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Role of norepinephrine in the hippocampal CA 1 region of the rat : inhibition and disinhibition Leung, Pak-Huen Patrick 1984

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R O L E OF  NOREPINEPHRINE  HIPPOCAMPAL  CA1  INHIBITION  R E G I O N OF  AND  IN THE THE  RAT:  DISINHIBITION  by  PAK-HUEN B.Sc,  A  University  THESIS THE  P A T R I C K LEUNG of B r i t i s h  Columbia,  SUBMITTED IN PARTIAL F U L F I L L M E N T R E Q U I R E M E N T S FOR T H E D E G R E E OF MASTER OF S C I E N C E in  THE F A C U L T Y OF GRADUATE S T U D I E S (Department of P h y s i o l o g y )  We  accept to  THE  ©  1980  this  thesis  the required  as. c o n f o r m i n g standard  U N I V E R S I T Y OF B R I T I S H April, 1984  Pak-Huen  Patrick  COLUMBIA  Leung,  1984  OF  In p r e s e n t i n g  this  thesis  i n partial  fulfilment of the  r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y of  B r i t i s h Columbia,  it  freely  available  agree t h a t for  I agree that f o rreference  permission  scholarly  the Library  shall  and study.  I  copying or p u b l i c a t i o n  gain  shall  Department o f  frfy^/QCO'tfY  %  The U n i v e r s i t y o f B r i t i s h 1956 Main Mall V a n c o u v e r , Canada V6T 1Y3  .'/foXU  S0  y  of this  It is thesis  n o t b e a l l o w e d w i t h o u t my  permission.  Date  thesis  p u r p o s e s may be g r a n t e d by t h e h e a d o f my  understood that financial  further  f o rextensive copying o f t h i s  department o r by h i s o r h e r r e p r e s e n t a t i v e s . for  make  ,?<Pf  Columbia  written  i i  Abstract  The  effect  of  norepinephrine  electrophysiological stratum  radiatum  hippocampal  the  stimulation  slice  potentials, and  the  in  excitatory  the  spike,  basket  assessed  examining  the  effect  radiatum  the  evoked  reversible resulting  in  a  extracellular animals  in  intracerebral 6-hydroxydopamine these  inhibition  of  population  spike  characteristic  the  of  EPSP as  a  NE  as  cell  of  NE  slices  had  been  the  on  the  obtained  depleted,  injections  multiple  epileptiform  evoked  as  in  an  a  intracellular  examined.  and  stratum  processes  results  significant  response  well  on-going  in  on  produced  with  recorded  was  conditioning  inhibitory  intraventricular  resulted  (EPSP)  reversible  (antidromic)  effects  also  field  inhibition,  preceding  similar  were  a  by rat  interneurons,  out  endogenous  (6-OHDA)  slices  exhibit  pyramidal  The  the  potential  perfusion  carried  responses  or  a  of  closely  which  of  evoked  in  Recurrent  recurrent  correlates. field  region  on  extracellular  cell  NE  disinhibition  showed  extracellular  on  in  to  pathway  responses.  Experiments  recordings  NE  alvear  decrease  responses.  from  to  Both  5 0 M M NE.  of  by  applied  CA1  examined  shown  mediated  pulse  perfusion  post-synaptic were  presence  the  were  presumably by  of  preparation.  population  decrease  activities  (NE)  by of  Perfusion  of  decrease  in  the  enhancement  of  the  spike  activity.  discharges  iii  It  is  directly latter cell  on  of  proposed both  which  pyramidal would  discharge.  as  perhaps  to  the  that  occurs  generation  An  and  result  exerts basket  inhibitory cell  between  these  6-OHDA l e s i o n s ,  epileptiform  activity.  influences  interneurons,  in disinhibition  imbalance  following of  NE  of  the  pyramidal  two  influences,  may  contribute  i v  Table  of  Contents  Abstract Table  i i  of contents  iv  List  of f i g u r e s  vi  List  of a b b r e v i a t i o n s  viii  Acknowledgements CHAPTER  I.  ix  INTRODUCTION  A. C e l l u l a r  Organization  B. E x t r i n s i c  Afferent  1. E n t o r h i n a l 2. S e p t a l 3.  Commissural  4.  Brain  A.  cortex/  Perforant  stem  5 path  afferents  norepinephrine  9  (5-HT)  9  (NE)  Study  Slice  AND  METHODS  Preparation Pharmacological  17  C.  Paired  D.  6-Hydroxydopamine III.  16 16  Procedures  CHAPTER  10 13  B. E l e c t r o p h y s i o l o g i c a l a n d  Pulse  6  8  afferents  b.  MATERIALS  1  ..7  serotonin  In V i t r o  Pathways  Pathways  a.  II.  and I n t r i n s i c  input  C. T h e P r e s e n t CHAPTER  , .1  Paradigm  19  Lesions  22  RESULTS  23  A.  The E x t r a c e l l u l a r  Fields  B.  Effect  o f NE  on F i e l d  C.  Effect  o f NE  on R e c u r r e n t  Potentials  Responses Inhibition  23 25 28  1. E x t r a c e l l u l a r  responses  28  2.  recordings  32  Intracellular  V  D. CHAPTER  6-Hydroxydopamine IV.  Lesions  ..  35  DISCUSSION  39  A.  Effect  o f NE  on  Pyramidal  Cells  39  B.  Effect  o f NE  on  Recurrent  Inhibition  42  C.  6-Hydroxydopamine in  D.  Epileptogenisis  General  References  Discussion  Lesion  and  Role  of  NE 44 50 53  vi  List FIG.  1.  Schematic  of  Figures  Diagram  of  the Hippocampal  Slice  Preparation FIG.  2.  Schematic  2  Diagram  of  the  Paired  Pulse  Paradigm FIG.  3.  Characteristic of  FIG.  4.  20  Time  Extracellular  the Hippocampal Course  of  NE  CA1  Action  Field  Responses  Region on  24  the  CA1  Evoked  Responses  26  FIG.  5.  EPSP  Amplitude  FIG.  6.  Effect  FIG.  7.  Relationship and  of  NE  8.  on  Stimulus  Paired  between  Population  Presence FIG.  vs  and  %Inhibition  Pulse  Spike of  27  Inhibition  Paired  Absence  vs  Intensity  Pulse  29  Inhibition  Amplitude  in  the  NE  Amplitude  30 of  Control,  Test  Responses FIG.  9.  31  Characteristic Hippocampal  FIG.  10.  Intracellular CA1  Intracellular  Pyramidal  Correlates  Responses  of  the  Neurons of  33  Paired  Pulse  Inhibition FIG.  11.  Effect  of  Responses .treated  34 NE  on  in Slices  A n i m a l s -.  the  Extracellular  Obtained  from  EPSP  6-OHDA. .36  vii  FIG.  12.  Effect Spike  of  NE  13.  Schematic and  the'Extracellular  Responses  OHDA-treated FIG.  on  in Slices  O b t a i n e d from  6-  Animals  Diagram  of  j3-receptors  in  treated  Population  Conditions  37 the D i s t r i b u t i o n Normal  and  of  a-  6-0HDA47  vi i i  List ACh AChE Alv C CA 1 CA2 CA3 CA4 CNS CSF C-T C-AMP DG EPSP GABA GAD Glu 5-HT Hz IPSP i .p. kg kHz M Mfi ug Ml MM Mm  mg min mM msec mV NE NS 6-OHDA RMP r Sch S.D. S.E. S.E.M. SL SM SO SP SR Tc Tp V  of  Abbreviations  acetylcholine acetylcholinesterase alveus, alvear conditioning pulse of a paired pulse paradigm c o r n u ammonis ( s u b f i e l d ) 1 c o r n u ammonis ( s u b f i e l d ) 2 c o r n u ammonis ( s u b f i e l d ) 3 c o r n u ammonis ( s u b f i e l d ) 4 c e n t r a l nervous system cerebro-spinal fluid conditioning-test c y c l i c adenosine mono-phosphate dentate gyrus excitatory post-synaptic potential gamma-amino-butyric acid glutamic acid decarboxylase glutamic acid 5-hydroxytryptamine (serotonin) hertz inhibitory post-synaptic potential intra-per itoneally k ilogram kilohertz molar megohm microgram microlitre micromolar micrometer, micron milligram minute mi 1 1 i m o l a r millisecond millivolt norepinephrine not significant 6-hydroxydopamine r e s t i n g membrane p o t e n t i a l correlation coefficient Schaffer collateral standard deviation standard error s t a n d a r d e r r o r o f t h e mean stratum lacunosum stratum moleculare stratum oriens stratum pyramidale stratum radiatum control, test pulse t e s t pulse of a p a i r e d pulse paradigm volt  ix  Acknowledgements  The patient Miller  author guidance  t o Is'tvan  Joe Tay  I patient thesis.  and  like  am  and  also and  Kurt  to  invaluable  i n the completion  indebted to  would  of  Mody Henze  forever endless  this  thank  most  sincerely  suggestions  of  thesis.  author  The  f o r d i s c u s s i o n and for technical  indebted  to  supports  and  my  Dr.  the J.J.  is also  cooperation,  and  assistance.  parents  their  for  interest  in  their this  1  CHAPTER  A.  I  INTRODUCTION  Cellular  Organization  Phylogenetically, portion is  multi-layered the  the hippocampus  of the a r c h i c o r t e x  intermediate  and I n t r i n s i c  between  in that  The b a s i c  single  layered  hippocampal  been  described  in detail  have  Lorente  d e No  neurons  are  pyramidale) CA2  (1934).  and d i v i d e d  hilus  (Figure  1).  which  extends  apical  dendritic  radiatum  zone), These  toward  Shorter  oriens  (SO)  packed  into  subfields  CA1  of  layer  (stratum  superior),  inferior)  a dendritic fissure  superficial  and  the  arborization and forms the  into, t h e  project  by  principal  (SL) and stratum  dendrites  the  later  (regio  i s subdivided  lacunosum  basilar  along  (regio  have  the  arrangement  (1911) a n d  a tightly  cells  and  the pyramid-shaped  CA3/CA4  a  and i t s c o n n e c t i o n s  in  which  (SR), stratum  (SM).  by C a j a l  as  arrangement  paleocortex  cellular  the hippocampal  layer  classified  i t sneuronal  formation  Briefly,  organized  (intermediate  is  the non-laminar  neocortex.  Pathways  into  stratum  moleculare the  surface  stratum  of  the  hippocampus.  In there do  to the p r i n c i p a l  are a variety  not  these  addition  project  of interneurons  out  are the c l a s s i c a l  of t h i s basket  neurons  described  above,  regions  which  i n these  structure. cells  The b e s t  first  known o f  described  by  2  FIGURE  1.  