .  to  the  second  of  to  include  by  interest  were see  integrated  an  w i t h i n an  time window.  Selected which  then  a  and  a  The  channel to  be  of  dis-  screen.  i t s peak a m p l i t u d e lying  or  Hewlett-Packard  window d i s c r i m i n a t o r s e l e c t e d  i t s width  puter  (constructed  device  of  was  A-3440, or  brigade  i n the  and  this  bucket  played  Golgi  olive  adjusted  a window d i s c r i m i n a t o r ( c o n s t r u c t e d  o s c i l l o s c o p e and  D11  action potentials  3960),  the  and  frequency  a b o u t 5 ms to  or  amplified,  frequency  amplified signal  (Sony TC-399, Teac  this  a unity  neurones.  and  line  then  Purkinje  However, the  these  through  was  f o r neurones with  filtered  recorder  to  filter  recorded  oscilloscope (Tektronix,  filter  1 ms.  from  equipment,  an  used  optimal  when r e c o r d i n g  tape  pass  was  This  on  pass  p o t e n t i a l has  pass  other  follower.  filtering  consisted kHz  unit activity  action potential amplitude  window  These windows  a c t i o n p o t e n t i a l s were input  to  a  spike  H a r r i s , 1979)  spike  rate  could  or be  could convert-  integrator to  a  microcom-  recorded  on  a  52 polygraph  (Gould  2200S o r Narco  Extensive the  Physiograph),  u s e w a s made  o f the microcomputer  i n t e g r a t i o n and d i s p l a y o f n e u r o n a l  construction and  of peri-stimulus  latency histograms  (see  software).  administered  i f required.  (PSTH),  firing  rate  system f o r  and t h e  interspike interval (ISI)  (LH) and s u b s e q u e n t  statistical  analysi.s  In a d d i t i o n , i t c o n t r o l l e d the equipment  drugs  locally  6400) o r m i c r o p r e s s u r e  to neurones  by i o n t o p h o r e s i s  ejection (Medical  Systems  which  (Dagan  Corpration  PPM-2) . The  microcomputer  system  hardware  consisted  of the  following: -Apple -16  I I plus  k i l o b y t e random  Computers -two  5 1/4  -monitor -dot  48 k i l o b y t e s o f r a n d o m access  I n c . 16K inch  floppy  printer  a parallel another  memory e x t e n s i o n  access  memory;  board  (Orange  Card);  (Electrohome  matrix  via -and  with  disk  drives  Disk I I ) ;  ESM-914);  ( I n t e g r a l Data  i n t e r f a c e board  parallel  (Apple  Systems  (Apple  i n t e r f a c e card  460) i n t e r f a c e d  Parallel  (constructed  Card); by t h e  author) . A laboratory stimulator pulsed  voltages  for  electrolytic  The  "prepulse  channel the  for electrical  (Grass,  s t i m u l a t i o n and t h e c u r r e n t s  l e s i o n i n g and t h e m a r k i n g  sync"  o f the tape  output  was r e c o r d e d  recorder  SD9) s u p p l i e d t h e  when a p p r o p r i a t e  and p r o v i d e d  o s c i l l o s c o p e and m i c r o c o m p u t e r  of recording  system.  a trigger  used  sites. on one  signal for  53 III.D.  Software. Extensive  the  microcomputer  ysis  and  either or  the  system  real  i n BASIC,  software  time  to  be  written  used  control  f o r the  i n 6502 a s s e m b l y  was  of  display,  language  by  the  f o r data  author  collection,  equipment.  I t was  control  analysis  f o r the  and  data  to  allow anal-  written  collection  programs,  and  timing  routines. Various interval ten  (ISI),  versions of  and  latency histogram  to allow a n a l y s i s  treatments. ultaneous ISI  For  SS.  The  in  this  on  the  spike  ated  and  basis of interval  of  a SS  to  less  collect  than  completion  the  complex  c o n t a i n a CS. with  a  interspike  from  only  those  increased  to  a l l o w the  collected  by  these  of  1 ms.  the  a CS  the  SS  to  simto  the  simple an  CS first  spikes  7 ms  of  intervals  histograms the  longer  this  example, which  did  consisted of  bin width time  s t o r e d onto  a  indic-  a consequence of for  as  inter-  beginning  exceeding  As  However,  then  and  histograms, to  the  Purkinje cells,  complex  CS  Specifically,  measurement o f  p r o g r a m s was  allowed  from  interval  SS  different  each  indicated  time  writ-  from  spike.  In most c a s e s  bin width  data  interval. 4 ms  to  ISI histogram,  between  following  SS  programs  SS  interspike  programs were  responses  latency histogram  a  the  the  to  spike, while  the  ettes .  one  interspike of  (LTH)  neuronal  distinquished  were c o n s t r u c t e d  bins  a  programs used  distinction,  not  the  example,  example,  complex  of  c o n s t r u c t i o n of  histogram,  p o s t - s t i m u l u s (PSTH),  could  periods. floppy  250 be Data  disk-  54 Companion play  and c a l c u l a t e  Mean i n t e r s p i k e the  mean  bitory  accessed  the required  periods  i n t e r v a l s , together  were d e t e r m i n e d  and s m o o t h i n g  average.  the time  the  rate  control  with  using  data  measures  their  standard  by c o n s t r u c t i n g  the f i r i n g  ( t h e average  rate  of the last  from i t . error  formulae.  of  Inhi-  a PSTH o f t h e by u s i n g  o f i n h i b i t i o n was t h e n  a t which  to redis-  standard  the resulting histogram  The p e r i o d  determining  the stored  statistical  (SEM), were c a l c u l a t e d  inhibition moving  programs  found  returned  25 b i n s  a by  t o 50% o f  of the histo-  gram) . Other of  drugs  programs were w r i t t e n  by m i c r o p r e s s u r e  recording  and d i s p l a y i n g  as  versus  a time  collected programs allowed  data  rate  averaged  display  response  decrease  from  the averaged  display  from  of the control Statistical paired  The d a t a  subtracting  the average  each  forrecall  during  by o t h e r  programs  t o be a v e r a g e d from  was  this (percent-  calculated  t h e mean r a t e the control but expressed  during period. as a  rate.  significance  from  Again, the  decrease  similarly,  firing  v i s u a l l y , both  or r e l a t i v e  by s u b t r a c t i n g  t - t e s t with  rate  be d e t e r m i n e d  Absolute  t h e mean r a t e  simultaneously  These  trials  the absolute  c h a n g e was c a l c u l a t e d  percentage  Student's  and a n a l y s i s .  rate.  response  firing  diskette  application  as e i t h e r  i n firing  GABA a p p l i c a t i o n Relative  on f l o p p y  the application  while  and n u m e r i c a l l y .  I n h i b i t i o n b y GABA w o u l d  age)  p<0.05.  the neuronal  a number o f d r u g  together.  or iontophoresis  was s t o r e d  f o r further  to control  was c a l c u l a t e d  a two-tailed experiment  of the control  using  c r i t i c a l value of  trial values  were n o r m a l i z e d from  each  by  of the  55 test  points.  experiments istic. and  these  a t each  This  thus  that  Then  time  procedure  measured  of the test  differences point  system.  III.E.  DMP-4)  Experimental Ethanol  III.E.1.a.  though  examined  positioned allow  ing  and  activity  electrode  Purkinje  cell  pattern,  minimum  of ethanol  Apple  was w r i t t e n  Cell  ethanol  I I microcomputer Fawzi .  Synapse decreases  CS  o n t h e CS a c t i v i t y stimulating  (-4.5 A P , - 2 . 5 DV, o f complex  was r e c o r d e d  1.8  spikes.  ipsilaterally  located  required  was m e a s u r e d .  t o evoke  consecutive  stimulations. and a f t e r  was d e f i n e d a complex  by  electrode lateral)  was to  Purkinje  After  evoke  complex  as t h e v o l t a g e spike  cell  a rate  spike of  i n a l l o f 10  T h i s m e a s u r e m e n t w a s made a t ethanol  we  had been o b t a i n e d , t h e  to consistently  required  evoked  by i t s c h a r a c t e r i s t i c f i r i n g  recording  This  synapse,  to the stimulat-  had been  and a s t a b l e  activity  cell  IV and V o f t h e c e r e b e l l u m .  before  as  (Houston  b y M r . Ahmad  fibre-Purkinje  A bipolar  evocation  stimulation  intervals  as w e l l  plotter  i n lobes  voltage  activity  whether  juxtafastigially  unit  values  Spikes  stimulation.  the subsequent  single  by a n o t h e r  at the climbing  the effect  juxtafastigial  on a d i g i t a l  Fibre-Purkinje  determine  an a c t i o n  the t-stat-  SEM's f o r t h e c o n t r o l data  a l l the  Protocols  on Complex  Climbing To  over  to calculate  of the control  controlled  The p l o t t i n g s o f t w a r e  III.E.1.  averaged  data.  Graph's were p l o t t e d Instruments,  and used  calculated  the variance  were  administration  regular  (1.5 g/kg,  56 i.v.  in a  min)  .  s i n g l e dose over  The  recorder  neuronal  for  later  The simple the  and  evoke complex voltage was  at  t-test  spike  olive  cortex  according cell  The  level  which  to  averaged  on  an  FM  22  tape  counting  numbers  epochs over  the  voltage  were compared the  the  to  spontaneous  (p<0.001) w i t h  a  the  of course  required  the  of  to  pre-control  complex paired  spike  rate  Student's  CS  An  1 mm  activated array  below  method  been  ethanol  activity  was  indirectly  by  further,  stimulation  stimulating  the  surface  of  of  Freedman complex  0.4  spike  activity  bipolar  ms  i n t e n s i t y was  complex  CS  of  located,  stimuli,  on  et  the  spikes  adjusted  recorded  cerebral  a l . (1977).  duration,  activity  elec-  were evoked 1Hz,  to  a  every  at  5  submaximum  consistently.  during  After  the  Neuron-  periods  stimuli.  histograms  was  recorded  minute  e f f e c t of  the  had  evoked  The  tions  the  stimulation  spontaneous  after  was  doses over  Stimulation  i n t e r v a l s (80  min).  CS  activity  positioned  Purkinje  between  in divided  experiment  cortex.  was  al  by  one  neurones were  cerebral  regular  per  t i m e s when  study  trodes  a  analyzed  each  Cerebral  To  the  or  .05) .  III.E.I.b.  of  activity  significantly  (p<0  inferior  In  those  reduced  was  spikes  experiment.  min  analysis.  data  total  spike  10  data  (LTH,  each  in addition  stimuli.  taken at  were a n a l y z e d  each  from time  The  each  to  SS  constructing and  number o f  LTH.  period  by  The over  CS  latency  PSTH's) o f  evoked  CS  per  r e s u l t i n g data  a l l experimental  time  the 80  was  first stimulapointwise  trials.  From  57 this the by  averaged  data,  pre-ethanol a  Student's  I I I . E . 1 . c . The  control paired  record  effect drug  lation  ethanol  (two  time  using  of  the as  on  inferior  firing  olive  r a t e was  locally  recording  had  displayed  by  venously  the  neuronal  tested  (used  three minute of  an  to  verify  as  experiment,  analysed  identity  The  effect  by  counting  data  from  wise  averaged  determine  a l l of  the  average  istration averaged  of  at  of  of  each  the  applied  time  on  point of  trials  used The  micropip-  -7.5  evoked -2.5  DV,  0.6  by  stimu-  DV,  After  1.8  a stable  collected  g/kg)  was  and  intra-  administered f o r one  ethanol  minute  control.  i . v . ) was  the  At  at  the  end  administered  neurone.  firing  pre-ethanol  experiments,  locally  t o 5mg,  intravenous  significance  together  (up  ethanol  cell  the  the  while  The  was  (1.5  under microcomputer  harmaline  the  firing  were  administering  AP,  1976) .  Ethanol  a c o n t r o l ) was  intervals  of  determined  activity.  AP,  (-4.5  neuronal  min,  (-4.5  Lodge,  microcomputer. 10  by  potentials  matter  and  achieved,  i n f u s e d over  sucose  field  white  (Headley  been  p o i n t s ) was  by m i c r o p r e s s u r e .  characteristic  aid  average  multibarreled glass micropippettes  cerebellar  an  the  (p<0.05).  were p o s i t i o n e d s t e r e o t a x i c a l l y  lateral)  the  or  d i f f e r e n c e from  Olive  extracellular  of  lateral)  or  t-test  i n t r a v e n o u s l y or  pettes  counts  Inferior  Single to  significant  inferior  during ethanol and  changes  the  controls.  In  firing  change  The point-  was  used  rate  from  local  ejection  t o o b t a i n mean p e r c e n t a g e  were  t-test  the  was  epochs.  experiments  a paired  similar  firing  s i x second  to  at  olive  admin-  pressures in  to  firing  were  58 rate  from  used  to  pre-drug  determine  control rate. i f there  between  the  glucose  applications  III.E.2.  