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Lecture 5

Week 5 notes

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Department
Psychology
Course
PSYC 3030
Professor
Rob Foster
Semester
Winter

Description
Serotonin   Week  Lecture  5   Chapter  6   5-­‐hydroxytryptamine  (5-­‐HT)   A  serum  factor  in  the  gastrointes▯nal  tract  capable  of  producing  vasoconstric▯on  (1930)          Sero  (from  Serum)  tonin  (affec▯ng  muscle  tone)          Found  is  serum  gastrointes▯nal  tract  of  leeches,  scorpions,  lobsters……      Serotonin  distribu▯on  in  humans:         90%  in  the  gastrointes▯nal  system       8%  in  blood  platelets  (used  during  clo▯ng  process)       2%  in  the  central  nervous  system  (pineal  gland:  for  the  produc▯on  of  melatonin)     Lysergic  acid  diethylamide  (LSD;  1953)  antagonizes  the  contrac▯le  effect  of  serotonin  on   smooth  muscles.       Synthesis   Serotonin  is  a  indolealkylamine.     Tryptophan  Hydroxylase  (TH)  is  the  Rate-­‐limi▯ng  enzyme   Synthesized  in  5-­‐HT  nerve  cell  bodies  (cellular  marker  of   5-­‐HT  neurons)  and    transported  to  the  nerve  terminal  by   axonal  transport.       Try  H  ac▯vity  is  primarily  regulated  by  neuronal  firing   through  depolariza▯on-­‐induced  phosphoryla▯on  of  Ca+/ calmodulin-­‐dependent  protein  kinase  II  (CaM-­‐K  II)     5-­‐HT  synthesis  occurs  in  the  nerve  terminal   Storage  &  release     Tryptophan  –  dietary  manipula▯ons     Tryptophan  is  an  essen▯al  amino  acid  derived  from  diet  (animal  &  plant  proteins)       Tryptophan  is  transported  into  the   brain  by  a  special  transport  system   which,  however,  is  also  targeted  by   other  amino  acids  such  as  leucine,     isoleucine,  valine,  phenylalamine,     and  tyrosine  (known  as  large  neutral   amino  acids  –  LNAA).     Thus,  a  meal  rich  in  proteins  does  not  necessarily  leads  to  high  tryptophan  brain   concentra▯ons:  what  ma▯ers  is  the  ra▯o  between  tryptophan  and  the  sum  of  all   compe▯ng  LNAA.           Also,  a  low-­‐protein  but  rich   carbohydrates  meal  can   significantly  increase  brain  5-­‐HT   Tryptophan depletion and attenuation of cue-induced craving for cocaine. Satel et al., 1995 Regula▯on  of  release   5-­‐HT  autoreceptors   and  therefore  suppress  cell  firing.  increase  in  membrane  potassium  conductance   Pre-­‐synap▯c  autoreceptors  reduce  Ca+  influx  and  thus  inhibit  exocytosis.     Inac▯va▯on   Uptake  and  metabolism   The  uptake  of  5-­‐HT  displays  high-­‐affinity,  Na+  dependence,  and  a  requirement  for   metabolic  energy.   final  product  of  this  metabolisms  is  5-­‐hydroxyindoleace▯c  acid  (5-­‐HIAA),  which  diffuses   out  of  the  5-­‐HT  neuron  and  readily  enters  the  CSF.   Drugs  that  affect  5-­‐HT  synthesis,  storage,   release,  and  inac▯va▯on   Blockade  of  5-­‐HT  synthesis   para-­‐chlorophenylalamine  (PCPA):  irreversibly   block  Try  H  thus  leading  to  a  profound   deple▯on  of  5-­‐HT  that  can  last  weeks.    Mostly   used  in  animal  research.     Blockade  of  5-­‐HT  storage   Reserpine  (Serpasil):  blocks  the  vesicular   monoamine  transporter  and  leads  to  a   profound  5-­‐HT  deple▯on.  Used  as  a   an▯hypertensive  agent  at  low  doses.     Enhancement  of  5-­‐HT  concentra▯on      Subs▯tuted  amphetamines  such  as  para-­‐chloroamphetamine  (PCA)  and    fenfluramine  (used  as  an  appe▯te  suppressant):  these  drugs  reverse  the  direc▯on    of  5-­‐HT  transport  by  the  5-­‐HT  uptake  transporters  and  thus  promote  5-­‐HT    release  from  the  cytoplasmic  compartment.      An▯depressants      The  an▯depressant  imipramine  (1960)  blocked  NE  &  5-­‐HT  uptake    Selec▯ve  5-­‐HT  uptake  inhibitors  (SSRIs)  -­‐  Fluoxe▯ne  (Prozac)  &  Citalopram  (Celexa)        1.  increase  extracellular  concentra▯on  of  5-­‐HT       2.  suppress  neuronal  firing  (autoreceptors)       3.  decrease  5-­‐HT  synthesis  and  turnover  (autoreceptors)        Neurotoxins    5,6  or  5,7-­‐dihydroxytryptamine  (5,6/5,7-­‐DHT)  are  reuptaken  by  5-­‐HT  neurons    and    kill  their  terminals.    Amphetamine  deriva▯ves  such  as  3,4-­‐methylenedioxyamphetamine  (MDA)  and    3,4-­‐methylenedioxymethamphetamine  (MDMA).   5-­‐HT  Pathways   Most  5-­‐HT  cell  groups  are  associated  with  the  raphe  nuclei  and  the  re▯cular   region  of  the  lower  brain  stem.    The  largest  cluster  of  5-­‐HT  neurons  is  found  in   the  dorsal  raphe  nucleus.   Caudal  system   B1-­‐B4,  located  in  the  medial  region  of  the  medulla  and  caudal  pons  project  to   the  spinal  cord,  and  regulate  sensory,  motor  and  autonomic  func▯ons.   Rostral  system   B5-­‐B9,  associated  with  raphe  nuclei  of  the  rostral  pons  and  mesencephalon  as  well  as   with  caudal  linear  nucleus,  nucleus  pon▯s  oralis,  and  the  supralemniscal  region.   80%  of  all  forebrain  5-­‐HT  originates  from  the  dorsal  (B  6/7)  and  median  (B  5/8)  raphe   There  are  two  dis▯nct  ascending  5-­‐HT  projec▯ons:  ventral  &  dorsal  pathways   Ventral  &  dor
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