Schematic  Diagram  of  the  Hippocampal  Slice  Preparation  The  principal  hippocampus bodies  are arranged  aggregated  dendrites stratum  neurons  extending  into  electrode  positioned  Schaffer  spike  hippocampal  (Fm)  inhibitory  basket  activates  both  basket DG,  cells  dentate  elicits  into  via cells.  the  SR  from in  SR turn,  with  SP,  stimulation  cells  out  neurons,  EPSP  and  of  the  via  the  activate  the  (Alv  antidromically  orthodromically v i a the recurrent gyrus.  the  the dendrites  (Sub)  recurrent collaterals, Alvear  and  respectively.  project  subiculum  apical  activating  pyramidal  and  cell  dendrites  the c h a r a c t e r i s t i c  the  pyramidal  the  Stimulating  (SR S t i m )  t h e CA3  the  (SR)  basal  (SO).  synaptic contacts  neurons,  and  and  of  (SP) and  radiatum  oriens  the  responses  formation  pyramidale  stratum  (Sch) from  cells,  pyramidal  fimbria  in  cells)  fashion with  (SL-M)  stratum  'en p a s s a g e '  pyramidal  population CA1  the  collaterals  form  CA1  the  lacunosum-moleculare into  of  laminar  in the stratum  extending  which  in a  (pyramidal  Stim)  and the  collaterals.  2.1  3  Lorente  d e No  including these  i n 1934.  horizontal,  interneurons  The n e u r o n s polygonal  receives  collaterals  of  dense  ramifications  (SP)  axonal  and stratum  dense much  the  like  plexi  the  believed  to meditate  neurons.  It  gamma-amino-butyric mediating  been  acid  neuronal  different  techniques.  acid  studies  endogenous  GABA  distribution inhibitory that  GABA  uptake  synaptic  hippocampus has  been  around  of  that  glutamate-induced  discharges  et  In  both  a l , the  1971).  synaptically  cerebellum  and  the  are  on t h e p r i n c i p a l that  neurotransmitter  of  &  glutamic  GABA  uptake  measurements  to the  alter  1975).  that  of  layer.  of  The  GABA  i s mediating  neurons  i t or  (Curtis  shown  inhibitions  or  to the  spontaneous  i t was a l s o  GABA-induced  the  activity  Pharmacologically,  of hippocampal  a  GAD  indigenous  abolishes  study,  plexi  pyramidal  interneurons  GABA  four  1975) a l l d e m o n s t r a t e  the  not  by  of  (Storm-Mathisen  and  the idea  t h e same and  verified  e t a l , 1974),  corresponds  (Storm-Mathisen, shown  cells  localization  & Shimada,  supports  transmission  pyramidale  the pyramidal  assays  1973)  d e a f f e r e n t a t i o n does further  form  The  been  (Saito  interneurons  fact  has  Schon,  that  i n turn  established  i s  Biochemical  (Okada  pattern  axon  The t o p o g r a p h i c a l d i s t r i b u t i o n  (GAD) &  Each of  1963).  influences  immunohistochemical  (Iversen  Flood,  shapes  from  in stratum  well  elements  decarboxylase  inputs  and they  the  (GABA)  the i n h i b i t i o n .  1972),  in  of  pyramidal.  to envelop  inhibitory  GABA-ergic  Fonnum,  cells  (Blackstad &  cells  has  o r even  terminating  tend  basket  a variety  extensive  pyramidal  radiatum  terminal  have  that were  4  antagonized known  by b i c u c u l l i n e ,  that  prolonged  characteristic Wong  & Traub,  The cells) the  cell  organized  extending  mediating  cells.  On  components  of the  cell  t o t h e CA3  are also  form  stratum  found  in this  they  passage'  processes  the  pyramidal  cells  The  projections  axonal  (Lorente  stratum  o r i e n s and branch  fimbria  v i a the alveus.  studies  have  excitatory hippocampal  t h e major  d e No,  a c t i o n s on a w i d e pyramidal  cells  of  proper. which  contacts  pyramidal  cells  fibre  o f CA1  cells  bundle  of  (Schaffer t o form  dendrites et a l ,  'en of  1978).  run toward  the  or j o i n the  electropharmacological ( G l u ) t o have  of neurons  (Dudar,  various  bundle  the subiculum  glutamate range  the  well  to the  1934; Swanson  A number  granule  proximal  distal  pyramidal  most  i s a  collaterals  the  o f f into  demonstrated  the  synaptic  output  radiatum  with  o f CA1  region,  fibre  o f t h e CA3  stratum  synaptic contacts  moleculare.  there  neurons  in  dendritic  hippocampus  make  and v i a unmyelinated  into  on  studies,  and  (granule  apical  the  t h e mossy  where  the fimbria,  hippocampus,  collaterals)  (e.g.  located  interconnecting  gyrus  region  gyrus  fashion  influences  loop  cells  Efferent  into  well  results in  activity  an e x t e n s i v e  t h e d e n d r i t e s o f CA3 p y r a m i d a l  project the  with  dentate  of the granule  layer.  spike  the dentate  the basis of anatomical tri-synaptic  with  It i s also  bicuculline  in a laminar  inhibitory  described  projects  of  throughout  interneurons  likely  Axons  to  multiple  neurons  granulosum,  arborization  blocker.  1983).  are also  Basket  exposure  seizure-like  principal  stratum  a GABA  1974).  potent  including The  the  dendritic  5  region  of  to  than  the  and  the  GIu  1974) the  shape  the  of  pyramidal cell  Storm-Mathisen, the  GIu  be  Extrinsic  above,  the  the  to  afferent  innervation  sources,  including  cingulum,  septum,  contralateral commi s s u r e s .  lesion  a_l,  the  in  this  a  (Iversen  &  afferents a  region,  (Storm-Mathisen,  1978).  showed  CA3  in  substance  to  highly suggesting  mediating  the  1977).  Pathways  the  tri-synaptic formation  from  both  entorhinal amygdala,  hippocampal  et_  regions  of  et a l ,  in accordance  results  transmitter  hippocampal  responsive  (Schwartzkroin  CA1-CA3  uptake  pathway  more  tritiated-Glu  region  GIu  be  (Spencer  the  Surgical  Afferent  addition  of  CA1  in  collateral  In  tree using  SO  1976).  drop  might  Schaffer  B.  and  ipsilateral  significant that  SR  to  is distributed  studies  in  seemed  themselves  dendritic  Autoradiographic  to  bodies  sensitivity  the  concentration  cells  circuit  also  receives  cortical cortex,  locus  formation  and  the  other  subcortical  pyriform  coeruleus via  described  and  cortex, also  the  hippocampal  6  1.  Entorhinal  The  first  described  'en  neurons  passage'  cells from  in  SM  cortices to  gyrus, &  also  of  from  (Ramon the  of  dendrites  to  1966).  the  The m e d i a l and  one-third  medial  of the  CA1  hippocampus  & Scoville,  projections gyrus  of  and  and 1976).  CA3  is  entorhinal paths  the  dentate  1972;  Steward  lateral onto  form  granule  perforant  & Jeune,  topographically  lacunosum-moleculare  The  and l a t e r a l  o f t h e SM  Cajal,  and  the  dentate  lateral  y  the  entorhinal  the  & Cowan,  The  path  axons  (Hjorth-Simonsen  project  (Steward  afferents  previously  fissure  cortex  1976).  loop  the hippocampal  v i a the medial  respectively  Scoville,  cortices  (Laatsch  and outer  path  perforant The  with  specific.  project  the middle  the  1934).  entorhinal  topographically  principal  perforate  synapses  the  the  via  d e No,  Perforant  of the t r i - s y n a p t i c  i t s  cortex  Lorente  cortical  synapse  receives  entorhinal 1911;  cortex/  entorhinal the  regions  stratum of  the  7  2.  Septal  input  Denervation staining  of  Shute,  both  neurons  from  and  the  AChE  staining  and  below  Lewis,  passing  neurons  for  septal  nucleus  through  being  the  Most  (e.g. (1978)  Bland,  et  al  a  differential pyramidal studies.  using  a  granule  1974;  Wheal  septum  layer  ACh  similar  via  the  &  regions cell  (ACh)  sensitivity those  the  (Storm-Mathisen  & Miller,  to  via  or  a  of  pattern just  layers  on  (Shute  & an  hippocampal  1980).  Spencer have  in areas the  of  above  mainly  microiontophoretic technique of  band  considered  reported  acetylcholine  pattern  cell  to  investigators  of  cholinergic  distribution  mainly  &  (ChAT)  diagonal  ChAT,  in  Lewis  hippocampus  neurons  earlier  and  that  medial  by  cholinergic  pyramidal  action  the  staining  localized  (e.g.  and  i n n e r v a t e the  the  . decrease  acetyltransferase suggested  bundle  confirmed  1961).  excitatory  ChAT  medial  marker 1973),  subsequent  1974)  Histochemical  superior Fonnum,  choline  a l ,  forebrain  fimbria.  the  et  projections  medial  showing  a c e t y c h o l i n e s t e r a s e (AChE)  1967)  (Oderfeld-Nowak  from  studies  shown around  AChE  and  8  3.  Commissural  Two carry  commissures,  the  fibres  hippocampal psalterium cortex,  of  contains  dorsal  of  axons  o f CA1-CA3  that  contains  also  (Lorente  de  a l ,  projections dentate  from  region  of  hippocampus  t o SO m a i n l y  lacunosum-moleculare  the  entorhinal  cortex  Commissural  (Blackstad,  projections  t h e c o n t r a l a t e r a l CA3  The  in  SO  innervation homotopic  than  SR  t o SR  mainly  projection  from  1956).  t o t h e CA3  and  CA3,  a minor  hilar  1 9 7 3 ; S w a n s o n e_t a l , 1 9 7 8 ) w i t h pronounced  from  receives  1973; S w a n s o n e t a l , 1978)  to stratum  Swanson  hippocampal  1956; G o t t l i e b &  the  and  more-or-less  the  psalterium  1978).  ( G o t t l i e b & Cowan,  reciprocal  ventral  (Blackstad,  gyrus, p r e - s u b i c u l u m and  Blackstad,  from  more  lacunosum-  Cowan,  1934;  afferents  Cowan,  stratum  No,  contralateral  from  dorsal  entorhinal  gyrus  The  The  the  the  dentate  1975).  from  cortex  CA1  the h i l u s  to  psalteria,  the para-subiculum, and the e n t o r h i n a l  Swanson e t a l ,  The  project  the  t o the hippocampus,  possibly  hemisphere.  subiculum,  interhemispheric  region  ventral  innervations  each  and  et  and  reciprocal  formations  Goldowitz  1973;  the  para-subiculum,  moleculare 1956;  afferents  region region  mainly  (Gottlieb  the innervation  (Swanson  e_t a l , 1 9 7 8 ) .  