change  Ethanol To  absence of was  the  on  to  the  olive  lateral  to  the  be  by  activated  of  CS  ethanol  CS.  cell  and  c o n t r o l data  AP,  in  2-5  i n the  ethanol  (1.5  olive  electrode DV,  IV  and  located olive,  in  0.6  recorded  min),  latcontra-  V  of  which the  Purkinje was  the  could  inferior  resulting in  g/kg)  the  experiments  -7.5  lobules been  in  inferior  was  inferior  (0.1-0.6.mA o v e r activity  the  activity  stimulating  had  the  SS  These  activity  electrode  of  on  activity,  bipolar  single unit  CS  difference  cell.  the  After  infused  over  min. e f f e c t of  constructing  and  after  the  ISI  l e s i o n i n g and  interspike interval  each  experiment.  time  point  over  averaged  ethanol  histograms  mean  the  a  Purkinje  of  the  ethanol  spontaneous  stimulation  cessation  The by  a  lesioned  acquisition 10  e f f e c t of  stimulating  After  (p<0.05)  was  trial.  s t e r e o t a x i c a l l y (-4.5  cell  cerebellum.  during  t-test  Spikes  p o s i t i o n i n g of  Purkinje  complete  the  eliminate  eral) .  was  Simple  Student's  significant  rates  i n d i r e c t e f f e c t s of  inferior  olive  firing  a  i n each  examine  lesioned  involved  in  was  A paired  The  the  was  data  on of  SS SS  firing to  was  a l l experiments  using  Student's  analyzed  CS  to  administration  of  ethanol.  then and  at  each  pointwise  paired  means  time  CS  before  (two  t-test  The  point  averaged  significant  post-lesion, pre-ethanol  were d e t e r m i n e d  was  and  calculated  SS  rate  at  in each  differences time  from  points)  (p<0.05).  59 The comparing in  these  each the  point  pointwise from  III.E.3.  local  using  Ethanol  activity  barrels  with  microelectrode  ally  b y i t s mean a n d  point.  t-test  were c o n d u c t e d  on t h e p e r i o d  from  ethanol  time  to test  Purkinje cell  administered  the surface, diameter  the longitudinal was t h e n  ethanol  the effect of evoked  single  by  unit  whose two d r u g  A f t e r t h e e l e c t r o d e had the local silver  was p o s i t i o n e d a b o u t  Purkinje cell  points  l o b u l e s IV and V o f t h e c e r e b e l l a r  ( a 0 . 3 - 0 . 4 mm  along  differ-  (p<0.05).  of inhibition  and s u c r o s e .  below  glass)  trials  Significant  three- b a r r e l e d g l a s s m i c r o e l e c t r o d e s  electrode  suitable  the variance of  a l l experimental  paired  s t i m u l a t i o n (LOC) .  contained  insulated  time  measured  was c a l c u l a t e d a t  by d i v i d i n g  from  (LOC) s t i m u -  ball  1.0 mm  electrode  from t h e  axis of the folium.  l o c a t e d and t h e e f f e c t  and s u c r o s e  on l o c a l  of  A loc-  inhibition  tested . Inhibition the  LOC e l e c t r o d e  intensity  adjusted  Post-stimulus  of firing  was e v o k e d  ( 1 H z , 0.5 ms  duration)  to achieve  a 1 0 - 3 0 ms  histograms  by  Inhibition  experiments  been p o s i t i o n e d j u s t lating  intervals  post-lesion, pre-ethanol  on L o c a l  was r e c o r d e d  with  the data  Student's  applied ethanol  was a n a l y z e d  the I S I histogram)  a t each  the averaged  surface  cortex  (from  Again,  averaged  These locally  experiment,  interval  were determined  interspike  A measure o f r e g u l a r i t y  i n each  by 1 0 0 0 .  o n SS r e g u l a r i t y  o f t h e mean  experiments.  interspike  ences  of ethanol  the variance  time  scaling was  effect  were c o n s t r u c t e d  by s t i m u l a t i n g w i t h with  the stimulus  inhibitory at regular  period. intervals  60 with by  and w i t h o u t  micropressure  inhibition and  of  over  a t each  finding  control.  the local  For each  inhibition  of pressures.  point  was m e a s u r e d  a t which  trial,  during  same p r e s s u r e  a range  time  t h e time  administration of ethanol  firing  significant  ethanol  sucrose  The p e r i o d o f by s m o o t h i n g  had r e t u r n e d  t h e PSTH  t o 50% o f  differences i n the period  and s u c r o s e ,  were d e t e r m i n e d  or  administered  by S t u d e n t ' s  paired  at the  t-test  (p<0 .05) .  III.E.4.  Ethanol  To duced  test  by l o c a l  o n L o c a l GABA  the effect  application  Inhibition  of ethanol  o f GABA, P u r k i n j e c e l l  activity  was r e c o r d e d  from  cortex.  When e t h a n o l  was i n f u s e d  by  iontophoresis.  was  g/kg, i . v .  After a Purkinje cell  both  GABA  trials,  over  10 m i n ) .  o f experiments,  give  submaximal depressions Each  averaged as  had been  or percent  decrease  responses  value.  in firing  This  rate  from  average  were a v e r a g e d .  The d a t a  both to  time from  point  were  was c a l c u l a t e d  pointwise  a t each  In  t o GABA  In the case o f i n t r a v e n o u s l y administered  experiments  10 GABA  firing.  control.  o f the data  locally,  o f GABA w a s a d j u s t e d  consecutive  t o c a l c u l a t e one i n h i b i t i o n  absolute  (over  by m i c r o p r e s s u r e .  of cell  inter-  was i n f u s e d  was g i v e n  and e t h a n o l  the application  group o f f i v e  l o c a t e d , GABA  ethanol  When e t h a n o l  5 min) were a p p l i e d  sets  unit  c o n t r o l f o r 20 s a t 1 m i n  ( 1 0 s a t 30 s i n t e r v a l s )  i.e.  single  i n t r a v e n o u s l y GABA w a s a p p l i e d  A f t e r a s e r i e s o f c o n t r o l responses,  (1.5  pro-  l o b u l e s IV and V o f t h e c e r e b e l l a r  a p p l i e d under microcomputer  vals.  on t h e i n h i b i t i o n  pre-GABA ethanol, the  from  the local  a l lthe  application  61 of  ethanol  recovery tion  were grouped  values.  from  the  Student's  was  mental  on  trials  control  Golgi  rates  in  level  inhibi-  the was  ethanol  on  of  determined  by  Rate.  between  the  periods  of  III.E.4.b.).  were p o i n t w i s e from  the  determined  by  data  at  average  cell  stimulation  The  averaged  Golgi  each of  Student's  in  from  point.  two  paired  the  a l l experi-  time  the  firing  pre-ethanol  t-test  .05) .  III.E.5.b.  I n h i b i t i o n by  Inferior Olive  e f f e c t of  on  The evoked  by  inferior  cell  single  unit  cerebellar  cortex  using  Golgi  stimulating inferior Golgi action and  and  controls  intravenous  (section  was  ethanol,  Cells  Firing  difference  during  (p<0.05).  e f f e c t of  below  Significant  (p<0  t-test  measured  protocol  pre-ethanol  Spontaneous The  rate  averaged  Ethanol  III.E.5.a.  pre-ethanol,  Significant diffences  paired  III.E.5.  as  cell  was  (-4.5  inhibition  evoked  single  pulse,  0.5  single  AP,  p o t e n t i a l and 1981).  activity  was  located  Bloom,  the  olive stimulation  electrode  olive  ethanol  To by ms),  a  using  from  test  the  the  of  examinined  lobules  IV  1.8  lateral).  criteria  poststimulus  of  rate  e f f e c t of of  V  of  A  the  a  of  the  A  amplitude Hz  ethanol  of  the  suitable  12-20  histograms  the  bipolar  large  inferior  cells  recording  stereotaxically in  firing  stimulation  Golgi by  and  barrel electrodes.  DV,  regular  inhibition  was  positioned -2.5  Stimulation  on  olive the  (Schulman the (1-2  Hz,  neurone's  62 response ethanol  to the stimulation  were  constructed  before  and  after  administration. The  PSTH a n d  finding  control.  The  experimental significant inhibitory ( p < 0 .05) .  i n h i b i t o r y period the time  pointwise trials  was  a t which  average  measured firing  a t each  was  then  calculated.  differences  from  the average  period  was  determined  by s m o o t h i n g  returned  time  point  From  t o 50%  of  from a l l  this  pre-ethanol  by S t u d e n t ' s  the  paired  average control t-test  63 IV.  IV.A.  Ethanol  on  Complex  IV.A.1. Climbing  olive been  fibres,  (10). found  a c t i o n was  which  reduce  that  by  i s due  climbing  fibres lar  activate of  CS  to  (1.5  this  58  and  was  resulted  i n the  complete  cessation  evoke  g/kg  fibre  rate of  activity  the  was  regular  CS  to  do  test  activity  failing  to  over  caused  climbing  the  cerebel-  required  intervals. 22  the  cross  this,  voltage  doses  has  l o c a l i t y of i t s  To  the  from  inferior  ethanol  s t i m u l a t i o n of and  input  the  designed  activity  synapse.  at  to  The  effect  min)  upon  studied. a  Purkinje  i n Figure had  a  rate  cell's 1 .  administra-  Administration  0.8  Hz.  in divided  activity  rose  ethanol  this  of  However, the only  Before  to  simple  spike  rate  22  100  Hz  and  the  (significant  at  p<0.001,  to  over  voltage  from  10.9  required to  11.2  to V,  of  of  doses over  increasing  CS  response  spontaneous  intravenously SS  afferent  i n spontaneous  i.v., in divided  spike  t-Test) . CS  however  electrical  cell  complex  by  administered  experiment  measured  example of  1.5  ly  by  then  Purkinje a  caused  (juxtafastigially)  ethanol,  Student's  This  is illustrated  tion,  activity,  climbing  g/kg,  Synapse  intravenously  fibre-Purkinje cell  threshold  protocol  are  reduction  activity  An  Hz  this  matter  ethanol  this  CS  were a c t i v a t e d  white  (CS),  Cell  o r i g i n a t e e x c l u s i v e l y from  n o t ^determined.  hypothesis  the  spikes  Previously, to  ethanol  Spikes.  Fibre-Purkinje  Complex climbing  RESULTS  min, almost  consistenta  nonsigni-  64  F i g u r e 1: An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n t h e v o l t a g e f o r e v o k i n g a c o m p l e x s p i k e by juxtafastigial stimulation. ( A , B , a n d C) T i m e h i s t o g r a m s r e p r e s e n t i n g a P u r k i n j e c e l l ' s (A) t o t a l and (B) c o m p l e x s p i k e a c t i v i t i e s , and (C) t h e v o l t a g e v o l t a g e r e q u i r e d t o evoke a complex s p i k e ( C ) . T h r e s h o l d s were measured d u r i n g the time p e r i o d s r e p r e s e n t e d by t h e s h o r t b a r s . C e l l u l a r a c t i v i t y was n o t d i s p l a y ed d u r i n g t h e s e p e r i o d s b e c a u s e o f c o n t a m i n a t i o n by t h e s t i m u l a t i o n a r t i f a c t . E t h a n o l a d m i n i s t r a t i o n was s t a r t e d a n d d i s c o n t i n u e d a t t h e up a n d down a r r o w s , r e s p e c t i v e l y .  66  ficant  (p>0.2).  change This  six  experiments  spontaneous  CS a c t i v i t y  The spikes their  action  were h i g h l y  i n Figure  CS, and e x a m p l e s and a f t e r  IV.A.2.  source  by e t h a n o l  was t e s t e d  by s t i m u l a t i o n  the ability  CS a c t i v i t y .  i n Figure  post-stimulus  activity i s  examples o f spontanous  fibres:  CS  an a c t i o n  the inferior  administered indirectly,  SS  activity  olive.  o n 10  on  This  neuronal  cortex.  o f ethanol  spike  activity  these  cell  effects  o f a sample  i n t h e form  that  t o evoke  of Purkinje  illustrating  ethanol, Note  was f o u n d t o  stimulation  reduction  An e x a m p l e  (PSTH).  o f ethanol  b y t h e a c t i v a t i o n o f 10  cortical  a parallel  of Purkinje  In the f i r s t , the  ethanol  of the cerebral  and a f t e r  histgrams  the reduction  by two m e t h o d s .  3, t h e t o t a l  before  that  represents  of cerebral  spontaneous  cell,  spike  SS a n d e v o k e d  administration  and t o cause  Purkinje  changes t o  the administration of  and complex  o f spontaneous  activity  shown  o f t h e complex  Stimulation  Intravenous  is  spike  after  I t includes  was i n v e s t i g a t e d  excitability  CS  2.  of intravenously  decrease  were  (p<0.001).  significantly  H o w e v e r , no d i s c e r n a b l e  were o b s e r v e d  of the climbing  hypothesis  neurones  the voltages  potential configurations  may be h y p o t h e s i z e d  CS a c t i v i t y  effect  the other  ethanol.  Cerebral It  cell  was r e d u c e d  Examples o f simple  illustrated  before  In a l l cases,  variable.  configurations  ethanol.  and  performed.  o f t h e r e s u l t s from  (p>0.20, S t u d e n t ' s t - t e s t ) a t t h o s e t i m e s w h e n t h e  unchanged  the  e x a m p l e was t y p i c a l  o f two  t h e i n i t i a l peak o f  67  F i g u r e 2: E x a m p l e s o f s p o n t a n e o u s and e v o k e d e x t r a c e l l u l a r Purkinje c e l l activity. ( A ) An o s c i l l o s c o p e t r a c e s h o w i n g t y p i c a l s p o n t a n e o u s s i m p l e and c o m p l e x s p i k e a c t i v i t y . (B,C) O s c i l l o s c o p e t r a c e s s h o w i n g c o m p l e x s p i k e s e v o k e d by j u x t a f a s t i g i a l s t i m u l a t i o n (B) b e f o r e and (C) a f t e r e t h a n o l (1.5 g / K g i n d i v i d e d d o s e s o v e r 22 m i n ) . S t i m u l a t i o n o c c u r r e d at the arrows .  