o f t h e c o n t r a l a t e r a l CA3 in density  arise  regions  ( G o t t l i e b & Cowan,  &  being The are 1973;  e t a l , 1978) .  dentate  gyrus  receives  commissural  afferents  from  9  the al,  contralateral 1978; B e r g e r  hilus  and e n t o r h i n a l  aJL,  e_t  1981).  The  projections  to the c o n t r a l a t e r a l  termination  patterns  projections: the  outer  intense  as  medial  one-third  of  innervation  projection  from  terminates  in  4.  source  stem  o f 5-HT  selective  raphe  autoradiographic that  axons  forebrain the  from  innervation similar  to  nucleus  a  more  t h e upper The  blade  commissural dentate  o f t h e SM & Cowan,  has  (Lorens  by M o o r e  and a r r i v e  and cingulum. p a t t e r n o f 5-HT  been  gyrus  (Blackstad,  1973).  shown  to the hippocampal  technique  t h e median  the  and  to  (5-HT)  study  bundle  fornix  1967; G o t t l i e b  innervation  lesioning  one-third  path  afferents  serotonin  median  than  1976).  similar  and l a t e r a l  to the c o n t r a l a t e r a l  inner  & Cowan,  Brain  a.  The  the  have  1976),  blade  cortical  perforant  one-third  (Steward,  Steward,  the h i l u s  gyrus  ipsilateral  t o the lower  e_t a l , 1 9 7 5 ;  Laatsch  SM  (Swanson e t  entorhinal  dentate  to the middle  (Goldowitz  1956;  the  cortex  raphe  course  noradrenergic  the  formation  by a  through  study  1974).  (1975)  i n the hippocampal  afferents  be  & Guldberg,  & Halaris  T h e same  to  also  An  suggested  the  medial  formation v i a suggested  the  t o the hippocampus  is  innervation  which  will  be  10  discussed  in detail  terminals  in  concentrated border (1974)  of  remain  in a  of  depressant  of  5-HT  formation  65*xm  gyrus  wide  (Moore, action  cells  in this  Serotonergic are  along  the  1975). of  region  the of  ventral  Segal  5-HT  but  mostly  &  to  Bloom  neuronal  mechanism the  and  hippocampus  unclear.  norepinephrine  Early presence  densely  of  noradrenergic formation  innervated  Blackstad content  a l ,  (Anden  et  generally  agreed  exclusively mainly  the  via  peduncularis a  concentrating  the  1971;  (Loy  et  diffuse i n the  SR  gyrus  the  being  more  investigations  NE  uptake (Uretsky  above et the  1980).  Iversen,  a l , 1978)  revealed  hippocampus  arises  The  hippocampal  Moore  &  that almost which  formation  Bloom  of  noradrenergic  of  but  fibres  are  1970)  bundle-ansa  plexus CA1,  NE  recent  projection,  amygdaloid  of  Thompson,  More  the  ventral  &  &  1965;  findings.  coeruleus. at  (Fuxe,  (Gage  the  of  Biochemical  of  a l ,  regions  proper  arrives  the  demonstrated  hippocampus  Koda  locus  ipsilateral,  principally  reported  with  in a l l dentate  hydroxylase  innervation  from  the  a_l, 1966),  (Ungerstedt,  noradrenergic  the  1967).  tyrosine  studies  terminals  with  than  e_t  and  studies  (NE)  immunohistochemical  hippocampal  is  about  pyramidal  role  b.  1980)  band  a  following section.  hippocampal  dentate  reported  functional  the  the  the  discharge  in  also  (1979)  terminals observed  11  to  course  branch  along  off  the  to  dendritic shafts  ,run  laterally  described  fluorescent  along  the  dendrites  found  to  whether are  appose  these  truly  discussed  in  types  the  1980)  in  showed,  the  in  the  first  the  spontaneous  might  gyrus  that  and  NE  seemed  ACh-induced  its  of  to  Using  al_  significant  also  question  binding of  of  and  studies both  a-  (Crutcher  The  latter  &  study  ligand,  a-receptor  that  found  Segal  &  affect  dose-dependent  the  firing  inhibitory of  binding in  the  the  a  on  reported the  Perfusion  by  NE  a  slight  conductance  increase  to  both  pulses  recording although  spike with  the  that  extracellularly  population  manner.  that  on  demonstrated  response  extracellular  effect  (1974)  pyramidal  action by  Bloom  hippocampal  depolarizing current  (1981)  effect  an  recordings  decrease  al,  1981).  technique,  accompanied  and  does  were  a-receptor  twice  inhibitory  hyperpolarizing  et  is  mainly  investigated  region.  density  exerts  Intracellular exert  Mueller  the  (1980)  innervations  /^-adrenoceptors  specific  iontophoretic  hyperpolarization which  The  Receptor  hippocampal a  few  and  proper.  showed  neurons.  a  concentrations and  al  situated  but  be  cells  et  terminal  will  thesis.  that  dentate  hippocampus  Using  not  using  Loy  interneurons.  or  1977)  SP.  neurons  putative  significant  tritiated-WB4101, sites  of  pyramidal  varicosities  of  present  e_t a l ,  along  pyramidal  functional  (U'Prichard  also  of  somata  two  demonstrated  Davis,  terminal  of  (Langmoen  NE  recorded  at  5MM  et  potentials,  amplitudes NE  constant  has  no  EPSP,  it  in  resulted  a in  1 2  a  potentiation  25/iM of  NE  of  resulted  response  the in  whereas  amplitude a  perfusion  inhibition.  The  (^"adrenergic  agonist,  other  hand,  the This  effect  suggested  inhibitory  effect  potentiating opposing  actions  at  same  study had  low  on  the  that of effect  a  high  with  NE  spike,  showed  resulted that  inhibitory  ^-adrenergic population  whereas on  population  50MM  a-receptors  relationship and  the  potentiation-inhibition  also  an  isoproterenol,  potentiating authors  biphasic  of  0-receptors  pyramidal could  agonist,  might  explain  concentrations.  cell the  in  clonidine,  effect;  spike  type  on  an an the  exerted  a  response.  The  mediate  the  might  mediate  excitability. reversal  of  NE  1 3  C.  The P r e s e n t  The of  functional role  the hippocampus  addressing  1.  three  What  This  placed  the  (EPSP)  a l (1981) spite  al,  o f NE  t h e s i s by  on t h e d e n d r i t i c a n d  was NE  an  on  attempt  CA1  i n view  of  NE  confirm  pyramidal  investigators.  effect  to  cell  Special  on t h e p o p u l a t i o n  of the s u r p r i s i n g report  the population  EPSP  innervation  o f CA 1 ( B l a c k s t a d ,  1967; Moore  activity  in  was  dendritic  by  Mueller  i s not a f f e c t e d  i s concentrated  the  emphasis  of the anatomical/immunohistochemical  noradrenergic region  i n the present  region  responses?  of  that  i n t h e CA1  questions:  study  by p r e v i o u s  response  in  field  action  on  investigated  major  initial  inhibitory observed  was  of norepinephrine  i s the e f f e c t  somatic  et  Study  by  evidence the  & Bloom,  NE  that  dendritic  1 9 7 9 ; L o y et_  1980).  2.  What  i s the e f f e c t  o f NE  on r e c u r r e n t  basket  cell  i n h i b i t ion?  The  effect  hippocampus, examined. reduced spinal  of  like  Engberg the  many  action  on  most  processes  o f t h e CNS,  (1970)  first  post-synaptic  Jordan on  inhibitory  parts  & Thaller  inhibitory  motoneurons.  depressant  NE  &  McCrea of  the  in  has s c a r c e l y reported  potentials (1976) spinal  the been  that  NE  (IPSPs) i n reported  a  interneurons  14  responsive studies  to  have  motoneurons et  al,  and  of  duration, In  et  al  (1981)  and  Madison  also  the  their Loy  the  basket  cell  was  the  and  influence  on  pyramidal  3.  of  What  i s the  cells.  cell  that  NE  NE  of  not  the only  neurons the  the  but  present  the  system  its in  in  Langmoen  IPSPs  In  cells  the  NE-containing  principal  monitoring  effect  of  NE  on  field  6-hydroxydopamine  hippocampal  the  using  interneurons  that  basket  Nicoll,  paired via  the  inhibitory absence  or  NE.  following  On  &  investigated using  collaterals  presence  (Jahr  mentioned  system.  The  amplitude  (1980),  of  likely the  inhibitory  both  revealed  (1982a)  recurrent  CA1  al  pyramidal  on  recently  mitral cells.  firing et  near  (Jordan  was  s y n a p t i c a l l y evoked  activating  the  NE  in  somata  influences  by  the  decreased  seems  possibility  paradigm,  onto  & Nicoll  It  recurrent  this  of  found  fibres  bulb,  technique,  the  cells.  inhibitory  study,  cells  the  dendrites  decreased  interneurons  dendrodendritic  facilitating  the  on  the  were  to  histochemical  NE-containing  hippocampus,  exerts  pulse  cells  apposed  pyramidal  small  olfactory  to  invariably CA1  the  histochemical  varicosities addition  thus the  fluorescence  with  granule  mitral  Fluorescence  many  attenuate  the  the  1982).  In  to  of  that  invested  1977).  feedback  treatment.  shown  are  demonstrated  IPSPs  NE  noradrenergic  basis  electropharmacological  of  lesion  of  the  inputs?  previous  studies,  responses  histochemical  i t seems  likely  t h a t NE  and is  15  involved  in  neurons  and  and  the  depend to  r e g u l a t i n g the the  proper on  balance  examine  ascending  inhibitory  NE  altered  noradrenergic number  lesion  catecholaminergic  reduction  leaving  Jacobowitz,  1973).  a  similar  content  in  the  showed,  early  as  five  neurotoxin, more  days  lesions  1969).  In of  the  i t s endogenous  NE  The  possibility  disrupted  differential and  the  reported  to  produced  (1975,  of  a  the  CNS  1979)  &  using  5,7-dihydroxytryptamine a  70% the  decrease above  treatment.  