I  50  ms  F i g u r e 3: An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l on t h e e v o c a t i o n o f c o m p l e x s p i k e s i n a P u r k i n j e c e l l by s t i m u l a t i o n of the c e r e b r a l c o r t e x . (Top) P e r i s t i m u l u s t i m e histogram of the t o t a l p r e - e t h a n o l s p i k e a c t i v i t y . (Bottom) Response of c e l l a f t e r e t h a n o l ( 1 . 5 g / k g , o v e r 10 m i n ) . Cerebral stimulat i o n (1 H z , 0.4 ms d u r a t i o n , 2-4 V) o c c u r r e d a t t h e a r r o w heads. E a c h h i s t o g r a m was c o n s t r u c t e d f r o m 80 trials.  70 activity  present This  effect  where n e u r o n a l activities, latency  reflect  figure sents the  after  each  evoked  i t i s clear that  This  complex  ity  recorded  the  cerebral cortex,  ethanol  increase bition  This  CS a c t i v i t y parallel  per  this  from  the other Only  after  was  data  ethanol  reduced  o f 19.9 H z . the start  CS a c t i v i t y  only  were  seen  from  seen  i n Figure  i n both  after  of ethanol was r e d u c e d  3  part  activ-  after rate  of  SS  the other  was  this inhi-  histogram. cells  i s graphed i n  the reduction  CS a c t i v i t y .  o f evoked by a  Spontaneous  CS  o f 4 0 . 2 Hz t o a l o w  significantly  from  administration.  9 min a f t e r  by  o f CS-induced  level  this  repre-  T h e CS  SS f i r i n g  a minor  from  a  the post-  62 t o 7 c o u n t s  that  from  only  80 s t i m u l a t i o n s o f  a l l o f these  a pre-ethanol  I t was r e d u c e d  80 c e r e b r a l s t i m u l i  CSs  was g r e a t l y r e d u c e d  hand,  CS  first  From  a d m i n i s t r a t i o n i s accompanied  o f spontaneous from  the  o f these  i n the pre-ethanol  figure illustrates  reduction  after  evoked  On  responses  5.  min  peak  i s illustrated  visible  Figure  SS a n d  CS a c t i v i t y .  c a n be a t t r i b u t e d t o t h e r e d u c t i o n  and t h e a v e r a g e d  4,  In a d d i t i o n , a  PSTH a n d l a t e n c y h i s t o g r a m .  tested  level  and t h a t  36.7 t o 51.6 H z .  Similar  activty  PSTH.  spontaneous  was r e d u c e d  o f SS a c t i v i t y  separate  included  i n the latency histograms,  from  into  the second.  i n Figure  The m a j o r i t y  the i n i t i a l  administration.  increased  from  by t h e c e r e b r a l s t i m u l a t i o n w i t h  reduction  spike  that  stimulus.  CS a c t i v i t y  ethanol.  ethanol  by i t s own  c o n t r i b u t i o n from  evoked  i s absent  divided  was c o n s t r u c t e d  activity  minor  h a s been  represented  histogram  PSTH  c a n be s e e n m o r e c l e a r l y  activity  each  CS o c c u r r i n g  very  i n the f i r s t  6.5  Similarly,  37.1 t o a l o w o f 13-3 the beginning  t o 16.5  of the  spikes ethanol  71  F i g u r e 4: An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n t h e e v o c a t i o n o f c o m p l e x s p i k e s i n a P u r k i n j e c e l l by s t i m u lation of te cerebral cortex. (A) Three p r e - e t h a n o l posts t i m u l u s time h i s t o g r a m s showing from t o p t o bottom: simple s p i k e a c t i v i t y ; complex s p i k e a c t i v i t y ; and l a t e n c y t o t h e f i r s t complex s p i k e a f t e r each s t i m u l i . ( B ) Same a s ( A ) , e x c e p t a f t e r e t h a n o l a d m i n i s t r a t i o n ( 1 . 5 g / k g , o v e r 10 m i n ) . The number a b o v e e a c h s e t o f h i s t o g r a m s i s t h e a v e r a g e d t o t a l spike rate during the period o f histogram construction. The numbers a b o v e t h e l a t e n c y h i s t o g r a m s a r e t h e number o f e v o k e d CS a n d t h e i r mean a v e r a g e l a t e n c y a n d SEM ( i n b r a c k e t s ) . E l e c t r i c a l s t i m u l a t i o n ( 1 H z , 0.4 ms d u r a t i o n , 2-4 V) o f t h e cortex occurred a t time zero. E a c h h i s t o g r a m was c o n s t r u c t e d f r o m 80 t r i a l s .  73  F i g u r e 5: The e f f e c t o f i n t r a v e n o u s e t h a n o l on s p o n t a n e o u s c o m p l e x s p i k e a c t i v i t y , and t h a t e v o k e d by c e r e b r a l e l e c t r i c al stimulation. The s o l i d l i n e r e p r e s e n t s t h e e f f e c t o f e t h a n o l on t h e a v e r a g e d r a t e o f s p o n t a n e o u s c o m p l e x s p i k e a c t i v i t y from nine neurones. The b r o k e n l i n e r e p r e s e n t s t h e e f f e c t o f e t h a n o l on t h e number o f c o m p l e x s p i k e e v o k e d o v e r 80 s t i m u l a t i o n s o f t h e c e r e b r a l c o r t e x (1 H z , 0.4 ms d u r a t i o n , 2-4 V) i n t h e same n e u r o n e s . Each p o i n t r e p r e s e n t s t h e a v e r a g e d d a t a f r o m nine P u r k i n j e c e l l s , a n d i s p l o t t e d a s mean a n d SEM. S i g n i f i c a n t d i f f e r e n c e from the p r e - e t h a n o l cont r o l s i s i n d i c a t e d by t h e a s t e r i s k s (p<0.05, S t u d e n t ' s p a i r e d t - T e s t ) . E t h a n o l ( 1 . 5 g / k g , o v e r 10 m i n ) w a s g i v e n o v e r t h e p e r i o d i n d i c a t e d by t h e s o l i d b a r .  • SPONTANEOUS COMPLEX SPIKES PER MINUTE  75 administration. min  after  This  ethanol  reduction  administration.  stimulation  was  IV .A.3.  Inferior Olive  The  The action  on  unit  ethanol  on  either  22.6  +/-  second  inferior  taneous  olive  neurones  typically  3.5  Their  acteristic recorded display  had  action  illustrating  ments  i s shown An and  in  by  administering  by  micropressure  spontaneous  neurone  firing  to  rate  to  the a  very  a recording  site  an  inferior both  effect  of  of  The  0 .4  were  to  •  char-  potentials 6.  sharp  They  onset  Occasionally,  this  triphasic configuration to  from  the one  ethanol  and  gradually  next  30  olive  cell. of  cell's  administered  rate  of  discharge  A  these  microexperi-  minutes.  The  response  to  intravenously, of  recovered  after harmaline  neurones.  spon-  ejection.  in Figure  initial  an  ethanol  rates  action  cell.  close  The  the  the  larger  8 .  over  the  7.  harmaline,  immediately 10  after  The  configurations  example of  approaching  example of  the  of  phase  in Figure  Figure  discharge eristic  slow  approached  graph  ethanol  tested  is illustrated  electrode  after  neurones.  locally  convert  22  has  recording  10  10  would  from  ethanol  from  an  configuration  4 through  latency  involved  from  upon  ed  neurones  An  seen  at  t e s t whether  neurones.  typically  shown  was  to  10  plateau  ethanol  mean CS  of  long  the  The  p o t e n t i a l (AP)  a  if  used  directly  or  significant  ms.  (10)  activity  intravenously  Hz.  1.4  method  activity  this  was  this  cell  toward  the  subsequent  administration  is  is  decreaspremassive charact-  76  F i g u r e 6: Three superimposed o s c i l l o s c o p e t y p i c a l a c t i o n p o t e n t i a l s f r o m an i n f e r i o r the long p l a t e a u phase.  traces showing olive cell. Note  77  F i g u r e 7: M i c r o g r a p h showing a t r a n s v e r s e s e c t i o n o f the caudal i n f e r i o r o l i v e . The a r r o w p o i n t s t o t h e d y e mark e j e c t e d by t h e r e c o r d i n g barrel  78  L I . 1 1 In  •  --s.ih^L.lliiiillkl  F i g u r e 8: An e x a m p l e o f a n i n f e r i o r o l i v e c e l l ' s r e s p o n s e t o i n t r a v e n o u s e t h a n o l and h a r m a l i n e . This figure represents a continuous e x t r a c e l l u l a r rate recording. E t h a n o l was g i v e n o v e r t h e p e r i o d i n d i c a t e d by t h e l o n g b a r ( 1 . 5 g / k g , i . v . , o v e r 10 m i n ) a n d h a r m a l i n e a t t h e a r r o w h e a d ( 5 m g / k g , i . v . ) . The v e r t i c a l a n d h o r i z o n t a l c a l i b r a t i o n b a r s i n d i c a t e 1 Hz a n d 3 min, r e s p e c t i v e l y .  79 Over in  a major  rate.  In  ethanol  Hz  to  a  low  t-Test)  to  firing In  ethanol  was  The  in  of  1.0  Hz  Firing  example of ethanol  an  was  at  by  inhibited  pressures  i t was  of  inhibited  can  from  be  a pre-ethanol min  after  did  not  four  their  olivary  the  start  (p<.05,  a l l times cause  mean  of paired  after  any  6  significant  firing  neurone's  ethanol,  ejection directly rate  studied.  firing  micropressure  i s shown  by  8,  22,  33,  and  3,  7,  10,  and  15  only  5%  by  the  cells.  micropressure on  experi-  control rate  systemically administered by  after  these  seen,  significantly  saline  firing  rate observed  c o n t r o l at  i n another  i t s effect  inferior  As  9-12  from  of  applied  administered  cell  ethanol  and  at  neuronal  results  from  r a t e was  different  rate  firing  9.  reduced  administration resulted  olive  averaged  Figure  a d d i t i o n to also  neurones  while  increased  Similar injections  changes  This  an  r a t e was  infusion.  Student's  10  was  illustrated firing  ethanol  min.  case  ethanol  o f mean i n f e r i o r  administration.  neuronal 1.7  reduction no  ments are  of  a l l , intravenous  77%  onto  An  rate response in Figure  by  to  10.  application  of  psi, respectively,  when s u c r o s e  was  applied at  19  psi . Table neurones of  nine  of  these  t-Test) at  an  which of  by  inhibited  possibility  extent  pressure. ethanol that  summary o f  the  responses  successfully tested.  fourteen  greater  equal  ficantly  were  the  were  I is a  but  these  cells to  a  was  decreased  by  significantly  by  ethanol  Two  other  had  The  no  than  by  inhibitions  the  fourteen  spontaneous ethanol.  (p<0.05, sucrose  neurones were  sucrose  of  administered  inhibited  solely  Seven  Student's  controls, allowing  w e r e due  firing  to  signithe  pressure  80  F i g u r e 9: The e f f e c t o f i n t r a v e n o u s e t h a n o l o n i n f e r i o r o l i v e neuronal f i r i n g rate. Each p o i n t r e p r e s e n t s the avera g e d d a t a f r o m t w e l v e n e u r o n e s , a n d i s p l o t t e d a s mean a n d SEM. E t h a n o l was a d m i n i s t e r e d d u r i n g t h e p e r i o d i n d i c a t e d by t h e s o l i d b a r ( 1 . 5 g / k g , o v e r 10 m i n ) . Significant differe n c e ( p < 0 . 0 5 , S t u d e n t ' s p a i r e d t - T e s t ) f r o m t h e two p r e e t h a n o l c o n t r o l s i s i n d i c a t e d by an a s t e r i s k .  81  (N=12)  Ethanol 1  -5  1  0  1  5  1  10  T i m e (min)  1  15  1  20  82  F i g u r e 10: An e x a m p l e o f t h e e f f e c t o f l o c a l e t h a n o l o n i n f e r i o r o l i v e neuronal f i r i n g . Each h i s t o g r a m r e p r e s e n t s the c e l l ' s f i r i n g over t h r e e minutes. Those i n the r i g h t m o s t column are the p o i n t w i s e averages of the histograms to t h e i r i m m e d i a t e l e f t . The n u m b e r s t o r i g h t i n d i c a t e t h e p e r c e n t decrease i n f i r i n g r a t e d u r i n g drug a p p l i c a t i o n ( i n d i c a t e d by the bars) from the c o r r e s p o n d i n g c o n t r o l p e r i o d i m m e d i a t e l y before. The n u m b e r a n d l e t t e r t o t h e l e f t o f e a c h r o w indic a t e t h e p r e s s u r e o f a p p l i c a t i o n ( p s i ) and t h e d r u g a p p l i e d , r e s p e c t i v e l y . Drug a p p l i c a t i o n o c c u r r e d d u r i n g the p e r i o d s i n d i c a t e d by t h e s o l i d b a r s . The v e r t i c a l a n d horizontal c a l i b r a t i o n b a r s a r e 1 Hz a n d 1 m i n , r e s p e c t i v e l y . C c o n t r o l , i . e . no d r u g a p p l i c a t i o n ; S - s u c r o s e c o n t r o l ; E ethanol.  83  10E  15E ^  afttfiafe itfl  84  TABLE neous  I : Summary o f t h e e f f e c t o f l o c a l e t h a n o l firing rate of inferior olive neurones.  Response Decreased F i r i n g Rate S i g n i f i c a n t l y More t h a n Decreased F i r i n g Rate b u t No S u c r o s e C o n t r o l s I n c r e a s e d F i r i n g Rate No C h a n g e Total  Number o f N e u r o n e s  on t h e s p o n t a -  Number o f  Sucrose  neurones  7 2 0 5  85 effects.  In  the  significantly sures  of  did  different  application.  reduction possibly  remaining  of  spike  effect In  neurones, than  three  amplitude  indicating  ethanol  five  did  ethanol  sucrose  neurones,  at  higher  the  firing  have  equal  pres-  at  ethanol  produced  application  a nonspecific effect.  increase  d i d not  a  pressures,  However,  r a t e above  a  that of  i n no  case  i t s sucrose  control.  IV.B.  Ethanol  on  There simple  and  increase tion,  ments which  increase due  to  result SS  ethanol's reported al.,  reduce  of  Again,  the  an  Although study,  the  CS  harmaline SS  SS  such  after  as  to  an  on  ethanol  due  to  treat-  3-acetyl-  Therefore,  the  a d m i n i s t r a t i o n may  the  neurone.  ethanol  firing  as has  (Sinclair  a direct  or  be  Another  a c t i o n such  Similarly, SS  or  which  stimula-  Conversely,  indirect  of  stimuli  electrical  ethanol  ethanol  be  or  activity.  activity.  may  example,  activity.  variability  this  For  between  been  et  indirect  ethanol. the  influence of  electrolytic trates  seen  i t i s due  the  inverse correlation  activity,  action of  Therefore, remove  CS  reduction of  1980).  action  as  in increased  i s that  to  an  activities.  such  activity  a direct  possibility  be  i n a reduction of decrease  of  to  spike  activity,  result  Spikes  appears  complex  CS  pyridine,  Simple  lesioning  example of each  lesion  histological  following CS  of  by the  experiments  eliminating inferior  a unilateral h a l t e d the examination  CS  their  olive.  inferior activity  found  were d e s i g n e d activity Figure  olive  PC  three  under of  the  illus-  lesion.  i n the  that only  11  via  to  the  86  Figure 1 1 : A micrograph of a transverse section through the inferior olive showing a unilateral electolytic lesion.  87 lesions fore,  appeared  climbing  trials  was  did  regularity  An lesioning  allow  to  be  SS  the  rates  are  intervals inferior  CS  e f f e c t s of  ethanol  the  of  o l i v e caused  the  complete  firing  rate  firing  to  42.3  Hz  This  r e s u l t was  Purkinje  firing  rate  effect  of  and  cells over  decreased  (p>0.05, p a i r e d  interspike  two  ethanol  lesioning  t-Test)  further  significantly  on  SS  rate,  an  of  CS  23  to  attempt  interspike the  increased  .65  and to  SS  ms. two  Purkinje  of  the  other  averaged cells,  ethanol not  of  corresponded  shows the  and  These  activity,  SS  and  the  administration. significantly  d i f f e r e n t from after  the  pre-lesion  ethanol  (p<0.05) d i f f e r e n t from  measuring  sponta-  Lesioning  further  reduction  pre-ethanol to  CS-CS  which  l e s i o n i n g was  Student's  addition  13  interval  a mean  i n a l l but  a l l eleven  10  after  post-lesion In  Figure  from  Hz,  10  of  cessation  ISI  activity.  respectively.  ethanol  the  and  administration  SS-SS and  33.2  repeated  olive  However, the was  reduced  tested.  time  ISI  to  Intravenous  inferior  istration  Hz,  as  CS  this  to  respectively.  ms.  and  1.3  ms,  30.2  the  and  most  cell  t h i s n e u r o n e had  775  of  of  14  several  and  ISI  values.  as  in  rate  a Purkinje  intravenous  12  SS  absence of  response of  There-  However,  on  of  an  The  i n the  Initially,  rates  SS  cortex  the  12  the  nucleus.  eliminated.  in Figure  57.1  10  cerebellar  r e f l e c t e d in Figure  increased  ten  the  completely  subsequent  (ISI).  and  the  investigated  i s shown  neous  to  destroy  not  example of  and  histograms  completely  f i b r e input  probably  treatment  ethanol  to  admin-  the  average  points. the  e f f e c t s of  was  made t o  10  lesioning  measure  the  o  effect  of  these  two  treatments  on  the  r e g u l a r i t y of  SS  firing  in  88  F i g u r e 12: The r e s p o n s e o f a P u r k i n j e c e l l t o e l e c t r o l y t i c l e s i o n i n g o f t h e i n f e r i o r o l i v e and t o t h e i n t r a v e n o u s admini s t r a t i o n of ethanol. ( A ) Two i n t e r s p i k e i n t e r v a l histograms o f ( t o p ) s i m p l e and ( b o t t o m ) c o m p l e x s p i k e s b e f o r e inferior o l i v e l e s i o n i n g and e t h a n o l a d m i n i s t r a t i o n . ( B a n d C) S i m p l e spike i n t e r s p i k e i n t e r v a l histograms: (B) i m m e d i a t e l y after i n f e r i o r o l i v e l e s i o n i n g a n d ( C ) 18 m i n u t e s a f t e r t h e s t a r t o f e t h a n o l a d m i n i s t r a t i o n . The n u m b e r s a b o v e e a c h histogram r e p r e s e n t t h e mean i n t e r v a l b e t w e e n t w o s u c c e s s i v e s p i k e o f t h e same t y p e a n d SEM ( i n b r a c k e t s ) , a n d t h e n u m b e r (N) o f i n t e r v a l s used to c a l c u l a t e them. Means w e r e c a l c u l a t e d w i t h i n t e r v a l s up t o 2 5 0 ms b u t w e r e p l o t t e d t o 200 ms only. C o u n t s a t g r e a t e r t h a n 200 ms w e r e a d d e d i n t o t h e b i n a t 200 ms .  89  SS-SS <N=445> 57. 68 <1.87) • * t » - » J - • »• .1.  J — •  1. •  —«-  CS-CS <N=68> 775.65 < 56.94 >  200  ms  6400 m: 100  100n  SS-SS <N=1997> 30 . 16 < . 18) 200  ms  200  ms  SS-SS <N=1997> 23.65 < . 11 )  90  F i g u r e 13: The e f f e c t o f i n f e r i o r o l i v e l e s i o n i n g and i n t r a v e n o u s e t h a n o l a d m i n i s t r a t i o n o n t h e mean i n t e r s p i k e i n t e r v a l between P u r k i n j e c e l l s i m p l e s p i k e s . Each p o i n t r e p r e s e n t s t h e a v e r a g e d d a t a from e l e v e n P u r k i n j e c e l l s , and i s p l o t t e d a s mean a n d S E M . The i n f e r i o r o l i v e was l e s i o n e d a t t h e t i m e d e n o t e d b y b y t h e a r r o w h e a d ( a t t i m e -4 m i n ) , a n d e t h a n o l was a d m i n i s t e r e d d u r i n g t h e p e r i o d i n d i c a t e d b y t h e b a r ( 1 . 5 g / k g , o v e r 10 m i n ) . T h e i n t e r s p i k e i n t e r v a l s w e r e n o r m a l i z e d around t h e two l e s i o n e d c o n t r o l s ( i . e . t i m e s -2.5 and z e r o min) .  91  IV ETHANOL ON PC'S AFTER 10 LESIONINS (o) (N=ll)  63 n  92 these the  same P u r k i n j e c e l l s .  mean  time  interspike  point  resulting ularity  Ethanol  on L o c a l  antagonizes  stimulation  resulting  ethanol  a dose  a t which This  cells of  evoked  tested  these  ethanol  sucrose  intravenous  that  intravenous  irregularity.  ethanol  surface  by  of ethanol  stimula-  response  i n Figure  period,  on  were this  micropressure.  of locally  had l i t t l e  from  effect  to  local  applied ethanol 15.  In t h i s  on  case,  3 4 . 0 t o 1 3 . 3 ms, (35.5 ms).  e x a m p l e was r e p r e s e n t a t i v e o f t h e m a j o r i t y o f  i n this  manner, and T a b l e Eight  shortened  inhibitory  were  shortened  significantly  ance  could  at  locally  the i n h i b i t o r y  experiments.  55%  values  The f o l l o w i n g e x p e r i m e n t s  i s shown  have  reduced  irreg-  t o 2.2, t h e  SS  by t h e l o c a l  and t h e e f f e c t  inhibition,  shortened  SS  upon  example o f a P u r k i n j e c e l l ' s (LOC),  The  Inhibition.  the i n h i b i t i o n  An  at  effect  of  a t each  pre-lesion  Similarly,  l a b o r a t o r y has reported  by a p p l y i n g  9.2  from  to further investigate the effect  inhibition  the  t-Test).  Although  from  different  of the cerebellar cortex.  designed  variance  was a v e r a g e d  14.  10 l e s i o n i n g ,  a l s o h a d no s i g n i f i c a n t  This  tion  Student's  a l l cells  i n Figure  was n o t s i g n i f i c a n t l y  (p<0.05, p a i r e d  IV.C.  after  from  the scaled  a m e a s u r e o f SS i r r e g u l a r i t y .  i s displayed  was r e d u c e d  reduction  ethanol  interval  and r e p r e s e n t s curve  To do t h i s ,  I I summarizes  o f the twelve  periods  after  (p<0.05).  cells  ethanol.  t h e same p r e s s u r e  of ethanol  increased  firing  were  found  Seven  In the eighth,  n o t be c a l c u l a t e d , b u t i t s i n h i b i t o r y by a p p l i c a t i o n  the results  period  a t 12 p s i , w h i l e by o n l y  4%.  of  to these  significwas sucrose  Another  93  F i g u r e 14: The e f f e c t o f i n f e r i o r o l i v e l e s i o n i n g and i n t r a v e n o u s e t h a n o l on P u r k i n j e c e l l s i m p l e s p i k e r e g u l a r i t y o v e r t i m e . E a c h p o i n t r e p r e s e n t s t h e a v e r a g e d d a t a f r o m f r o m 11 c e l l s , a n d i s p l o t t e d a s mean a n d SEM. The i n f e r i o r o l i v e was l e s i o n e d a t t h e t i m e d e n o t e d b y a r r o w h e a d (-4 m i n ) , a n d e t h a n o l was a d m i n i s t e r e d d u r i n g t h e p e r i o d i n d i c a t e d by t h e s o l i d b a r ( 1 . 5 g / k g , o v e r 10 m i n ) . The o r d i n a t e r e p r e s e n t s t h e v a r i a n c e o f t h e i n t e r s p i k e i n t e r v a l d i v i d e d b y i t s mean and m u l t i p l i e d by 1 0 0 0 . The p o i n t s w e r e n o r m a l i z e d t o t h e a v e r a g e o f t h e two l e s i o n e d c o n t r o l s ( i . e . t i m e p o i n t s -2.5 and z e r o ) .  94  E f f e c t of l , v , Ethanol on SS R e g u l a r i t y (o) A f t e r 10 L e s i o n i n g (n=ll)  20 n  Time  (min)  95  F i g u r e 15: The e f f e c t o f l o c a l e t h a n o l on t h e i n h i b i t i o n o f a P u r k i n j e c e l l e v o k e d by l o c a l s t i m u l a t i o n . The t h r e e p o s t s t i m u l u s h i s t o g r a m s r e p r e s e n t r e p o n s e s (A) b e f o r e d r u g a p p l i c a t i o n , (B) d u r i n g s u c r o s e a p p l i c a t i o n (12 p s i ) , and (C) d u r i n g ethanol a p p l i c a t i o n (12 p s i ) . L o c a l s t i m u l a t i o n o c c u r r e d a t t i m e z e r o . The r e s u l t i n g h i s t o g r a m s w e r e s m o o t h e d by a r u n n i n g a v e r a g e ( 2 5 ms w i d t h ) a n d t h e t i m e t o 50% o f t h e r a t e d u r i n g t h e l a s t 25 ms measured (1-50%). T h i s t i m e i s i n d i c a t e d by t h e a r r o w a n d q u a n t i t a t e d by t h e n u m b e r a b o v e e a c h h i s t o g r a m . Electrical s t i m u l a t i o n (1 H z , 0.5 ms d u r a t i o n , 5.5 V) o f t h e c e r e b r a l cortex occurred at time zero. E a c h h i s t o g r a m was constructed f r o m 50 trials.  96  I-58V.  :  34 MS  260 MS I-503s = 35.5 MS  200 MS I-503s < 13.26 MS  +  200 MS  97  TABLE I I : Summary o f t h e e f f e c t o f l o c a l e t h a n o l on t h e p e r i o d o f i n h i b i t i o n e v o k e d by l o c a l s t i m u l a t i o n o f t h e c e r e b e l l a r cortex . Response  Number o f n e u r o n e s  Decreased I n h i b i t o r y Increased I n h i b i t o r y No C h a n g e Total  Number o f  Period Period  Neurones  8 1 3 12  responding  98 cell's  inhibitory  sucrose  control,  remaining IV.D.  cells  Ethanol  evoked  butyric above, the ly  this  of ethanol  by  a p p l i e d GABA  example  the ethanol  to  o f GABA after  since  ten minutes  (83%)  g/kg,  reported Therefore,  induced  either  by  local-  included  intravenously  appears  t o have  i n Figure antagonized  the start  firing  of ethanol  by  In this  the inhibitory evoked  b y GABA w a s  Initially,  by a b o u t  82%. S i x  administration, this  t o 65% but had r e t u r n e d  to control  levels  23 m i n . 17 s u m m a r i z e s  a p p l i e d GABA  i . v . over  cell  administered  SS f i r i n g 16.  t h e amount o f i n h i b i t i o n  I t shows t h e a v e r a g e d  mean r e d u c t i o n  of intravenously  of a Purkinje cell's  o f GABA r e d u c e d  after  Figure  locally  was a d m i n i s t e r e d  i s illustrated  was r e d u c e d  by a b o u t  iments.  o f PC  the administration of the ethanol.  application  inhibition  As was  The f o l l o w i n g e x p e r i m e n t s  example o f t h e e f f e c t  locally  each  t o be g a m m a - a m i n o -  micropressure.  on t h e i n h i b i t i o n  reduced  f o r the i n h i b i -  by e t h a n o l .  on t h e i n h i b i t i o n  ethanol  action  changed.  e t a l . , 1971).  i s antagonized  ethanol  i t s  o f the three  s t i m u l a t i o n i s thought  inhibition  over  Inhibition.  (GABA, Woodward  An  periods  putative transmitter responsible  i n which  locally  significantly  were n o t s i g n i f i c a n t l y  a p p l i e d GABA w a s s t u d i e d .  protocols or  the inhibitory  by s u r f a c e  acid  effect  while  was l e n g t h e n e d  o n L o c a l GABA  The tion  period  the results response  of this  of cell  Before  firing  ethanol  produced  exper-  o f 12 P u r k i n j e c e l l s  and i n t r a v e n o u s l y a d m i n i s t e r e d  10 m i n ) .  