A  (6-OHDA),  showed  noradrenergic study, slice  the  to  NE will  the  between be  .studies  more  and as  popular  similar  but  (Uretsky of  preparation  f u n c t i o n i n g of  NE  sprouting  effect  was  in  axonal  neurons  treatments  processes  the  (Richardson  by  6-OHDA  of  of  hippocampal  area  processes  supersensitivity  inhibitory  al  order  selectively.  wide  A l l of  hippocampal by  been  to  levels  histochemistry,  present  of  of  the  of  In  lesions  intact  of  after  physiology  cells  et  these  the  to  in a  including  6-hydroxydopamine  complete  Iversen,  of  likely  processes.  has  neurons  Bjorklund  degeneration  hippocampus,  endogenous  NE  fluorescence  pyramidal  is  6-hydroxydopa  forebrain region.  using  terminal  in  result,  the  neurons  injections  showed  the  i n n e r v a t i n g the  of  dopaminergic  intraventricular  two  neurotoxins  injection  of  selective  system  A  while  these  by  formation.  dose-dependent  of  both  hippocampus  possibility,  were  Intraventricular  the  between  this  of  interneurons  f u n c t i o n i n g of  the  hippocampal  activities  NE  & on  deprived  investigated. system the  due  pyramidal  discussed.  16  CHAPTER  A.  II  MATERIALS  In V i t r o  Slice  Experiments obtained  from  decapitation  and  their  oxygenated  containing  ( i n mM):  K HP0 2  of  1.25;  4  the  NaHC0  (450£tm  septo-temporal slices  were  chamber  and  Warmed over  and the  then  CSF,  recuperate hour  before  removed  and  KC1  a  The  in  a  to a  the  cut  a  0 ,  5%  trauma  commenced.  placed  in  gas to  4  2;  transverse  perpendicular  to  chopper. in a of of  The  recording  34.0  ±  1.0°C.  also  flowed  ensure  least  the  oxygenated,  mixture  allowed to for at  MgS0  tissues,  temperature 2  (CSF)  dissection  2ml/min  C0  fluid  Following  tissue  chamber were  by  and  2  n y l o n mesh  of  to 2  slices  recording  10.  were  rate  95%  surgical  CaCl  Sorvall  transferred at  5;  slices  sacrificed  cerebro-spinal  surrounding  warmed  slices  from  brains  D-glucose  using  humidified  oxygenation.  were  in thickness)  perfused  artificial  Animals  from  axis  hippocampal  rats.  124;  24;  3  on  artificial  NaCl  hippocampus  sections  performed  Wistar  ice-cold,  METHODS  Preparation  were  male  AND  adequate  equilibrate 45min  to  and an  17  B.  E l e c t r o p h y s i o l o g i c a l and  Bipolar visually  stimulating  positioned,  microscope,  in  orthodromic to  evoke  of  single  square of  Glass  of  2-6  extracellular  of  through  response  the  EPSP  in was  were  the  CA1  (Fig.  the  peak  positivity  spike  from  was  amplified,  oscilloscope signal  orthodromic  led  micropipettes solution.  a  peak to  PDP  alveus  consisted  to  and 1).  having  a  the  the  population  The  amplitude  to  spike  peak,  the  response  from  and  Electrical and  tip  record  negativity,  peak.  11/23  the  and  baseline  (1-0.1kHz),  recordings  (50-80MO)  filled  Cell  penetration  capacitance  compensation  oscillation frequency. the  to  in  for  activity  displayed  computer  the  for  on  an  on-line  averaging.  Intracellular  high  to  SR  population  baseline  filtered  or  from  NaCl  used  the  of  antidromic  the  2M  in  measured  region  unit.  response of  CA1  Stimuli  isolation  (Mfl)  SP  dissecting  0.1msec) d e l i v e r e d a t  with  amplitude first  (1-15V,  were  a  and  1).  filled  megohms  EPSP  (Fig.  an  of  cells,  Procedures  diameter)  hippocampal  pyramidal  pulses  (62 jum  aid  the  responses  wave  0.1Hz  the  of  micropipettes  resistances  spike  SR  a c t i v a t i o n of  antidromic  frequency  electrodes  with  the  Pharmacological  and Once  electrode  vibrates penetration  t i p resistance  were  performed  with  1M  was  aided  which the was was  with  potassium by  a  creates  balanced  acetate  sudden  break  high  frequency  electrode  successful  glass  tip  and out  at  to  high  stabilized, by  electronic  18  subtraction bridge.  which  Membrane  resting  membrane  current  pulse  i s functionally  equivalent  properties  assessed  potential  injections.  criteria  were  of  potentials  action  (RMP) m o r e  Once added  stabilized  time  from  experiments amplitude  pre-exposure changes  were  input  resting  -60mV  and input  15min  monitored  by  met t h e f o l l o w i n g  were  20MO.  v i a a three-way  valve.  a n d c o n c e n t r a t i o n s o f NE was  used Changes  a  drug  percentage  intracellular potential  measurements.  >  o b t a i n e d , NE was  or following as  potential  resistance  effect.  For  by a c t i o n  resistance  membrane  50;iM  during  expressed  controls.  resistance  responses  maximal  of the responses  the  experimentation: amplitude  although  ensure  and  that  75mV;  for  10 t o 50uM,  monitored  cells  CSF p e r f u s a t e  lasted  to  Only  control  to the a r t i f i c i a l  ranged  and  >  by m e a s u r i n g  (RMP) a n d t h e i n p u t  for further  n e g a t i v e than  Perfusion  were  chosen  were  t o a Wheatstone  in  most  i n the exposureof  the  recordings,  generation,  RMP  19  C.  Paired  The cycle a  Pulse  paired  Paradigm  pulse  of a c o n t r o l ,  conditioning  intervals.  paradigm  test  (Tc) pulse  (C) a n d t e s t Data  was  of eight  electrode  to synaptically  test  pulses pulses  at not  C-T  spike  were  pulse  intervals  only  but  also  averaging  either  the test  conditioning by  taking  the  SR-evoked paired degree control  was  obtained  pulse  control the  test  test  pulse  was  was the  percent  amplitude  population  the  recurrent  interneurons. last  5  the  was  pulses  paired of  with  determined of  obtained  conditioning pulse  of the  inhibition  amplitudes  and that  as a  On-line  by the when  ( T p ) . The  percentage  of  the  amplitude:  inhibition  compared  antidromic  antidromic  pulse  expressed  spike.  (Alv)electrode  The d e g r e e  between  SR  stimulation  ( T c ) o r when  (C)  the  Alvear  the  (Tc) response  %inhibition The  alone  antidromic  inhibition  by a n  activates  from  and  by e i g h t a d d i t i o n a l  ( F i g . 2A).  cell  to  of C-T  periods  population  preceded  (C-Tp).  difference  min  to the alvear  v i a basket  responses  3  particular  delivered  characteristic  the conditioning  with of  (C) a p p l i e d  orthodromically  Alv  produced  was  by a p a i r i n g  at  followed  of which  inhibition  signal  at  (0.2Hz)  immediately  the  (Tp)  a c t i v a t e t h e CA1  o f 20-30msec  evokes  collateral  Tc p u l s e s  (Tp) each  conditioning  pulse  of a s t i m u l a t i o n  followed  collected  consisted  These  consisted  before  =  (Tc - Tp / Tc) x  100%  ( % i n h i b i t i o n ) of the p o p u l a t i o n and during  of the p o p u l a t i o n  50MM N E p e r f u s i o n s . spike  itself  was  spike Since,  influenced  20  FIGURE  2.  A.  Schematic  In  control,  the  test  stimulating inhibition a  Diagram  control (Tc)  SR  the  Paired  condition  response  alone.  i s assessed  preceding,  of  is  Then  by  pairing  conditioning pulse  (no  Pulse  drug),  first  a  stable  established  the  degree  this  test  (C)  Paradigm  of  recurrent  pulse  d e l i v e r e d to  by  (Tp) the  with alveus  (Alv).  B.  In  control,  the test  according  to  argument  that  amplitude  of  its  pre-NE  inhibition  presence pulse  Mueller the  the  NE  would  (50/LIM), be  e_t a _ l , 1 9 8 1 ) . degree  control  amplitude is  of  of  reassessed.  response  smaller In  to  be  before  to  the  trace;  avoid  i s dependent  i t would  trace)  (dotted  order  inhibition  response,  (solid  the  the  on  readjusted paired  the to  pulse  21  by  NE  avoid  (as reported t h e argument  might  somehow  spike  itself,  response the a  control  degree  amplitudes during  NE  NE  was  of  the  unaltered  to  activating  intensities  activated  keep  intensity  of  1.2x the  Tc  of  pulse  amplitude  established  both  recurrent  (C)  which  range  before  However,  conditioning  a  in  of and  a l l the  pulses  inhibitory  as  reason,  in  against  responses  (Tc)  were  interneuron  constant.  of the p a i r e d  Pyramidal  test  inhibition  test  population  F o r t h e same  plotted  cells  by  conditioning  degree  assessed  was  to  inhibition  of the  t o t h e same  2B).  was  threshold  the paired,  then  curve  correlates  inhibit  was  the  examined. at  amplitude  (Fig.  i n order  recurrent  perfusions.  alvear  Intracellular  of  readjusted  the  1981) a n d  of the c o n t r o l  inhibition  (50/xM)  also  the  response  (1-5mV)  experiments,  were  on  y_s a m p l i t u d e of  e_t a l ,  the degree  the amplitude  %inhibition  the  that  depend  during  pre-NE  by M u e l l e r  SR Alv  (Tp) p u l s e  produced  by  i n the presence  pulse  were  synaptically  stimulation pulse  50% o f  was the  NE.  and  adjusted time.  the conditioning o f 50MM  paradigm  the to The  (C) .pulse  22  D.  6-Hydroxydopamine L e s i o n s  This in  vitro  slice  subjected the  s e t of  experiments  preparations  injections,  prevent  premature  bilateral dorsal  (n=5)  central  intracerebral  result  (Assaf,  of  NE  levels.  in a consistent  fifteen  the  injected  to  Both (n=3) o r  o f 6-OHDA i n t o t h e were  used  NE l e v e l s  85-95% r e d u c t i o n  to  were n o t  been  shown  o f h i p p o c a m p a l NE  A l l in v i t r o  6-OHDA-treated a n i m a l s was p e r f o r m e d  with a  6-OHDA.  have p r e v i o u s l y  1978; A s s a f e t a_l, 1979).  to  i.p.)  and u n i -  2vg/uD  Although  rats  Prior  (50mg/kg  injection  (2M1 o f  measured, b o t h t y p e s o f l e s i o n s to  were  pargyline  oxidation  n o r a d r e n e r g i c bundle  deplete  animals  (n=5) (25M1 o f lOuq/ul)  intraventricular  on  (6-OHDA) l e s i o n s .  the  monoamine o x i d a s e i n h i b i t o r ,  performed  o b t a i n e d from male W i s t a r  t o 6-hydroxydopamine  6-OHDA  was  r e c o r d i n g on  6-8 weeks f o l l o w i n g t h e  lesion. The used  in  experimental this  extracellular were m o n i t o r e d .  paradigm  s e t of field  described  experiments  as  in section  well.  B was  Both  the  r e s p o n s e s o f EPSP and p o p u l a t i o n  spike  23  CHAPTER  A.  III  The  RESULTS  Extracellular  Stimulation negative-going which  was  (Fig.  1 &  of  the  EPSP  maximal 3).  intensities  were  as  controls.  pre-NE  response  on  the  reflection  of  the  is  manifested  intensities,  as a  superimposed  on  discharge  a  et  a l ,  of  positive  peak  experiments. the  an  of  positive-going  of  positivity  amplitude the latency  stimulation  (±  of  1mV  latency  for  this  in of  2mV,  evoked  reflects  to  peak  SP.  the  was  averaged  the  6.0  ±  the  of  At  SR  higher  spike  is  synchronous (Andersen between  the  used  first  for  (negative) 0.8msec  characteristic  the  i n the  standardize from  is a  to  neurons  stimulus-to-peak  response  Due  population  measured  negative of  in the  The  response  recorded  pyramidal order  n=3l).  characteristics  wave  and  region  amplitude  EPSP  EPSP  CA1  experiments,  ( F i g . 3A).  the  of  this  S.D.;  the  negative-going  Again,  region  of  EPSP  dipole  p o p u l a t i o n of  The  an  volley  a  to  third  s l o p e of  reflection  the  dendritic  1.1msec  ±  fibre  population spike  Alvear  evoke  a  1971).  experiments,  apical  characteristic  s t a n d a r d i z e between  downward  sharp  the  stimulus-to-peak  relationship  cells,  evoked  middle  to  The  5.5  inflection  pyramidal  the  adjusted to  averaged  source-sink  the  order  Responses  SR  in in  In  Field  short  most of  (n=l7). latency  24  FIGURE  3.  Characteristic  Extracellular  the  CA1  Stratum of  SR  fibre the  radiatum  the  occasionally  i n t e r r u p t e d by  volley  stratum  Alvear going  the  of the somatic  EPSP  (SP)  population  discharge  baseline (C).  (A)  inflection  recorded  of  spike  (B)  spike  level  which of  by  the  representing of pyramidal  the short arising  is the  intensities,  at the l e v e l  i s superimposed  of a p o p u l a t i o n  population  at the  suprathreshold  (Alv) stimulation e l i c i t s antidromic  response  slight  At  negative-going synchronous  EPSP  (arrowhead).  pyramidale  Responses  Region  (SR) s t i m u l a t i o n e l i c i t s  negative-going  positivity  the  Hippocampal  Field  latency straight  of sharp the  neurons. negativeoff  the  25  negative-going SP.  The  (n=l0)  B.  antidromic  stimulus-to-peak  (Fig.  3).  Effect  of  Although 50MM  NE,  with  10MM  NE  NE  in  the  in  This  perfusion. to  control  application. consistently possibilty 4).  obtained. inhibitory higher the  exhibited of  dual  Stimulus As  the  at  the  the  in low  the  0.2msec  but  no  in  the  Perfusion  EPSP  of  50MM  with amplitude  4~7min  population  termination  rebound  excitation,  suggesting  action  of  pyramidal  vs  Fig.  EPSP 5,  stimulus  NE  on  amplitude had  a  more  intensities  became  less  spike  evoked  by  orthodromically  evoked  fibre  spike  of  spike  NE  of  (20-23%)  following  and  the  significant  spike  maximal  with  population  inhibition  population  the  out  perfusion  following  intensity  shown  effect  levels  nor  a  a  ±  carried  population  usually  Both levels  1.6  tested.  50%)  reduction  the  was  Moreover,  antidromic  alveus  and  in  enhancement  However,  consistent  effect  also  (about  response.  (25-28%)  were  were  consistent  response  a  averaged  experiments  a  recorded  Responses  concentrations  EPSP  EPSP  returned  (Fig.  the  spike  latency  Field  produced  the  drug  on  of  spike  responses. of  most  resulted  both  NE  lower  population change  population  drug  response the cells  plots  were  pronounced whereas  marked.  Neither  s t i m u l a t i o n of volley  at  the  response  26  FIGURE  4.  Time  Course  of  NE  Action  on  t h e CA1  Evoked  Responses  NE  (50/uM)  population  produced ( A  spike  ) a n d EPSP  ( •  responses  were  least  six  30min  a n d an  Note  the  spike  but n o t t h e EPSP  subsequent  control average  computer-averaged during  NE  of these  consistent  graphs,  and  Note  the lack  EPSP  responses  a consistent  error  30min  of e f f e c t  as  recovery.  (n=11).  (At  "100%  (In  pre-NE  after  termination  o f NE  on  i  the  e x c i t a t i o n of the  from  (arrowheads).  both  recorded over  b a r = ± S.E.M.).  responses  in  ) responses  i s taken  rebound during  reduction  the  more  control"). population  this  and a l l  Traces  show  control, of drug  fibre  than  the  15min  perfusion.  volley  in  the  26.1  + 10  20  30  40  50  60  Time (min)  CONTROL  15 min  45 min  Pop. Sp. imV  EPSPwfl  0-2mV 5 ms  27  FIGURE  5.  In to  EPSP  the  the  of  t-test  significant p<0.05)  presence  right  Student's  but  increasing intensities correlation  at not size is  of  traces  profiles  of  vs  Stimulus  50MM NE  that  of  the  demonstrated low  significant of  ( A  Intensity  ),  the  pre-NE  that  stimulus  the  at  high  SEM  with  however  not  readily  show  averaged  for the  field  the  control  intensities  (N.S.)  ( • were  (***,  and  shifted )  (n=4). highly  p<0.0l;  intensities.  explicable.  linearity  before  was  increasing  corresponding EPSPs  curve  changes  the  coefficient  Bottom  perfusion.  Amplitude  of  the  *, The  stimulus (r  =  curve).  stimulus-response during  50/nM  NE  27.1  0.8 - i  0.6  H  0.4  H  > E  ^ Q.  E < CO  Q_'  UJ  0.2  0.0  T  0 Stimulus  Control  1 Intensity  2 3 4 ( I n c r e m e n t s in V o l t s )  NE 5 0 p M  .4mV 10 msec  28  were  a l t e r e d by  C.  Effect  1.  similar  o f NE  on  a  electrode,  consistently  inhibited  activation  the  The  paired  conditioning-test  was In  6A).  of  therefore  chosen  the c o n t r o l  was  spike,  such  that spike  50MM  a  inhibition  Fig.  8,  range to  be  the  pulse  inhibition  effective  of  as  population  to  (Fig.7  2mV  was of  8).  potent this  In  over  and  amplitude  of  inhibition  the  population when  paired  when  of  As  of  pulse  shown  in  amplitude  decrease the  the  the c o n t r o l  the whole  this  period  the presence  in  8).  at  paradigm.  greater  observed  (Fig.7 &  5 0 M M NE the  &  reduced  and  was  reduction was  interneurons  the degree  inhibition  was  presumably  most  of  alvear  spike  experimental  the amplitude  63%  at  was  20-30msec  (no d r u g ) ,  the  20-60msec,  inhibition  interval  small  pre-set  to  inhibitory  f o r the present  i n the presence more  applied  recurrent  (disinhibition)  ( T c ) was  pulse  of  consistent  pulse  Inhibition  SR-evoked  the percent was  NE.  for periods  related  population NE,  the  situation  inversely  of  responses  conditioning  stimulating  (Fig.  Recurrent  Extracellular  Following  by  concentrations  appeared  population  29  FIGURE  6.  A.  Effect  In  evoked  the  evoked,  test  B.  In  response the  evoked  control. antidromic  (C)  drug),  (Tc)  spike,  a  stable  SR-  response  preceded  antidromic  presence  response was  by  which  i n h i b i t o r y system,  of  50MM  (dotted  NE,  trace)  (solid  trace).  of  bottom  the  significantly  the  spike  (no  control When  Inhibition  the  was  alvear-  presumably reduced  the  response.  reduced  Note  Pulse  condition  recurrent  amplitude  (Tp)  inhibition  (Tp)  was  pre-NE  the  the  Paired  trace).  conditioning  paired,  on  spike,  (upper  activated  NE  control  population  established  also  of  lack  of  response.  effect  the and  As  reduced NE  was  the as  on  the  test  readjusted  evident  trace,  of  control,  from  the  paired compared  to SR-  pulse with  alvear-evok'ed  29.1  30  FIGURE  7.  R e l a t i o n s h i p between Population Absence  Spike  of  control,  test  pulse  (Tp)  As  shown  in  %inhibition, lower NE  of  amplitude,  pulse  the  in  show  (Tc)  paired upper  pulse  spike  and  pulse traces  amplitudes.  in  the  In  the  reduced  Tc  more  over  potent  seemed  of  the  6).  at 50MM  entire  inhibition  amplitude  amplitudes.  Fig.  presence  pulse  %inhibition  response  the  was  paired  a b o l i s h e d at  of  corresponding  inhibition  that  responses  and  Note  higher  and  (cf  range.  at  Presence  the  paradigm  was  reduction  and  the a l v e a r - c o n d i t i o n e d ,  %inhibition  NE-induced  Inhibition  superimposed  traces),  completely  effective  traces  the  paired  population  (bottom  almost  test  Amplitude  Pulse  NE  Computer-averaged the  Paired  was  of  5mV.  The  to  be  more  ^U/y ^ 2  CONTROL  MEAN 67-5  v. INHIBITION  (n-5)  DURING N E  J  MEAN v. INHIBITION  REDUCTION INHIBITION  CONTROL  268  IN (%•)  60-3  PULSE  AMPLITUDE  (mV)  1  31  FIGURE 8.  %Inhibition  vs  Amplitude  of  Control,  Test  Response  The against treated  mean % i n h i b i t i o n the ( O  exponential  Tc )  (± S.E.)  from  Fig. 7  a m p l i t u d e s from b o t h c o n t r o l  conditions. curves.  