set of  to  ethanol (1.5  administration, the  b y e a c h GABA  application  99  F i g u r e 1 6 : An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n t h e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d b y GABA a p p l i e d l o c a l l y by m i c r o p r e s s u r e . The m a i n b l o c k o f 35 h i s t o g r a m s represents a continuous record of the c e l l ' s f i r i n g rate. Each o f the histograms i n t h e r i g h t m o s t column i s t h e p o i n t w i s e average of the f i v e histograms t o i t s immediate l e f t . The number t o i t s r i g h t i s t h e p e r c e n t i n h i b i t i o n p r o d u c e d by t h e a p p l i c a t i o n o f GABA ( f o r 20 s d u r i n g t h e p e r i o d s i n d i c a t e d b y t h e b a r s ) f r o m t h e c o n t r o l p e r i o d ( t h e 20 s i m m e d i a t e l y p r e c e d i n g t h e bar). The l o n g b a r s i n d i c a t e t h e p e r i o d o f a p p l i c a t i o n o f e t h a n o l ( 1 . 5 g / k g , i . v . o v e r 10 m i n ) . The v e r t i c a l and h o r i z o n t a l c a l i b r a t i o n b a r s r e p r e s e n t 2 5 Hz a n d 20 s e c , r e s p e c t ively.  100  101  F i g u r e 17: The e f f e c t o f i n t r a v e n o u s e t h a n o l on t h e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d by l o c a l GABA. The s o l i d l i n e r e p r e s e n t s t h e s p o n t a n e o u s f i r i n g r a t e d u r i n g t h e p e r i o d s w h e n GABA was n o t b e i n g a p p l i e d . T h e b r o k e n l i n e r e s p r e s e n t s t h e a m o u n t o f i n h i b i t i o n e v o k e d b y a p p l i c a t i o n o f GABA ( p e r c e n t decrease o f f i r i n g r a t e f r o m t h e i m m e d i a t e l y p r e c e d i n g 20 s e c o n d s ) . Each p o i n t r e p r e s e n t s t h e averaged data from t w e l v e neurones, a n d i s p l o t t e d a s t h e mean a n d S E M . E t h a n o l was a d m i n i s t e r e d d u r i n g t h e p e r i o d i n d i c a t e d by t h e s o l i d b a r ( 1 . 5 g / k g , i . v . o v e r 10 m i n ) . S i g n i f i c a n t d i f f e r e n c e f r o m t h e a v e r a g e d p r e e t h a n o l c o n t r o l s i s i n d i c a t e d by a s t e r i s k s (p<0.05, Student's paired t-Test).  102  E f f e c t of I.v, E+honol on (x) PC F i r i n g Ro-te (n=12) (o) up-GflBfl Inhlbl-tlon o f PC (n=12) 80-i  103  was  6 5 .8% .  istration returned  S i x to ten minutes this  value  Student's  the start  had f a l l e n t o 5 4 . 0 % . of 58.1%.  to a value  inhibition  after  of ethanol  By 25 m i n i t h a d  The o b s e r v e d  reduction of the  b y GABA w a s s i g n i f i c a n t l y ( p < 0 . 0 5 ,  evoked t-Test)  reduced  a t the time  admin-  point  paired 6 and 2 0  between  minutes . An the  example  of the effect  i n h i b i t i o n o f PC f i r i n g  18.  In this  reduced 76%  cell  t h e GABA  reduction  b y e x o g e n o u s GABA  application evoked  in firing  of l o c a l l y applied ethanol  of ethanol  i n h i b i t i o n from  minutes  after  minutes  t h e i n h i b i t i o n had r e t u r n e d 19 summaries  Figure had  on a b s o l u t e  GABA.  only  the  start  of ethanol  of the c e l l s  only  reduced  to  application.  i t b y 1 2 . 7 Hz a t 2 . 5 also  caused  rate,  from  5 minutes  after  the start  cent  o f GABA  change  ethanol  from  induced control,  application  By  2.5  ethanol  produced  nine  by  Purkinje  after  t h e mean  firing  was a p p l i e d , b u t  a significant ethanol  of application.  However, t h e  fall  i n PC  sponta-  t o 2 3 . 8 Hz a t 2 . 5 Therefore,  expressed  the  as a  was n o t s i g n i f i c a n t l y c h a n g e d 20) .  (76%) .  levels  t o 5 minutes  to 5 minutes.  i n h i b i t i o n , when  ( Figure  thirteen  t h e i n h i b i t i o n b y GABA  ethanol  2 7 . 8 Hz b e f o r e  firing  from  GABA r e d u c e d  b y 1 5 . 3 Hz b e f o r e  application  reduction  from  firing  of a  to 7.5  locally applied  results  s i g n i f i c a n t l y antagonized  rate  ethanol  to pre-ethanol  by t h e a s t e r i s k s ,  value  at 2.5  application.  inhibition of Purkinje cell  As i n d i c a t e d  was  a pre-ethanol  the effect  I t i l l u s t r a t e s the averaged  cells.  neous  of ethanol  i n Figure  micropressure  to a 63% reduction  rate  the beginning  by  i s shown  on  per-  by t h e  104  F i g u r e 1 8 : An e x a m p l e o f t h e e f f e c t o f l o c a l e t h a n o l o n t h e i n h i b i t i o n o f a P u r k i n j e c e l l i n d u c e d by l o c a l GABA. The b l o c k o f 30 h i s t o g r a m s r e p r e s e n t s a c o n t i n u o u s r a t e r e c o r d i n g o f t h e neurone. Each h i s t o g r a m i n t h e r i g h t m o s t column i s t h e p o i n t wise average o f t h e f i v e histograms t o i t s immediate l e f t . The a s s o c i a t e d number r e p r e s e n t s t h e p e r c e n t i n h i b i t i o n p r o d u c e d by t h e a p p l i c a t i o n o f GABA ( f o r 10 s d u r i n g t h e p e r i o d s i n d i c a t e d by t h e b a r s ) f r o m t h e c o n t r o l p e r i o d ( t h e 10 s p r e c e d i n g t h e b a r ) . The l o n g and s h o r t h o r i z o n t a l b a r s i n d i c a t e t h e p e r i o d o f a p p l i c a t i o n b y m i c r o p r e s s u r e o f e t h a n o l a n d GABA, r e s p e c t i v e l y . The v e r t i c a l a n d h o r i z o n t a l c a l i b r a t i o n b a r s r e p r e s e n t 2 5 Hz a n d 10 s , r e s p e c t i v e l y .  76 68 63 63 66  106  F i g u r e 19: The e f f e c t o f l o c a l l y a p p l i e d e t h a n o l on t h e a b s o l u t e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d by l o c a l l y a p p l i e d GABA. The l e f t m o s t b a r o f e a c h p a i r r e p r e s e n t s s p o n t a n e o u s f i r i n g r a t e o f t h e n e u r o n e s d u r i n g t h o s e 20 s p e r i o d s immedi a t e l y b e f o r e GABA a p p l i c a t i o n , w h i l e t h e r i g h t m o s t r e p r e s e n t s t h e a v e r a g e d a b s o l u t e i n h i b i t i o n o f f i r i n g r a t e e v o k e d by t h e 20 s a p p l i c a t i o n o f G A B A . E a c h b a r r e p r e s e n t s t h e d a t a f r o m n i n e n e u r o n e s o v e r 2.5 m i n . T h e b a r s r e p r e s e n t mean a n d S E M . E t h a n o l was a p p l i e d d u r i n g t h e c o l l e c t i o n o f t h e c e n t r a l b a r s . The l e f t p a i r o f b a r s a r e t h e c o n t r o l r a t e a n d i n h i b i t i o n , w h i l e t h e r i g h t p a i r i s t h e r e c o v e r y v a l u e s a t 5-7.5 a f t e r t h e application of ethanol. Bars s i g n i f i c a n t l y d i f f e r e n t from c o n t r o l a r e i n d i c a t e d by a s t e r i s k s ( p < 0 . 0 5 , p a i r e d Student's t-Test) .  RRTE OR ABSOLUTE INHIBITION (HZ) cn _I_  ?0  CO  _L_  _J_  108  F i g u r e 2 0 : The e f f e c t o f l o c a l e t h a n o l on t h e r e l a t i v e i n h i b i t i o n o f P u r k i n j e c e l l s i n d u c e d by l o c a l l y a p p l i e d GABA. The d a t a was c a l c u l a t e d a s t h e p e r c e n t d e c r e a s e o f s i m p l e s p i k e f i r i n g d u r i n g 2 0 s o f a p p l i c a t i o n o f GABA b y m i c r o p r e s s u r e f r o m t h e i m m e d i a t e l y p r e c e d i n g c o n t r o l 20 s . E a c h b a r r e p r e s e n t s t h e a v e r a g e d d a t a f r o m n i n e n e u r o n e s a n d o v e r 2.5 m i n , a n d i s p l o t t e d a s t h e mean a n d S E M . E t h a n o l was a p p l i e d by m i c r o p r e s s u r e d u r i n g c o l l e c t i o n o f t h e d a t a m a k i n g up t h e m i d d l e p a i r o f b a r s . None o f t h e b a r s a r e s i g n i f i c a n t l y d i f f e r e n t f r o m t h e i r c o n t r o l s (p>0.05, p a i r e d t w o - t a i l e d S t u d e n t ' s t-Test).  PERCENT INHIBITION Qt  _l_  Q _L_  Q _i_  GO _L_  Q -J  II  UD  o  m  110 The marized  i n Table  firing but  from  I I I .  inhibition, reduced  this  when e x p r e s s e d four  third  decrease of  of the c e l l s .  as percent  of the nine  i t was u n c h a n g e d  absolute  a r e sum-  i n the m a j o r i t y o f P u r k i n j e c e l l s (6/9)  i n the remaining  i n only  s e r i e s of experiments  The G A B A - i n d u c e d  r a t e was r e d u c e d  unchanged  cells  results  decrease  from  neurones, while  and i n t h e r e m a i n i n g  However, t h e control,  i n two  three  was  other  i t was  enhanc-  ed .  IV.E.  Ethanol  on G o l g i  Golgi circuitry ly  and t h e i r  studied.  the  effect  cells  cells  Therefore, of ethanol  cell  spontaneous  time  of five cells'  from  Student's  t-Test)  this  n o t been  previous-  were d e s i g n e d firing  to  study  rate of Golgi  o f these  cells  evoked  cells  I t shows t h e a v e r a g e d  by  rates  (p>0.05,  of intravenously  10 m i n ) o n t h e p e r i o d  The l o n g  lasting  by e t h a n o l ,  the start  response  over  ethanol. different  paired  time.  of ethanol  from  period  administered  of inhibition  by s t i m u l a t i o n o f t h e i n f e r i o r 22.  on G o l g i  r a t e was n o t s i g n i f i c a n t l y  of the pre-ethanol a t any  of ethanol  to intravenously administered  firing  was r e d u c e d  after  the effect  example o f t h e e f f e c t  i n Figure  cell  minutes  the i n h i b i t i o n  discharge.  (1.5 g/kg, over  cell  trated  on t h e s p o n t a n e o u s  of the cerebellar  have  experiments  summarizes  averaged  An  Golgi  to ethanol  these  upon  21  Golgi  the average  ethanol  part  olive stimulation. Figure  The  a r e an i n t e g r a l  responses  and i t s e f f e c t  inferior  Cells.  olive  of a  i s illus-  of inhibition i n  7 7 4 t o 6 0 0 ms,  administration.  at 5  B y 21 m i n -  111  TABLE I I I : Summary o f t h e e f f e c t o f l o c a l e t h a n o l on t h e i n h i b i t i o n o f P u r k i n j e c e l l s e v o k e d by l o c a l l y a d m i n i s t e r e d gamma-aminobutyric acid. Response  Number o f n e u r o n e s Absolute  Inhibition  Relative  Inhibition  Decreased I n h i b i t i o n (>10% c h a n g e ) Increased Inhibition (>10% c h a n g e ) No C h a n g e (<10% c h a n g e )  6  4  0  2  3  3  Total  9  9  Neurones  112  F i g u r e 21: The e f f e c t o f i n t r a v e n o u s e t h a n o l on t h e s p o n t a neous f i r i n g r a t e o f G o l g i c e l l s . Each p o i n t r e p r e s e n t s the a v e r a g e d d a t a f r o m f i v e c e l l s , a n d i s p l o t t e d a s t h e mean a n d SEM. E t h a n o l was a d m i n i s t e r e d d u r i n g t h e p e r i o d i n d i c a t e d by t h e s o l i d b a r ( 1 . 5 g / k g , o v e r 10 m i n ) . None o f t h e p o i n t s a r e significantly d i f f e r e n t f r o m t h e a v e r a g e o f t h e two pre-ethanol c o n t r o l s (p>0.05, p a i r e d S t u d e n t ' s t-Test).  113  EFFECT OF IV ETOH ON (o) GOLGI CELL FIRING RATE (N=5)  15-i  5H  Ethanol  0H -10  1  1  1  1  1  1  0  10  20  30  40  50  TIME  (MIN)  114  F i g u r e 22: An e x a m p l e o f t h e e f f e c t o f i n t r a v e n o u s e t h a n o l o n t h e i n h i b i t i o n o f a G o l g i c e l l e v o k e d by s t i m u l a t i o n o f t h e inferior olive. The t h r e e p o s t - s t i m u l u s h i s t o g r a m s w e r e c o n s t r u c t e d ( A ) p r e - e t h a n o l a n d ( B ) 5 m i n a n d ( C ) 21 m i n after s t a r t of e t h a n o l . In each of the histograms the p e r i o d of i n h i b i t i o n was m e a s u r e d by s m o o t h i n g t h e h i s t o g r a m w i t h a m o v i n g a v e r a g e ( 2 5 0 ms w i d t h ) a n d d e t e r m i n i n g t h e 1 - 5 0 % , t h e t i m e a t w h i c h t h e f i r i n g r a t e r e t u r n e d t o 50% o f t h e c o n t r o l p e r i o d ( t h e r i g h t m o s t 25 p o i n t s ) . T h i s t i m e i s i n d i c a t e d by t h e a r r o w a n d q u a n t i f i e d by t h e v a l u e a b o v e e a c h h i s t o g r a m . The i n f e r i o r o l i v e was e l e c t r i c a l l y s t i m u l a t e d ( s i n g l e p u l s e , 1-2 H z , 0.5 ms) a t t i m e z e r o . E t h a n o l was administered i n t r a v e n o u s l y o v e r 10 min (1.5 g / K g ) .  115  I-505J: 773.75 MS  A  1-505:: 746.66 MS  ii  +  iiii,  2000 MS  116 utes  i t h a d r e t u r n e d t o 7 4 7 ms,  rate  had  shown  i n Figure  inhibitory of  period  inhibition  administration inhibitory  23. was  The about  average 70 ms  data  from  latency  these  the  firing  b y 10 s t i m u l a t i o n  was  experiments  to the start  ( r a n g e 53-80 m s ) .  Student's t-Test) reduced  The  of the period  significantly after  the intravenous  o f e t h a n o l a t 1 0 , 1 5 , a n d 20 m i n , r e d u c i n g t h e  period  By f o r t y  pre-ethanol  o f the averaged  evoked  (p<0.05, p a i r e d  ively.  case  decreased. The g r a p h  is  although i n this  from  5 2 0 t o 4 1 2 , 4 1 2 , a n d 4 3 6 ms,  minutes  value.  i t had a l m o s t  respect-  r e t u r n e d ( 5 0 3 ms)  to the  117  F i g u r e 23The e f f e c t o f i n t r a v e n o u s e t h a n o l on t h e i n h i b i t i o n o f G o l g i c e l l s e v o k e d by s t i m u l a t i o n o f t h e i n f e r i o r o l i v e . Each p o i n t r e p r e s e n t s t h e averaged data from f i v e c e l l s , plott e d a s t h e mean a n d SEM. E t h a n o l ( 1 . 5 g / k g ) was a d m i n i s t e r e d d u r i n g t h e p e r i o d i n d i c a t e d by t h e s o l i d b a r . The i n f e r i o r o l i v e w a s e l e c t r i c a l l y s t i m u l a t e d ( s i n g l e p u l s e , 1-2 H z , 0.5 ms) a t t i m e z e r o . The a s t e r i s k s i n d i c a t e t h o s e t i m e p o i n t s a t w h i c h t h e mean p e r i o d o f i n h i b i t i o n d i f f e r e d s i g n i f i c a n t l y from the p r e - e t h a n o l c o n t r o l (p<0.05, p a i r e d S t u d e n t ' s t - T e s t ) .  118  EFFECT OF IV ETOH ON (o) 10 STIM INHIBITION OF GOLGI (N=5)  600 -i  300 H -10  , 0  1  ,  ,  ,  ,  10  20  30  40  50  TIME  (MIN)  119 V.  V.A.  Ethanol  on  Complex  DISCUSSION  Spikes  Spontaneous complex to  be  reduced  after  spike  intravenous  ethanol  that  action of  ethanol  was  the  climbing  fibre-Purkinjecell  synapse  to  ity  arriving  on  spike  stimulation, studied.  and  the  fact,  effected  by  neous  activity  CS  result  ethanol  CF  the  dendritic  cells  are  cessation extended was  SS  time.  the  even  reduced  ethanol  the  to  activity,  at  fibres  to  of  an  ethanol be  This  the  the  and  often  stimula-  in  was  activity  parallel. not  when  sponta-  (p<0.001).  to  that  complete for  f o r CS  an  ethanol  synapse.  the  as  results  Purkinje  cause  this  the  covering  This  when  surprizing  of  unexpected  continues  required  This  security  i s not  as  activ-  evoked  times  the  of  electrical  reduced  Indeed,  safety of  voltage  failure  i s extensive,  extent  activity  the  this  We  hypothesis,  activity  reduce  security.  in decreasing  this  m u l t i p l e synapses.  such CS  be  those  synapse.  reported  a  transmit  spontaneous  CS  I t i s , t h e r e f o r e , not  stability  upon  Purkinje cell  synaptic  to  juxtafastigial  would  does not  been  due  test  significantly  forming  damaged, even of  by  ethanol  activity  infusion,  was  degree of  implies that  climbing  of  To  predicts that  spike  t r e e and  ineffective  addition, tion  effect  innervation of  a high  evoked  fibre-Purkinjecell  the  in  fibre.  stimulation-evoked  implies that  climbing  was  hypothesis  complex  In  climbing  activity  The  tion-evoked  the  has  administration.  hypothesized  complex  this  activity  In  activa-  also did  not  effect  ability  of  a c t i v a t e d by  the  electrical stimulation.  120 Complex evoked 1977; the  by  above,  e t a l . , 1978) .  complex  and  the  venous e t h a n o l confirming Lo, CS  confirming  has  spontaneous  reports  ( f o r example  to reduce  CS  the  site  the  fibres,  the  inferior  two  reduction  the  actions  inferior  10, would  olive  interposed  while  ity  isolated  polysynaptic  Kalant  and  account these  Woo,  for only  has  nerves  1964),  CS  been  fibres  1981).  mechanisms would  be  the  with  the  of action i s the  could  source  of  reflect  between  the  site  10  the  reported  of  neurones.  stimulaThe  e x c i t a t o r y input CS  rate.  of the  An  two  former to  to increase  the  and  sensitiv-  Binstock,  since  cortical  unlikely  input  to produce  on  possibilities  s e n s i t i v e to ethanol  total  the  action  quite  the  a  s t i m u l a t i o n , an  to s t i m u l a t i o n (Armstrong  a portion of  of  the  likely  However,  again  by  reduce  pathways are  evoked  et a l . , 1977).  site  activity  consequently decrease  ethanol  ms,  and  olive.  a c t i o n on  i s t h e more  1.4  s t i m u l a t i o n and  interposed  presumably  and  of  o f evoked  a direct  synapses  since, of  or  Intra-  Sinclair  Together  implies ethanol's  of c o r t i c a l  synapses  cerebral  the a b i l i t y  activity.  between  +/-  to  significantly,  Freedman  significantly  intermediate  of  eta l . ,  measured.  e t a l . , 1980;  reports  recruitment  be  similar  the  activity  previous  The  to  s t i m u l a t i o n of the c e r e b r a l cortex  result  and  CS  l a t e n c y o f 22.6  climbing  from  ethanol  average  found  reported  (Freedman  evoked  (Sinclair  s t i m u l a t i o n to evoke  inhibition  was  of intravenous  this  tion  been  an  above,  reduced  also  In a s e t of experiments  activity  decreased  with  was  finding  effect  Electrical  activity  cortical  spike  previous  1981).  Ethanol  activity  s t i m u l a t i o n of the c e r e b r a l cortex  Hoffer  cortex,  spike  (cf.  projections  to the the  10,  both  parallel  of  121 reduction study.  of  spontaneous  Therefore  and  i t can  be  CS  either  inhibiting  the  synapses  olive  neurones  themselves.  This  proposal  i s supported  experiments  micropressure the  10  on  reduction of  m e n t s may  total  where the  have  effect  due  to  olive  neurones,  afferent  input  to  upon  synapses  clear  that  or  ethanol  have r e f l e c t e d  tions  the  at  depression  of  has  between  local  the  depressant  result  in mild In  systemically increase  i n 10  conflict  with  Specifically,  neurone.  effects  on  to moderate  any  event,  or  locally neuronal  the they  data have  on  may  10  local  few  However,  neuronal  i t is  area  by  or  of  local of  the  concentra-  cause n o n - s p e c i f i c action  cells,  results  the  neurones  produced to  experi-  upon  immediate  enough  by  a m o d i f i c a t i o n of  nearby  However, a l t h o u g h  and  the  Again,  ethanol  activity  have  in a  by the  i n these  neurones. i n the  membrane h i g h  systemic  of  a non-specific inhibition  changes were noted the  be  was  or  studied.  reflected  spontaneous  application  cellular  configuration ence  reduction of  results  observed  10  ethanol  applied ethanol  either  the  a c t i o n must  The  since  on  the  action of  have  neurones,  recording.  neurones  may  this  f o r example  r a t e was  a direct  in  i t s neurones,  by  activity  seen  the  10,  the  locally  firing  impinging  ethanol's  may  of  spontaneous  these  to  t e r m i n a t i n g on  inferior  the  input  neuronal  been  activity  postulated that  depressing  inferior  the  evoked  potential  the  correspond-  implies that  activity  at  ethanol  levels  which  intoxication.  i n none o f  the  administered firing  trials,  e t h a n o l , was  rate observed.  reported reported  by an  with  Rogers  et  increased  a  This  either significant is in  a l . ( 1980, PC  direct  1982).  activity  after  122 intraperitoneal peritoneal unit  ethanol  recordings  1980), tials al.,  injection  and  recorded 1982)  ethanol.  increases  from  single  of  Purkinje  and  from  both  cells  multiple  the  unit  inferior  a  s e r i e s of  Sinclair  et  respired  rats, failed  18  a l . (1982)  i t , thus  1980;  after  exhibited  a  the  bursts  spike  because the died  bursting within  blood  15  or  from  (Bloom  et  single  et a l . ,  field  g/kg,  caused  not  CS  poten-  i . p . , Roger  et  not  In  appear  those  of  to  due  be  halting artificial  of  majority  bursting blood  500  behaviour  ethanol  about  and this  reported  cause  other route that  bursting  the  to  9  that in  min  Purkinje  by  of  animals  resulted  i n the  Rogers  administration  the  very after  cells.  been r e p o r t e d  have  to  laboratory  expressed (Grupp,  agents,  i n an  (6/8)  halted  concluded  l e v e l s have  behaviour  and  anoxia  non-respired  at  et  complex  the  mg/100 m l  anaesthetic  7  cells  typical  which  reseachers of  between  configuration  I t was  ethanol,  de-  (Sinclair  respiration also of  injection.  l e v e l s (about  the  in  rather  findings  most o f  However,  i.p.),  but  addition,  injection  The  Rogers' e t anaesthesia,  g/kg,  activity,  previous  1981).  resemble  (4  intraperitoneal administration  (1980) has can  Lo,  behavior.  did  ethanol  their  i n j e c t i o n s of  a l . , 1982)  reservations  ethanol,  (2  Roger and  intra-  from  including; halothane  that  ethanol  minutes  non-uniform  result  Roth  did  ethanol  injection), Indeed,  g/kg,  activity  olive  increase  behaviour.  intraperitoneal high  the  they  reducing  to  and  bursting  Also  found  confirming  Sinclair  minutes  spikes.  (1-4  recorded  e x p e r i m e n t s which repeated  a l . ' s .experimental parameters>  al.,  rate,  that  . In  creased  CS  They r e p o r t e d  1980).  including  isolated crayfish  123 stretch which iour  receptor  cause has  complete  tissue  that  "Lo . ( 1 9 8 2 )  was  Purkinje creased  cell CF  olive by  al.  due  Rogers  et  ( 1982)  potential  low  by we  10  activity  the  those  was  behav-  (1980a,b) this  by  i t  was  can  Sinclair  ethanol not  in  behaviour  Therefore,  of  their  are  due  and to  cell  since  examinations  details  the  were  studied.  wait  further studies.  i n these  and  altered  an  that the  in-  the  effect  of  firing  Roger  et  of  these  level  experiments  they  may  the  et  physi-  hindpaw. of and  cells  cells  in  this  action and as  a l . (1982) d i d the  repre-  Rogers  and/or  harmaline,  a l l indentified  infer-  that  studied.  population  neuronal  and  latter  contralateral the  on  ethanol  Alternately,  c h a r a c t e r i z a t i o n of  Resolution  study  reflect  populations  the  Unfortunately, of  ethanol  neurones h i s t o l o g i c a l l y  confident  neurones  used  of  in this  also  i.p.).  i n the  effect  found  dose  (2 g/kg,  the  may  s t i m u l a t i o n of  neurones.  include  between  characteristics,  histological olive  and  below  bursting  reported  concentrations  conductances,  although  verified  ologically,  are  that  conductances.  a l . ( 1982)  a dissimilarity  study  just  Sugimori  They r e p o r t e d  high  spontaneous  Similarly,  and  bursting behaviour to  mM)  Purkinje cell  Llinas  calcium  disparity  relatively  sent  the  (520  activity.  differences, was  by  slices.  calcium  The  found  depression.  upon d e n d r i t i c  speculated  ior  concentrations  been d e s c r i b e d  cerebellar based  at  neurones  discrepancies w i l l  the inferior not that have  to  124 V.B.  Ethanol  on  There increased cells  (Sinclair  et  Contrary  to  complex  total  activity  (SS)  and  spike  (CS)  SS  rate  d i r e c t e f f e c t of i t s depression To  drug  CS  this  rate,  question,  that  the  action  wholly  due  rather  to  indirect  to  SS  the  However,  decrease of  in  1981).  ethanol  a l . , 1971)  CS  to or  However,evoked to  also  Colin the  by  reduce  SS  et a l . ,  observed  ethanol  in-  w e r e due  Although  the  to  as  upon  variance was  the  the  that  ethanol  i t s other  electrolytic  (ISI)  interval.  able  to  post-lesion. SS  neurone's on  afferent  the  The  CS  lack spon-  is  a  suggests not  activity,  Purkinje  input.  not  produce  This  rate  an  was  in pre-lesion  still  a neurone's  activity  l e s i o n i n g caused  pre-lesion  large  from  of  by  CS  interspike interval  i t s e f f e c t s upon  a direct action  e f f e c t s of  eliminated  ethanol  ISI  ethanol  e f f e c t upon  Lo,  i n d i r e c t e f f e c t such  the  olive.  the  significance reflects  significant  et  decreased  and  found  whether  an  and  vivo  activity.  d i f f e r e n t from  rate.  have  causes  Purkinje in  Sinclair  a l . , 1971;  to  inferior  firing  CS  or  the  increased  1981),  been r e p o r t e d  clear  r e g u l a r i t y were  of  significantly  not  and  lesioning  Lo,  r e g u l a r i t y induced  this of  study  rate  taneous  has  ethanol  and  a l . , 1980).  r e g u l a r i t y ( F e r i n et  and  of  and  (Eidelberg  et  activity  in  a l . , 1977)  some w o r k e r s  (Rogers  creases  SS  et  that  regularity in  a l . , 1980;  activity  i t was  upon  et  reports  Therefore,  via  (Seil  reports and  Sinclair  1980).  a  rate  (Sinclair  activity  spike  several  in vitro  these  CS  been  a l . , 1980;  in vivo  PC  Spikes  spike  both  activity  increase  have  simple  (PC),  reduce  Simple  cell  However,  but or  an  recent  125 studies  have  (diffuse) and  indicated  inhibitory  Bloedel,  1982).  