the e n t i r e amplitude  NE  Curves  represent  is  plotted  ( • ) and  best-fitting  s h i f t e d the curve to the l e f t  range.  NE-  over,  80  32  spike  was  increased.  NE-induced effect  disinhibition  was  termination  2.  of  the  NE  cells  all  characteristic generation  action  of  which  retrograde  potential  (Fig.  arose  9C).  (Fig.  These  of  this  activation  was  (Fig.  10).  A pyramidal  100%  of  Alvear  the  examined  time  stimulation,  neuron  (8/8)  at  which  an  Mfl.  an  of  baseline action  orthodromically  and  were  followed  potentials  The  of  the  paired  pulse  synaptically of  the  effectiveness  intracellular  intensity  by  (IPSPs)  activation  on  also  spike  an  system.  was  The  antidromic  the  invasion  represent  using  amplitudes  stimulation  off  post-synaptic  influence  CA1  membrane  synaptic SR  straight  inhibitory  spike  the  spikes  IPSPs  cell  inhibitory  This  from twelve  produced  Both  inhibitory  basket  the  following  2 5 . 7 ± 1.9  and  somatic  hyperpolarizing,  recurrent  7).  stable  S.E.),  following  activated  9B & C ) .  (±  stimulation  which  reflecting  obtained  resistances,  elicited  potential  (Fig. 30min  displayed  response  Alvear  antidromically  were  66 ± 2 . 2 m V  EPSP  9A & B ) .  complete  (5mV),  recordings  input  were  amplitudes  perfusion.  RMP,  9 7 . 7 ± 4.7mV and  higher  approximately  recordings  characteristics:  (Fig.  in  Intracellular  pyramidal  the  was a l m o s t  reversible  Intracellular  of  At  1.2x  activated  spike paradigm activated  threshold. the  cell  33  FIGURE  9.  Characteristic Hippocampal  Sub-threshold EPSP  (A) a n d  generation  Pyramidal  stimulation  superimposed resulted  underlying  EPSP  in  after  post-synaptic the  CA1  supra-threshold  stimulation  B & C  SR  Intracellular  activation  (C).  on  in  spike  potentials  evoked  resulted  (IPSPs)  of the recurrent  EPSP  (B).  resulted cell  spike Alvear  with  no  hyperpolarizations  the so-called  basket  in  potential  the subsequent  generation,  the  the c h a r a c t e r i s t i c  the underlying action  of  Neurons  stimulation  an  Note  Responses  inhibitory  presumably system.  from  33.1  |20mV 20ms  34  FIGURE  10.  Intracellular  Correlates  of  Paired  Pulse  Inhibition  a. spike  Alvear  and  (arrows), (Tp)  the a  was  (Alv)  stimulation  characteristic  C-T  interval  delivered  to  of  evoked  IPSP.  At  30msec,  the  assess  the  the  the  antidromic  peak  of  paired,  potency  of  the  test  the  IPSP pulse  inhibitory  influence.  b. alone out  In  (left of  the  traces)  eight  conditioning of  the  c.  of  discharged in  a  the  cell  stimulations.  the  In  on  presence  the  eight  complete  (no  drug),  SR  spike  generation  When  preceded  discharged  Note  the  only  slight  stimulation eight by  four  times  the  Alv  times  out  hyperpoarization  IPSP.  the  NE  in  stimulations.  hyperpolarization effect  condition  resulted  pulse,  eight  indicating  control  due  of  probably  pyramidal times  50MM  out  disinhibition.  to  cell of  NE,  and  eight  despite a  the  slight  combination the  IPSP,  stimulations  of  the  the cell  resulting  a. Alv  20ms  b.  Control  -60-100  J  Freq. ot Discharge to S R Stim.  SR ft, 8  35  antidromically orthodromic presence  (Fig.  5 0 M M NE,  conditioning  pulse  disinhibition of  the  was  out  eight  this  disinhibitory  hyperpolarization  (3-4mV)  6-8  although  threshold  somewhat  lower.  change  significant  spike  compared  of to  enhancement addition,  the  RMP  (data  not  the  alvear  NE-mediated  In  or  (Fig.  eight  addition  produced  a  10C)  to  slight and  an  shown).  obtained  did  had not  required  Perfusion both  reduced  controls  spikes of  differ  by  of  EPSP  this  5 0 M M NE and  While  11),  response  and  later  which  was  normals  resulted population  the  NE  degree  of  50%  as  produced  an  (Fig.  tertiary evident  were  parameter  approximately  (Fig. spike  from  6-OHDA  activation  with  the  hippocampal  received  for  preparations.  population  from  measurements  in  was  neither  the  seven  10C).  the  In  of  The  also  previously,  EPSP  secondary  recorded,  NE  which  these  normal of  (Fig.  animals  analyzed.  the  10B).  discharge  the  intensities  in  inhibit  Lesions  alterations  responses  inhibition  were  of  Quantitative  not  to  recordings  weeks  were  cell  increase  from  lesions  in  the  influence,  Extracellular  (Fig.  attenuated.  stimulations  conductance  removed  time  to  inhibitory influence  6-Hydroxydopamine  slices  adjusted  the  greatly  allowed  times  D.  was  activation half  of  equivocal  10A),  12).  In  discharges in  normal  36  FIGURE  11.  Effect in  A in  Slices  reduction  of  6-OHDA-treated  compared were  with  o f NE  the E x t r a c e l l u l a r  Obtained  the  from  inhibitory  preparations  normal  significantly  on  slices  different,  ( V  ( •  )  EPSP  6-OHDA-treated  effect )  (n=5)  o f NE was  (n=11). V a l u e s  p<0.05  (Student's  on  Responses Animals  the  EPSPs  observed at  as  I0~25min  t-test).  37  FIGURE  12.  E f f e c t o f NE Spike  Responses  treated  Enhancement perfusions observed Values  as at  Occurrence is  in  spike  and  during  and  the  in Slices  the  population  6-OHDA-treated  compared l0-25min  with were  of secondary  Traces  Extracellular  Population  Obtained  from  6-OHDA-  Animals  of  represented  controls.  on  as  ( O a  preparations  the  ( A  ) (n=9)  inhibition  significantly  different,  ) and  tertiary  percentage  of  recordings  discharges  f o l l o w i n g NE  following  normal  show t y p i c a l  multiple  spikes  perfusion.  at  ( • the  )  ( A  NE was ).  p<0.fJ1.  discharges  pre-perfusion  of the  population  i n d i c a t e d time  periods  37.1  150-i  + 10  20  30  40  50  60  Time (min.)  Control  15 min.  4 0 min.  2 mV 10 msec  38  control (Fig.  slices  12).  multiple 1  In  resembling and  Following  spike  hour.  return  discharges one  of  response  6-OHDA-treated  The  from  essentially receiving  burst  discharges  same  bundle.  the i p s i l a t e r a l  multiple  spike  hippocampus  (with  exhibited  NE  intraventricular as  had  medium,  no  i n excess  firing  were  observed  effect  the of  patterns during,  on  population  In  normal  obtained lesions  injections  hippocampus  the exception the  lesioned  either spike i n  slices  animals  of  were  animals  the  dorsal  subjected  to  o f 6-OHDA, NE p e r f u s i o n  produced while  the  characteristic  the  contralateral  of one, which  contralateral  control-like  in  from  a l l preparations  discharge,  by  responses  6-OHDA  those  6-OHDA  intracerebral  contaminated  neuronal  or the antidromic  bilateral  unilateral  control  o f 5 0 M M NE o n e v o k e d  the  noradrenergic  the  o f NE p e r f u s i o n  preparations.  effects  obtained  period  p e r s i s t e d f o rperiods  preparation,  interictal  volley  the  to  f o l l o w i n g NE p e r f u s i o n .  fibre  of  regardless  responses.  was  6-OHDA  probably  injection)  39  CHAPTER  A.  IV  Effect  As results of  NE  of  at  the  EPSP  in  the  neurons  to  reported that  were  the  discrepancy  may  consideration  the  were EPSP  employed  the  inhibition amplitudes  study  and  underlying  and  of  that  evoke their  the  by  the NE.  EPSP  probably  effect The  is discussed NE  in  50juM  effect  of  50yM  NE  on  the  EPSP  the  present  study  of  the  population  perfusions for  the  was NE  on  if  the  Therefore,  one  into  takes  response, easily  the  in  intensities spike Fig.  relative at  and This  population shown  spike  ( F i g . 4).  stimulation  As less  not  the  since  (1981),  high  study.  (1981),  differential  changes  effect  both  both  al  first.  accounted  fact  et  concentrations.  the  e_t a l  NE  produced for  study,  50MM  by  a  However,  of  be  in  lack  Mueller  intensity,  insignificant  these  is discussed  the  Mueller  (50MM)  high  present  by  indicated  amplitudes  to  responses  higher  by  reduced  Cells  demonstrated  disinhibition.  contrast  response  Pyramidal  present  of  hippocampal  showed  on  mechanism  mainly  In  NE  (10MM)  low  context  used  of  originally  possible the  DISCUSSION  nearly  inhibition  detected.  and  the  5,  the  degree  of  maximal would  be  40  There  are  inhibition  of  a.  a  number  pyramidal  of  neurons  reduction  in  the  ways  in  could  be  which  NE-induced  initiated:  excitability  of  the  activating  fibres; b.  reduction  in  synaptic  c.  reduction  in  the  efficacy,  synchrony  and;  of  pyramidal  cell  discharges.  The  first  effect  of  NE  antidromic synaptic would  possibilty on  spike  a  the  change  in  of  the  dendrites.  effected  by  the  slight  conductance  reported  by  equivocally  of  Langmoen  reported  the of  the  evoked  ionic  action  shunting  slow  Bloom  fluxes  as  potential; ionic  in  the  but  fluxes  by  This case  i t might of  probably  (mean:  2.7  NE  (1981)  the  be  local  slight  inhibitory as more  attenuated  and  the  number  as  an  ionic  might  not  affect  working  an  and  neurons  increase  of  and  application  However,  pulses  be  mV)  The  for  shunt  amplitude  'information  study.  conductance  et. a _ l , 1 9 8 1 ) .  EPSP  (1974).  