1981;  Ebner  that  influence  Leonard  and  Bloedel  were c o r r e l a t e d  coincident  reductions  was  that  dependent  cells  from  increase  present those  upon  a  their  since  lytic  rate  seen  is possible  not  that  lesioning  of  the  necessary  to  better  cells  i n the  the  simply and  reflect  may  not  observed ity al.,  1980;  were not  of  e f f e c t of  3-AP  difference  true  from  the  situation.  the  ethanol  As  ethanol  the the  in in-  electro10,  Complete  on  c o n t r o l was  be  Purkinje  ( C o l i n et  a l . , 1980)  1981).  q u a n t i t a t i v e l y analyzed. more c o n s t r a i n e d  at  with or  However, The  reduced  ethanol  SS  may used  have CS  activ-  (Sinclair  these of  in  This  variability workers  variance  higher  found  studies.  Other  regularity associated  Lo,  cooling.  not  activity.  inadequacy of  and  did  example, w i l l  measure of  Sinclair  automatically  for  the  the  10  explanation. 3-AP  Purkinje  contralateral  in these  reflect  by  CS  the  the  regularity calculated  increased  induced  the  o l i v a r y n u c l e i , with  significant  measure of  destroy  cooling  nuclei  produced  administration.  i s indeed  evaluate  have  10  10  by  had  a l . (1982)  results in  activity  could  completely  this  absence  No  ethanol  of  the  PC  cells  neurones.  upon  explain  et  during  lesioned  significantly  et a l . ,  neighbouring  Purkinje  10  the  (Ebner  Montarolo  two  of  under  fibres  Montarolo  population  remaining  is  that  observed  depression  after  lesions did  in rate  l e s i o n s may  any  1982;  the  activity.  rates  o l i v a r y neurones  creased  SS  that  3-acetylpyridine  firing  cell  many c l i m b i n g  Simpson,  such  active  incomplete  study  of  and  increase  rats with  Therefore,  it  the  of  Purkinje  (1981) r e p o r t e d  activities  reported  each  et  observations a  ISI  frequencies  is due  to  126 the by  shorter these  firing  responses,  regularity explained  V.C.  Ethanol  on L o c a l  to Purkinje  H o w e v e r , a n y SS  i fi toccurred,  action exerted  cells  may be  by t h e 10 o n G o l g i  Inhibition  cells  t o be m e d i a t e d  ros,  1980a,b;  reported  administered  t o m o d i f y GABA  Newlin  ethanol  reduced  extended,  i n this  reduced The  study:  the period  This  latter  locally  LOC i n h i b i t i o n  inhibition.  Such  a displacement  ethanol  not reaching  action,  since  with  an e f f e c t i v e  ethanol  distance  exacerbated  o f the nerve  from  with  somatic  ethanol  intravenously  also  and  signifi-  o f the neurones. o f the neurones  mediating  be e x p e c t e d  would  recording  has  the position of the  terminals  the electrode.  transmission  was c o n f i r m e d ,  concentration  concentration  has  inhibition  i n three  could  inhibition i s  and  since  finding  between  local  LOC i n h i b i t i o n  i n the majority seen  by  Ethanol  o f LOC  applied  lack o f antagonism  t i p and t h a t  .  by e t h a n o l  been due t o a m i s m a t c h  electrode  This  function  e t a l . , 1981)  t o be a n t a g o n i z e d  and L o , 1981).  may h a v e  t o be i n h i b i t e d  by t h e t r a n s m i t t e r GABA.  (Sinclair  cantly  a r e known  (LOC) o f t h e c e r e b e l l a r c o r t e x .  p r e v i o u s l y found o  (Nest  been  effects,  inactivation  (see Section V.E).  thought  ially  input  CS a c t i v i t y .  these  by t h e i n h i b i t o r y  stimulation  been  beyond  observed  consequence o f t h e  numbers o f  asynchronous  o f the reduced  increase  in regularity  an a r t i f a c t u a l  r a t e , the reduced  Purkinje  been  the increase  been  and t h e r e d u c e d  a consequence  cells  Therefore,  w o r k e r s may h a v e  increased  as  ISI.  have This  the  to result i n  at i t s site fallen  problem  i fthe site  of  exponentwould  o f nerve  have  127 termination stellate  i s t h e d e n d r i t i c t r e e , such as i s t h e case  cell  innervation of Purkinje cells  1967).  Obviously,  uniform  distribution  to  systemic  i n a more  and does n o t p o s e t h i s  problem  thei n v e s t i g a t o r . I n one e x p e r i m e n t a l  ed  (Eccles et a l . ,  administration results  of ethanol  with  trial,  LOC i n h i b i t i o n  by t h e a p p l i c a t i o n o f l o c a l e t h a n o l .  s u p e r f i c i a l d i f f e r e n c e s from t h e other just represent  an a n o m a l o u s  Previous antagonize effect  was  prolong-  As t h i s n e u r o n e had no n e u r o n e s t e s t e d , t h i s may  finding.  s t u d i e s have r e p o r t e d  ( B a c k s t r o m , 1977; S i n c l a i r  ethanol  to variously  and L o , 1 9 8 1 ) , have no o  ( L a k e e t a l . , 1 9 7 3 ) , o r enhance ( N e s t o r o s ,  N e w l i n e t a l . , 1981) p u t a t i v e GABA t r a n s m i s s i o n  o r exogenous  GABA-evoked i n h i b i t i o n  i n nonspinal  presynaptic  a p p e a r s t o be e n h a n c e d by e t h a n o l , a t  least  inhibition  i n the s p i n a l cord  1973), although  (Miyahara  systems.  1980a,b;  In a d d i t i o n ,  e t a l . , 1966; D a v i d o f f ,  E i d e l b e r g and Wooley ( 1 9 6 9 ) f o u n d e t h a n o l  not to  o  have a s i g n i f i c a n t  effect.  system ( c e r e b r a l c o r t i c a l  Nestoros concluded cells)  ethanol  that i n h i s  was a c t i n g  post-synap-  tically. T h e r e i s some e x p e r i m e n t a l GABA r e c e p t o r s may d i f f e r  evidence t o suggest  over the b r a i n .  GABA r e c e p t o r s  been d i v i d e d i n t o  two s u b t y p e s on t h e b a s i s o f t h e i r  and  (Costa,  distributions  benzodiazepine  binding  1979).  (Braestrup  that  affinities  O n l y one o f t h e s u b t y p e s shows e t a l . , 1980).  d i f f e r e n c e s o f ethanol-GABA r e c e p t o r  Therefore,  i n t e r a c t i o n s between  v a r i o u s a r e a s o f t h e b r a i n may a c c o u n t f o r t h e d i f f e r e n c e s between s t u d i e s .  have  128 Alternatively, induced to  antagonism  ethanol's  Since  the  modifying  decreasing  that  i t s release  possibility  taurine  which  taurine  h a s been  (Nanima,  forstellate  cells  nificantly  (Carmichael  antagonizing  from  applied  spontaneous  guinea  I t i s inhibition  f o r example  by  receptor.  the release of since  pig cerebellar  noradrenaline  cells  of Purkinje  and Woodward,  1980) and  from  that  of Purkinje  Therefore, cells  of the inhibition  the cerebral  i t s post-synaptic  1980a,b) ethanol  by r e d u c i n g  by e i t h e r actions.  do n o t s i g -  In addition, ethanol  1975) and t o a n t a g o n i z e (Nesteros,  ( N A ) h a s be  inhibition  firing.  NA r e l e a s e  e t a l . , 1981).  enhancement  LOC  o f GABA,  e t a l . , 1978) a t doses  and I s r e a l ,  LOC i n h i b i t i o n  enhances  the GABA-induced  to inhibit  of cortical  (Sorensen  o f GABA  locally  (Hoffer  depress  been r e p o r t e d  transmitter.  the release  e t a l . , 1979; Moises  LOC i n h i b i t i o n  some o f  1983).  t o enhance  (Moises  at least  t o d e c r e a s e the d e p o l a r i z a t i o n - i n d u c e d  release  Similarly, reported  i s due  GABA.  the a f f i n i t y of i t s  ethanol  inhibits  study  than  transmitter,  or reducing  reported  calcium-dependent  bition  i n this  i s antagonizing  of this  i s that  i n turn  by t h i s  ethanol  the a c t i v i t y  Another  cells  transmitter  i s mediated  possible  the ethanol  of transmitters other  i s a proposed  LOC i n h i b i t i o n  slices  seen  that  e t a l . , 1983b) i t i s p l a u s i b l e t h a t  therefore by  o f LOC i n h i b i t i o n  modification  taurine  (Okamoto  o n e may p o s t u l a t e  has  cortex  NA-evoked  inhi-  and P u r k i n j e  cells  may a n t a g o n i z e t h e t h e NA-mediated  reducing  NA's r e l e a s e o r  129 V.D.  Ethanol  o n L o c a l GABA  Ethanol, intravenous found  Inhibition  administered  infusion  to antagonize  or l o c a l l y  either  by m i c r o p r e s s u r e  the i n h i b i t i o n  of firing  GABA a p p l i e d  locally  by m i c r o p r e s s u r e .  finding  locally  applied ethanol  since et  that  this  inhibition  a l . , 1971).  antagonizing  (e.g.  GABA's a c t i o n s  antagonized GABA.  1980a,b),  For example,  cortical  cells  neuronally  prolonged  disagreement  enhanced  the inhibition  o f these  results  be d u e t o d i f f e r e n t the observed  may r e f l e c t  as  as t h e mechanisms o u t l i n e d  enhanced  that  applied electroof cerebral  that  released  ethanol  (3  o f CA3 n e u r o n e s o f t h e mossy  t o be m e d i a t e d those  by i n t r a v e n o u s  fibre or by GABA.  o f the present  o f GABA  In a d d i t i o n ,  study  transiently  was  e t a l . , 1973), o r  Similarly,  with  present  ethanol  (Lake  populations  effects.  r e p o r t s suggest  (Woodward  the ethanol  the i n h i b i t i o n  i s thought  inhibition  following  inhibition,  ethanol  by s t i m u l a t i o n o f t h e d e n t a t e  GABA-mediated  well  that  that  stimulation.  pathways, which  mediating  LOC  by i o n t o p h o r e s i s , a n d a l s o e n h a n c e d  commissural  may  supports the  (1980a,b) r e p o r t e d  ethanol  evoked  study  reported  h a d no e f f e c t  hippocampus  The  result  1977) t h e a c t i o n s o f l o c a l l y  by e l e c t r i c a l  i.p.)  by e x o g e n o u s  post-synaptically.  Nesteros  released  was  caused  antagonized  i tsuggests  have  (Backstrom,  osmotically  g/kg,  workers  Nesteros,  This  slow  ejection,  i s b e l i e v e d t o be G A B A - m e d i a t e d  In addition,  Other  s y s t e m i c a l l y by  receptors  the antagonism o f  ethanol  seen  i nthe  a m o d i f i c a t i o n o f NA f u n c t i o n , s i n c e , above  i n S e c t i o n V.C., t h e  a p o s s i b l e mechanism  inhibits  locus  coeruleus  of action:  (1)  (LC) neurones  130 (Pohorecky fibres  and B r i c k ,  1977); (2)  to thecerebellar  (3) L C s t i m u l a t i o n g e n o u s GABA postulated neurones  enhances  (Moises that  cortex  cated  of Purkinje  cell  reduces  inhibition  ethanol  produced  a s i g n i f i c a n t absolute-  decrease  o f GABA-evoked  tion  i n such  (1983).  could  effect,  by m o d i f i c a t i o n  other  hand,  modulators  a lack  action  support  or a differential  differential  a s i g n i f i c a n t derate.  Locally applied  ethanol  Difficulties by S o j a  inhibition site  o f thepost-synaptic  would  such  effectiveness  d i s t r i b u t i o n o f ethanol  a n d GABA.  These  site of due t o a mechanisms  pharmacological  Cells  h a d no s i g n i f i c a n t e f f e c t o n t h e s p o n t a n e o u s  rate  o f t h eG o l g i  caused  a s i g n i f i c a n t decrease  stimulation  uptake,  recordings.  firing  by  for this  On t h e o t h e r  action  and i n t r a c e l l u l a r  Ethanol  by l o c a l  o f drug  tools  on G o l g i  and S i n c l a i r  a pre-synaptic  be d i f f e r e n t i a t e d b y t h e u s e o f a v a i l a b l e  Ethanol  i ninterpreta-  receptor,  a s NA.  suggest  percent-  of action  could  V.E.  cells.  compli-  a non-pre-synaptic  o f antagonism  be  This  expounded  o f GABA a c t i o n  by e x o -  LC-mediated  o f Purkinje  o f GABA-mediated  ethanol  or  inhibition.  and  d e p r e s s e s LC  but nonsignificant  s i t u a t i o n s h a s been  An a n t a g o n i s m  a tonic  firing  thei n t e r p r e t a t i o n o f thedata.  inhibition  ethanol  produced  spontaneous  1973);  I tcan therefore  administered  and, as a consequence,  applied  cell's  noradrenergic  et a l . ,  Hoffer  1980).  a n d Woodward,  enhancement o f GABA-induced  crease  (e.g.  Purkinje  intravenously  Locally  t h e LC p r o j e c t s  cells  of theinferior  i nthis  study.  i n theperiod olive.  However,  of inhibition  ethanol evoked  131 The firmed that  the  results  Golgi  Although long  cells  the  that  inhibition these  are  of  the  Golgi  by  to  be  on  Purkinje  under  an  Bloom  10  inhibition  seen  i n these  tonically  Also,  unless  since  such to  an the  climbing  transmitter.  More p r o b a b l y  multisynaptic  pathway to  10  the  the  the  would  response  climbing  release  cells  would  10.  via  The  of  be  70  expected fibres  more t h a n  i s the  the  (about  innervation  inhibition  Golgi  by  latency  of  10.  i s slow,  innervation  long  fibres  the  experiments  inhibited  the  con-  indicates  from  neurones  a monosynaptic  fibres  and  influence  of  are  stimulation  (1981),  rate  e x c i t a t o r y in analogy cells,  and  by  inhibitory  represent  out.  cells  firing  climbing  this  Golgi  Schulrnan  cells  does not  cells  rules  of  of  spontaneous  duration  suggest  ms)  inhibition  result  one  of  cerebellar  a  inter-  neurones .  