possibly  of  pyramidal  depolarizing current  spikes  (Langmoen  fast  &  firing  reduction  Segal  account  of the  of  from  present  might  in  lack and  could  (1981),  the  NE-induced  to  accompanying  shunt the  Segal  responses  by  spontaneously  by  importantly,  al  the  volley  efficiency change  of  of  decrease  resulting  et_  response  on  the  case  hyperpolarization  demonstrated  NE  fibre  the  This  increase  hyperpolarizing effect  In  NE-induced  transfer'  the  in view  presynpatic  amplitudes.  efficacy,  suggest  the  is unlikely  antidromically  highly  effective  synaptic  in  potentials  41  orthodromically  a c t i v a t e d as  in  the  case  of  the  present  study.  In the  the  pyramidal  population  case  of the lack  cells  (which  spike  'readiness'  of input  stimulation  t o t h e SR.  discharge  pyramidal the  cells  recurrent  arrives,  might  affect  i t  pyramidal  synchronous  to  might  response), each  of synchrony  as i n the case  depend  inhibitory  on  cell  disadvantage  of  bath  likely  be  influenced  the  population  the  excitability  overall by  NE.  output  spike of  come  contact  b y NE a s w e l l . response, the  Due  perfusion  into  one  pyramidal  of the hippocampal  or  Hence  when  CA1  a  'readiness' of the  from  either  the  alleged  to the  inherent  technique, with when  one  alone  region  these  and  i s not r e a l l y cells  the  electical  this  system  interneurons.  also  an  influences  inhibitory  would  on  'pre-setting'  'feed-forward'  interneurons  of  of  of the  discharge  that  the  inhibitory  basket  the  depend to  It i s believed  by c h r o n i c  the amplitude  would cell  of discharge  as  quite  examines  monitoring but  the  influenced  42  B.  Effect  Before  in  dependency  conditioning  only  a certain  recruitment  spike and  at  identical  during  percent number  NE  basket  (Fig. 7 &  exerts  (pyramidal) recurrent in  cells.  an  inhibitory  a disinhibitory  Hence  by  constant.  were  two  also  of  that  t h e same  on  pulse  response number  that  (basket  the former.  lower  by  i n the presence  their of the of  NE.  experimental that the  significantly  lower a  percentage  on  before  the  reflects  suggest  of  population  amplitudes  o f NE  pulse  paired  higher  effect  despite  test  at  different  interneurons  Hence,  activated  lower  10), the r e s u l t s  influence  that  inhibited a  in  i f one c o n s i d e r s  conclude  were a c t i v a t e d  but  decrease  (see  (Tc) response  being  apparent  amplitude  degree  could  pulse  population  to the e x t r a c e l l u l a r  inhibitory  neurons  the  at increasing  assuming  one  spike  kept  cells  cells  cells  involved  was  the presence  demonstrated  approaches only  basket  cells  As  in  pyramidal  corresponding  expected  decrease  control  perfusion,  inhibition of  population  the  contributes  region,  The  pyramidal  to  paired  considered.  intensity  Furthermore, cells  CA1  on  of the  of basket  appears  NE  the amplitude  be  Therefore,  amplitudes. pyramidal  pulse  o f more  inhibition  be  8) c o u l d  number  intensities.  on  increasing  in Fig.  of  hippocampal  should  with  Inhibition  the e f f e c t  of % i n h i b i t i o n  %inhibition  the  the  response  'CONTROL'  on R e c u r r e n t  discussing  inhibition  spike  o f NE  NE  not  principal  inhibits  cells) In view  the  resulting of  the  43  diffuse  innervation  of  locus  coeruleus,  this  seems  likely  extend  to  hippocampal  to  a-agonist  mediated  enhancement  neurons  the  of  and  at  latter  hippocampal  inhibition  of  the  synchronous  cells  inputs.  Moreover,  inhibited  more-or-less  which the  would  next  a  the  be  system  the  well  rhythm known  stimulation  but  ready  discharge  and  so  discharges  pyramidal  a of  improving fashion.  generator.  as  cells The  locus  of  the  This  generator  coeruleus  cycle  could basket  formation  to  would  each  output  be cell  similar is  especially  (e.g.  time cells  cycle  result  an  in  respond  after  recurrent  producing  were would  pyramidal to  the  afferent  instant  state  final  hence  probably  synchrony The  and  interneurons  the  on.  hippocampal  theta-rhythm the  of  locus  synchronous  other  similar  inhibition  the  a  they  quiet  feedback  rhythmic  a  in a  a  principal  from  to  inhibitory  at  former  action potentials  interneurons  simultaneously,  with  alternate  to  the  the  in  excitable  inhibition  continue  and  more  synchronous  then  positive  be  since  synchronous  probably in  would  the  interneurons.  of  result  inhibitory  pyramidal  pulse  the  mediated  that  formation  probably  (1981),  0-agonist  inhibitory  the  would  in a  al  of  the  1982).  et  the  a  i t  resulting  for  in  alleged  Mueller  suggest  NE  the  Nicoll,  inhibition  that  coeruleus,  from  the  including  spike  of  interneurons  and  the  action  &  population for  from  (Alger  inhibition  the  the  Supposing  recover  other  of  fibres  inhibitory  probably  study  responsible  arrives  to  interneurons  According  be  general  formation,  'feed-forward'  might  noradrenergic  Macadar  indeed after et a l ,  44  1974).  Naturally,  of  on  NE  rhythm  the  would  rhythm  gerenator  action  on  working going  into  C.  the  The then  hypersynchrony  6-Hydroxydopamine  or  the  on  the  Lesion  and  the  of  prevent  possibly  effective of  balance  principal  effect to  more  influence  functioning  depend and  mechanism  inhibitory  proper  dampening  safety  the  processes,  interneurons  with a  potent  be.  would  the  as  more  inhibitory  generator  possibly  the  NE  the  of  of  NE  NE  latter  system  epileptogenic  Role  this  neurons,  on  the  the  from  states.  in  Epileptogenesis  It that  a  exert upon  might system an  at  first  depleted  inhibitory  replenishment  actually  exhibit  epileptiform involvement  of  NE  epileptogenesis  i t s endogenous  the  same  enhancement  multiple of  in  spike  the  documented  (e.g.  Kilian  endogenous  NE  been  induced  Horton  et  al,  (Bourn 1980)  et  drug of  by  discharges. processes,  &  1973).  to  facilitate  (Mason  a _ l , 1977; by  paradoxical  which  to  would  application  and  eventually  The  notion  particulary has  been  of in well  Depletion  of  epileptogenesis  e_t  al,  Shaywitz  e_t a l ,  kindling  seems  cells,  exogenous  activity  Frey,  even  pyramidal  model  shown  or  the  NE,  kindling  pharmacologically  audiogenically  on  inhibitory  and  has  s u r p r i s i n g and  influence  of  an  seem  (Ehlers  et  1978), 1978; al,  and 1980;  45  Corcoran  e_t a l ,  seems o n l y only  one  NE p l a y s (1977)  to  animals.  The  response  of  that  the  response  dissociation  of  hypothesis is  from the  that  the  potentiation  result  section,  an  processes  hypersynchrony result  of  the  of  processes,  the  the  other  strongly the  are  normal  and  rhythm  epileptogenicity.  This  on  the  the  the  supports spike  pyramidal  likely  in  a  this  population of  of  than  fact,  NE-induced  cells  EPSP  inhibitory  influence  As m e n t i o n e d  pyramidal  on  factors  which  the  insensitive  In  of  al_  potentiation  'disinhibition'  between  drive or  to  responses  dendritic.  imbalance  could  the  where  convulsive  s t i l l  noradrenergic  field  instead  is  post-synaptically.  inhibitory  on  due  two  somatic  influences  is  that  the  a  NE  be  B l u m e_t  produced  of  NE  to  findings  previously  effect  of  studies,  seems  present  preparations  spike  these  There  the  but  suggests  nature  of  epileptogenesis.  the  11)  basic  all  NE a c t u a l l y  (Fig.  cells  cells  that  6-OHDA-treated  population  response  of  in  exogenous  fact  reduced  in  role  in  role.  6-OHDA-treated  pyramidal  the  correlate  a more d i r e c t  in  change  However,  a modulatory  behavioral  seizures  the  play  showed  though  1980).  to  be  previous inhibitory  the  inhibitory  generator imbalance  into could  from: a.  preferential onto  b.  regenerative  inhibitory  differential between  the  interneurons  sprouting  interneurons;  denervation pyramidal after  terminals  and/or,  supersensitivity  cells  6-OHDA  of  and the  lesions.  inhibitory  46  Regenerative boutons  after  adrenergic  sprouting chemical  toxins  biochemical  assays  has  been  (Schmidt  1979).  The  latter  regeneration  tends  to  Loy  (1980),  innervating  the  interneurons  in  comparatively  influence  normal  more  the  of  process extensive a  inhibitory  The  above  pyramidal  any  random  fibre abnormal  according  cells  to  interneurons  the  in  latter  of  the  during  result  as  is,  to  than  sprouting  degree  conjecture  although  varicosities  probably  higher  and  and  the  innervation  1975  original  fluorescent  would  and  al,  Since  by  1980)  that  the  formed.  more  animals,  subsequently  on  normal.  are  et  other  revealed  and  patterns  often  dendrites  regenerative  and  restore  are  there  1979,  and  and  as  showed  hyper i n n e r v a t i o n  arrangements  normal  a l ,  also  fibres  6-OHDA  (Bjorklund  study  terminal  the  by  reported,  et  histochemistry  e_t a l  noradrenergic  lesions  fluorescence  architecture,  of  a  than  inhibitory compared  however,  to  highly  speculative.  Post-synaptic CNS  has  that  been  well  supersensitivity after documented.  6-OHDA-induced  depletion  methods,  results  in  a  receptor  binding  in  the  1977;  Minneman  e_t a l ,  Several  50-64% rat  1979).  