influence cells  (see  parallel input  This  inhibition  that  climbing  Section  fibre  simple  spike  (Sinclair  et  such  a l . , 1980)  and  granule This kinje  (Colin  the  cells  tend  Purkinje  has the  expected  cell  SS  firing  as  the  the  i t would  the  decreased  with  CS  total  of  ethanol  activity not  PC  with  found  in  climbing  fibre  cerebellar Golgi  cells  fibres,  increase  increased  reduction  although  asynchronous  parallel to  of  of  Purkinje  i n an  not  the  cessation  inhibitory over  been r e p o r t e d  disinhibit  be  result  cells,  a l . , 1980),  cells'  the  exert  mediate  to  would  to  i t would  reduction  their  mediate  appear  or  Purkinje and  et  not  i t may  that  would  that  the  However,  Elimination  activity  to  regularity  3-acetylpyridine study.  fibres  V.A.1.) as  input  required.  could  the  result  input,  would  be  regularity  via  this  the  decreased. of  the  in a reduction  of  Purthe  132 asyncronous support  such  ethanol  may  and  hence  the  granule  input  to the c e l l .  a hypothesis reduce.a  reduce cells  the and  since  tonic  The  of this  intravenously  IO-mediated  asynchronous their  results  parallel  of Golgi  to Purkinje  fibres.  may  administered  inhibition  input  study  cells  cells via  133 VI.  1. a .  Infused doses)  ethanol  the b.  CS  activity  but d i d not e f f e c t  the a b i l i t y  of  juxtafastigial  c.  t o evoke  of climbing  CS a c t i v i t y .  fibres  In addition,  was n o t s i g n i f i c a n t l y  the  ethanol  reduced  t h e CS a c t i v i t y  cerebral  effected  (1.5 g/kg, i . v . evoked  over  10 m i n )  by  significantly  by e l e c t r i c a l  stimulation  cortex  in parallel  to i t s significant  i n spontaneous  CS a c t i v i t y  (p<0.05).  Ethanol,  activa-  (p>0.05).  Infused  tion  22 m i n i n d i v i d e d  spontaneous  ethanol  the  over  reduced  stimulation tion  (1.5 g/kg, i . v .  significantly  (p<0.001)  CONCLUSIONS  administered  micropressure,  both  reduced  intravenously  the spontaneous  reduc-  and l o c a l l y  firing  of  o f 10  by neur-  ones . These to  results  strongly  the i n f e r i o r  This  action  directly 2. a .  olive  could  interval  b.  Subsequent min) no  These  be e i t h e r  results  spontaneous  t h e e x c i t a b i l i t y o f 10  perfusion  SS r e g u l a r i t y ,  SS r a t e  neurones.  reduced  that  o n SS  a decreased although  SS t o  neither  (p>0.05).  of ethanol  effect  indicate  local  t o the neurones or  o f t h e 10 c a u s e d  significantly  significant  h a s an a c t i o n  themselves.  lesioning  significantly  ethanol  on t h e i n p u t  and i n c r e a s e d  were r e d u c e d  that  to reduce  on t h e n e u r o n e s  Electrolytic SS  suggest  (1.5 g/kg, i . v .  the interspike  over  interval,  10 but had  regularity.  at least  part  was due t o a m e c h a n i s m  of the increased which  was  independent  134 from  t h e r e d u c t i o n o f CS a c t i v i t y  increase CF  may s t i l l  reflect  by e t h a n o l .  a reduction  However,  by e t h a n o l  this  of the t o t a l  activity.  3. a .  Ethanol the  a p p l i e d onto  period  lation b.  of inhibition  evoked  by m i c r o p r e s s u r e by l o c a l  reduced  electrical  stimu-  of the cerebellar cortex,  Ethanol, onized tion  PCs l o c a l l y  administered  the inhibition  o f GABA  both  s y s t e m i c a l l y and l o c a l l y ,  o f PCs evoked  by m i c r o p r e s s u r e ,  by t h e l o c a l  antag-  applica-  i n the majority of the c e l l s  tested . These both  results  show t h a t  Infused ficant  b.  the actions of  b u t may r e f l e c t  p r e -or  actions of ethanol. ethanol  effect  Infused tion  These  can antagonize  e n d o g e n o u s a n d e x o g e n o u s GABA,  post-synaptic 4. a .  ethanol  (1.5 g/kg, i . v . over  on s p o n t a n e o u s G o l g i  ethanol  evoked  results  by e l e c t r i c a l  suggest  olive-Purkinje  cell  input  cells  to Golgi  significantly  that  neuronal  reduced  signi-  firing,  the period  of inhibi-  s t i m u l a t i o n o f the 10.  some o f t h e e f f e c t s  a x i s may from  10 m i n ) h a d no  be m e d i a t e d  the 10.  of ethanol  by e t h a n o l ' s  on t h e  a c t i o n on  135 VII. A L B U S , J . S. ( 1 9 7 1 ) . A t h e o r y B i o s c i . 10: 2 5 - 6 1 .  BIBLIOGRAPHY of  cerebellar  f u n c t i o n . Math.  A L E X A N D E R , R. W., D A V I E S , J . N. a n d L E F K O W I T Z , R. J . ( 1 9 7 5 ) . 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B r a i n Res. 3 3 : 91-100. WOODWARD, D. J . , S E I G E R , A., OLSON, L . a n d H O F F E R , B. J . ( 1 9 7 7 ) . I n t r i n s i c and e x t r i n s i c determinations o f d e n d r i t i c development a s r e v e a l e d by G o l g i s t u d i e s o f c e r e b e l l a r and h i p p o c a m pal t r a n s p l a n t s i n Oculo. Exp. N e u r o l . 57: 984-998. YONEDA, Y . a n d R O B E R T S , E . ( 1 9 8 1 ) . S y n a p t o s o m a l b i o s y n t h e s i s o f GABA f r o m o r n i t h i n e a n d i t s f e e d b a c k i n h i b i t i o n b y G A B A . I n : P r o b l e m s i n GABA r e s e a r c h f r o m B r a i n A n d B a c t e r i a , OKADA, Y. and ROBERTS, E . ( e d s ) . E x c e r p t a Medica, Amsterdam, O x f o r d , P r i n c e t o n , pp. 55-65. YOUNG, A . B., O S T E R - G R A N I T E , M. L . , HERNDON, R. M. a n d SNYDER, S. H. ( 1 9 7 4 ) . G l u t a m i c a c i d : s e l e c t i v e d e p l e t i o n b y v i r a l induced g r a n u l e c e l l l o s s i n hamster cerebellum. Brain Res. 73: 1 - 1 3 .  154 VII.  developed 1)  APPENDIX  The f o l l o w i n g a r e b r i e f d e s c r i p t i o n s o f t h e p r o g r a m s i n the course of the research reported i n t h i s t h e s i s .  WAITER  WAITER i s a m a c h i n e l a n g u a g e r o u t i n e w h i c h c o u n t s t h e number o f p u l s e s w i t h i n a s p e c i f i e d number o f s e c o n d s . I t r e t u r n s t h i s c o u n t t o t h e BASIC program w h i c h c a l l s i t . I t makes u s e o f t h e h a r d w a r e t i m e r s p r e s e n t on t h e c u s t o m p a r a l l e l i n t e r f a c e board.  2)  GABALC, GETGABALC and MULTIPLOT G A B A L C u s e s WAITER a n d d i r e c t m a n i p u l a t i o n of the custom p a r a l l e l i n t e r f a c e board t o c o n t r o l t h e l o c a l a p p l i c a t i o n o f e t h a n o l a n d GABA i n a d e f i n e d p r o t o c o l a s o u t l i n e d i n t h e Methods. Neuronal f i r i n g r a t e i s d i s p l a y e d both as a time v s r a t e h i s t o g r a m on t h e m o n i t o r i n h i g h - r e s o l u t i o n g r a p h i c s and numerically. D a t a c o l l e c t e d c a n be s t o r e d o n t o d i s k e t t e a n d r e c a l l e d by GETGABALC. GETGABALC r e t r i e v e s t h e d a t a f r o m d i s k e t t e p r e v i o u s l y s t o r e d by GABALC. I t allows the display of a selected series of GABA t r i a l s a n d c a l c u l a t e s a n a v e r a g e r e s p o n s e f r o m t h e m . The amount o f i n h i b i t i o n e v o k e d by t h e a p p l i e d d r u g i s c a l c u l a t e d and d i s p l a y e d a u t o m a t i c a l l y . The h i s t o g r a m s and c a l c u l a t i o n s c a n be p r i n t e d o n t h e d o t m a t r i x p r i n t e r . M U L T I P L O T r e t r i e v e s t h e same d a t a b u t p l o t s a l l t h e t r i a l s , t h e averaged response from each group o f f i v e t r i a l s , and i t s a s s o c i a t e d i n h i b i t i o n v a l u e . F o r an e x a m p l e s e e F i g u r e  3)  P S T H , P L O T . P S T H a n d PLOT .PSTH .INH The B A S I C p r o g r a m , PSTH, a n d i t s a s s o c i a t e d m a c h i n e l a n g u a g e r o u t i n e , a l l o w s p e r i - s t i m u l u s h i s t o g r a m s ( P S T H ) t o be constructed. E a c h h i s t o g r a m i s made up o f 2 5 0 b i n s a n d i s d i s p l a y e d on t h e m o n i t o r i n h i g h - r e s o l u t i o n g r a p h i c s a l o n g with t h e sweep number and t o t a l b i n c o u n t . The m a c h i n e l a n g u a g e r o u t i n e uses t h e i n t e r r u p t c a p a b i l i t i e s o f t h e custom i n t e r f a c e board t o i n t e r c e p t t r i g g e r and s p i k e s i g n a l s . Each t r i g g e r s i g n a l s t a r t s a new s w e e p t h r o u g h a l l t h e b i n s o f t h e h i s t o g r a m . E a c h s p i k e s i g n a l c a u s e s t h e v a l u e i n t h e c u r r e n t b i n t o be i n c r e m e n t e d a n d t h e h i s t o g r a m d i s p l a y t o be u p d a t e d . PSTH h a n d l e s u s e r q u e r i e s and s a v e s t h e d a t a o n t o d i s k e t t e . PLOT.PSTH r e t i e v e s d a t a p r e v i o u s l y s a v e d t o d i s k e t t e by PSTH a n d r e d i s p l a y s i t w i t h c a l c u l a t e d s t a t i s t i c s . PLOT .PSTH .INH i s s i m i l a r t o P L O T . P S T H e x c e p t i t d i s p l a y s t h e r a w d a t a , s m o o t h e d d a t a a n d c a l c u l a t e d 1-50 V a l u e s . F o r an e x a m p l e s e e F i g u r e 1 5 .  155 4)  DUAL .PSTH a n d PLOT .DUAL .PSTH T h e s e t w o p r o g r a m s a r e s i m i l a r t o PSTH a n d P L O T . P S T H except that they also construct a latency histogram concurrently w i t h t h e c o n s t r u c t i o n o f t h e PSTH. This l a t t e r histogram i n cludes o n l y the f i r s t spike s i g n a l t o a r r i v e a f t e r each t r i g g e r signal. PLOT .DUAL .PSTH r e p l o t s t h e h i s t o g r a m s a n d c a l c u l a t e s t h e mean l a t e n c y t o t h e f i r s t s p i k e r e s p o n s e . A period of time a f t e r the t r i g g e r s i g n a l , i n which spike s i g n a l s are ignored, c a n be s e l e c t e d i n o r d e r t o a v o i d s p u r i o u s c o u n t s d u e t o s t i m u lation artifacts.  5 ) T R I . P S T H a n d PLOT .TRI .PSTH T h e s e t w o p r o g r a m s a r e s i m i l a r t o t h e a b o v e PSTH programs, e x c e p t t h a t t h e y d i s t i n q u i s h between s i m p l e (SS) and complex s p i k e (CS) a c t i v i t y on t h e b a s i s o f i n t e r s p i k e i n t e r v a l . They c o n s t u c t t h r e e h i s t o g r a m s : a s t i m u l u s t o SS P S T H ; a s t i m u l u s t o CS P S T H ; a n d a s t i m u l u s t o CS l a t e n c y h i s t o g r a m . PLOT.T R I .PSTH r e p l o t s t h e h i s t o g r a m s a n d c a l c u l a t e s t h e mean l a t e n c y to t h e f i r s t CS. An e x a m p l e o f t h i s p r o g r a m ' s o u t p u t i s s h o w n i n F i g u r e 4.  6)  I S I and  PLOT.ISI T h e s e two p r o g r a m s c o n s t r u c t and d i s p l a y an i n t e r s p i k e i n t e r v a l h i s t o g r a m c o n s i s t i n g o f 250 b i n s . The m a c h i n e l a n q u a g e r o u t i n e a s s o c i a t e d w i t h the I S I program uses i n t e r r u p t s to i n t e r c e p t s p i k e s i g n a l s . Each s p i k e s i g n a l causes t h e c u r r e n t bin t o be i n c r e m e n t e d , t h e d i s p l a y e d p l o t t o be u p d a t e d , a n d a new s w e e p o f t h e b i n s t o be i n i t i a t e d . Mean i n t e r s p i k e i n t e r v a l i s c a l c u l a t e d and d i s p l a y e d w i t h t h e h i s t o g r a m by P L O T . I S I , s e e Figure 12.  7) T R I . I S I  a n d PLOT . T R I . I S I T h e s e two p r o g r a m s a r e s i m i l a r t o I S I and P L O T . I S I e x c e p t t h e y d i s t i n g u i s h SS f r o m CS a c t i v i t y . They c o n c u r r e n t l y c o n s t r u c t and d i s p l a y t h r e e i n t e r s p i k e h i s t o g r a m s : S S t o S S ; CS t o CS; a n d CS t o S S . Mean i n t e r s p i k e i n t e r v a l s a r e c a l c u l a t e d by P L O T . T R I . I S I and a r e d i s p l a y e d w i t h t h e h i s t o g r a m s . Part of a TRI .ISI d i s p l a y i s i n c l u d e d i n F i g u r e 12. 8)  Miscellaneous Programs V a r i o u s o t h e r programs were w r i t t e n . Some w e r e v a r i a t i o n s o f t h e above programs used f o r t h e p r e l i m i n a r y a n a l y s i s o f the data or f o r s p e c i a l i z e d t a s k s . Other programs w r i t t e n i n c l u d e d a s c r e e n t o p r i n t e r dump r o u t i n e , v a r i o u s statistical r o u t i n e s , and v a r i o u s d i s p l a y r o u t i n e s .  

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