denervation  supersensitivity  great  ^-adrenoceptors  et  as  the  a l , 1980).  undergone  a  In  34-50%  of  in  studies  cerebral  by  in  cortex  for  a-adrenoceptors  the  the  hippocampal  0-adrenoceptor  shown  different  (Sporn  general,  CNS  the  ^-adrenergic  In  the  in  have  applied  increase  throughout  particular, increase  NE,  denervation  e_t a l ,  extent i s not  of as  (U'Prichard formation  has  density  but  47  FIGURE  13.  Schematic  Diagram  j3-receptors  of  in  the  D i s t r i b u t i o n of  Normal  and  a-  and  6-OHDA-treated  Condi t ions  As (  )  proposed  adrenoceptors  pyramidal  cell  interneuron only  in  the  are  in  As  a  neuron  the  random  differential in  the  normal  of be  sprouting  presence  is  more the  Note  depicted  here (B),  inhibited  due  importantly,  /3 o v e r  exogenous  and  NE.  the  0the  inhibitory  (A).  treatment  preferentially and  of  ( c=> )  d i s t r i b u t e d on  situation  6-OHDA  s u p e r s e n s i t i v i t y of the  a-  recurrent  innervation  result might  the  differentially and  noradrenergic  inhibitory  especially  discussion,  (clear)  (shaded)  simplicity.  probable  the  that for the to to  a-receptors,  47-1  A.  NORMAL  B. POST - 6 - O H D A  48  insignificant  and  density  after  bundle  (U'Prichard  Scatchard  analyses  changes  lesioning  of  et  ^-adrenoceptor  also  binding  this  of  two  adrenoceptors  cells  imbalance  possibility. that  the  other  antagonized  sotolol  (Langmoen  1981),  t h e study  inhibitory mediated  further  de  Montigny  denervation  supported  agreement  with  Conversely,  with  the  It  is  basis  of  the  the  pyramidal  credence  to this  that  a  of  few  NE  on  the  studies  on p y r a m i d a l by  ^-antagonist,  et a l ,  1980; S e g a l ,  suggests  CA1  failed  to  after  neurons, lack  that  cells i s  the  that  pyramidal  by a - a d r e n o c e p t o r s . by t h e f a c t  showed  both  cells is  The  hypothesis  Segal  (1981) and  detect 6-OHDA  the  any  signs  treatment  respectively,  o f 6-OHDA-induced  which  in  of the  i s in  a-adrenoceptor  i n t h e hippocampus.  the potentiation of  by ^ - a g o n i s t s  the  lend  e t a l (1981)  supersensitvity  supersensitvity  response  NE  e_t a l ( 1 9 8 0 )  a n d CA3 p y r a m i d a l  in  i n the density  between  a_l, l 9 8 l ; S e g a l  of  increase  supersensitivity  the  also  but not blocked  predominantly  is  CA1  action  e_t  1981).  processes.  of Mueller  action  the  a l ,  e t a_l, 1981).  be  of i n h i b i t i o n  the fact  inhibitory  slightly  e l  denervation  could  findings  Despite  that  (Sharma  differential  and the i n h i b i t o r y  Several  coeruleus-dorsal  Sharma  shown  sites  that  aforementioned  a-adrenoceptor  was d u e t o a n i n c r e a s e  probable the  in  locus  a l , 1980;  have  of j3-agonists  binding of  6-OHDA  equivocal  (Mueller  disinhibitory  effect  et a l , of  the  population  1981), NE  v i a  spike  i n conjunction the recurrent  49  inhibitory  interneurons,  mediates  the  interneurons 34-50%  inhibitory  in  6-OHDA-induced  is  a-adrenoceptor As  drive This  the  Mueller  is  &  whereas  further  and  on  the  region.  on  by on  result the  a  this  type  by  (1983)  that  high  K  study  is  +  i n an  pyramidal  supported  reduce  density  similarly  the  the  the  (See  presence  recent  /3-agonists  jjn v i t r o  of  a  processes  Fig.  imbalance  epileptiform activity in  after  imbalance  cells.  the  the  supersensitized  of  in  inhibitory Hence,  inhibitory  hypersynchrony  Dunwiddie  a-agonists  penicillin  would  previously, to  CA1  /3-adrenoceptor  /3-adrenoceptor  population  system  theory  in  offset  discussed  the  influence  influence  not  that  hippocampal  denervation  inhibitory  which  13).  the  increase  potent  suggest  could of  NE.  report  of  facilitate induced  hippocampal  by slice  preparations.  The that  present  in  hippocampi  replenishment  of  epileptiform  activity  differential  NE  the  first  depleted  itself  of  physiological their  actually results  probably  supersensitivities  as of  the  a  report  endogenous in  generation  consequence  adrenergic  NE, of of  receptors.  50  D.  General  It  seems  inhibitory in  the  be  present  i n most  study,  could action  with  processes  hippocampus,  the  1981;  and  excitation  of  the  to  this  hypothesis  of  adrenoceptors  /3-adrenoceptors  is  likely  inhibition  to  control on  the  more  of  inhibition  Certain have  been  models based  than  interneurons  influence  direct  not  on  being  of a  on  the  on  The  key  been  distribution (alpha)  It  is  to  at  pyramidal  inhibitory  one  pyramidal  level  possible NE  in a  the in  athe  interneuron cell,  amplified  sensitive  a  cells.  of  available  be  and  resulting  one  epileptiform  rebound  hypothesis.  sensitivity  more  et  be  pyramidal  reduced  (Mueller  also  the  the  the  50MM c o u l d  cells  would  much  NE  In  consistent  a-receptors  s i n c e any  disinhibitory the  have  of  1982).  sensitive  influence  NE  enhancement  differential  more  of  no  corresponding  ( F i g . 13).  the  are  the  ^0^M.  after  a  (beta)  studies  Secondly,  to  on  shown  'disinhibitory'  the  pyramidal  than  comparative  of  and  spike  as  an  a  Nicoll,  effect  be  and  to  on  &  study)  could  CNS  exerts  interneurons  'disinhibition'  disinhibitory  literature.  acting  the  NE  the  attributed  i s based  on  of  that  NE-induced  (Jahr  same  concentration  However,  NE  interneurons  predominant  and  the  ^-adrenoceptors  lower  be  population  with  that  even  present  explained  inhibitory  areas  potentiating  the  true  inhibitory  likely  inhibitory  al,  generally  Furthermore,  responses of  to  influence  exception.  type  Discussion  with  than  any the that  cells.  discharge of  generation  GABA-mediated  51  inhibition Dingledine  (Meyer  disrupted  or  Prince,  & Gjerstad,  Other - studies was  &  in  also  multiple  epileptiform  activity.  generation  6-OHDA-treated level  IPSPs  have in  response  shown  the  NE  these  in  GABA  on  these  not  /3-receptors  release  upon  neurons,  meaning  totally  cells,  slightly  in  hyperpolarization.  by On  NE  in  reduces the  Madison  &  Nicoll of  the  a f f e c t i n g the  GABA.  This  finding  directly  o n GABA  i s  likely The  to  act  proposed interneurons  i n a potent  inhibition  a substantial  reduction  cells.  ignore  the fact  on t h e p y r a m i d a l  that  there  cells.  They  to the i n h i b i t o r y influence  addition  a-adrenoceptors,  activity  inhibitory  result  the pyramidal  f i n d i n g of  without  but  on t h e  /^-adrenoceptors  contribute  on-going  neurons.  o f NE,  one c a n n o t  reflect  amplitude  interfere  level  1977)  resulting  that  region  GABA-ergic  GABA-ergic  functional  probably  does  i n the presence  However, are  CA1  e_t a l ,  present  the  1980).  the  as well.  reduces  at the synaptic  super s e n s i t i z e d  of  NE  hippocampal  that  transmission  could,  suggests  to iontophoretically applied  indicates  directly  the  1979;  transmission  epileptiform  inhibition  that  Wyler,  1981),  Likewise,  preparations  &  (Oliver  discharges  of s i m i l a r  & Prince,  when GABA  (Segal,  spike  of GABA-mediated  (1982a)  that  perfusions  medium  extracellular  NE-induced  shown  by p e n i c i l l i n CI  Wong  1980; S c h w a r t z k r o i n  have  low  1973;  to a  the other  that small  hand,  recent  mediated  on by  c-AMP-mediated findings  by  52  Madison the  & Nicoll  repetitive  elicited  by +  a  current  prolonged.  conductance.  This  cells  pyramidal  cells  synaptic  activation  resulting  combined  enhancing  strong  proposed  by Woodward  that  a  priming with  et  further  by  NE,  for  a potent  block  in  rampant  repetitive  for  instance,  ^-antagonists recording  that  NE  processes might  drugs,  i n an  on t h e  readiness' to  of  subsequent  t h e weak  that  with NE  neurons.  reduction  of the C a  The  inputs  the concept  improves Moreover,  + +  and  the i ti s  -activated,  K  +  response  resulting  and e p i l e p t i f o r m  activity  preparations.  the  a  -activated,  synchrony.  CNS  studies  effect  of  recurrent  required  low  NE  conclude  the  to  examine,  concentrations  inhibition  inhibitory  including  indirect  are  i n the presence  one c o u l d  general  i n t h e CNS,  result  in  (1979)  + +  induced  effect  to respond  of suppressing  interneurons  exerts  Ca  'quiet  bursting  discharges  further  on  sympathomimetic  of the  o f t h e accommodation  the  from  i s presumably  due t o s u p e r s e n s i t i v i t y , i s r e s p o n s i b l e  the 6-OHDA-treated  though  a  a l  ratio  conductance  Even  b y NE  cells,  or G l u a p p l i c a t i o n , i s  ^-receptor-mediated the  o f NE,  pyramidal  a c t i v a t i o n s i s i n accord  'signal-to-noise' possible  effect  supports  action  i n the presence CA1  inhibition  dual  upon  the  injection  This  further  that,  of  ^-receptor-mediated  pyramidal  in  showed  discharges  by e i t h e r  significantly  K  (1982b)  and o f NE  quite  'disinhibition'.  direct and  other  confidently  influence  inhibitory  and  on  ones  most that  53  References Alger,  B.E., a n d N i c o l l , R.A. 1982. 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