RT Book, Section
A1 Nestler, Eric J.
A1 Kenny, Paul J.
A1 Russo, Scott J.
A1 Schaefer, Anne
SR Print(0)
ID 1174974821
T1 Reinforcement and Addiction
T2 Nestler, Hyman & Malenka’s Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 4e
YR 2020
FD 2020
PB McGraw-Hill
PP New York, NY
SN 9781260456905
LK neurology.mhmedical.com/content.aspx?aid=1174974821
RD 2024/04/20
AB KEY  CONCEPTSThe  defining  feature  of  addiction  is  compulsive,  out-of-control  drug  use,  despite  negative  consequences.Addictive  drugs  induce  pleasurable  states  or  relief  from  distress,  thus  motivating  repeated  drug  use.Drugs  of  abuse  are  both  rewarding  and  reinforcing.  Rewards  are  stimuli  that  the  brain  interprets  as  intrinsically  positive,  and  reinforcing  stimuli  are  those  that  increase  the  probability  that  behaviors  that  deliver  them  will  be  repeated.The  brain  reward  circuitry  targeted  by  addictive  drugs,  which  normally  responds  to  natural  reinforcers  such  as  food  and  sex,  includes  the  dopaminergic  projections  from  the  ventral  tegmental  area  (VTA)  of  the  midbrain  to  the  nucleus  accumbens  (NAc)  and  several  other  forebrain  structures.Repeated  use  of  addictive  drugs  produces  multiple  unwanted  changes  in  the  brain  that  lead  to  tolerance,  sensitization,  dependence,  and  addiction.Dependence  is  an  adaptive  state  that  develops  in  response  to  repeated  drug  administration;  when  unmasked  by  cessation  of  drug  use,  this  adapted  state  leads  to  withdrawal  symptoms.Tolerance  refers  to  the  diminished  effect  of  a  drug  after  repeated  administration  at  the  same  dose,  or  to  the  need  for  an  increase  in  dose  to  produce  the  same  effect;  sensitization  describes  the  opposite  response  to  repeated  drug  administration.Cocaine  and  amphetamines  produce  their  psychoactive  effects  by  potentiating  monoaminergic  transmission  through  actions  on  the  dopamine  transporter,  together  with  actions  on  the  serotonin  and  norepinephrine  transporters.The  reinforcing  effects  of  opioid  drugs  result  from  their  binding  to  endogenous  opioid  receptors,  most  notably  μ  opioid  receptors  in  both  the  VTA  and  NAc.The  immediate  effects  of  ethanol  result  primarily  from  facilitation  of  GABAA  receptors  and  inhibition  of  NMDA  glutamate  receptors.  At  higher  doses,  ethanol  inhibits  the  functioning  of  many  ion  channels  as  well.The  effects  of  nicotine  are  caused  by  its  activation  of  nicotinic  acetylcholine  (nACh)  receptors;  its  reinforcing  effects  depend  in  part  on  nACh  receptors  located  on  VTA  dopamine  neurons.Delta-9-tetrahydrocannabinol,  the  active  psychotropic  ingredient  in  marijuana,  exerts  its  primary  pharmacologic  effects  by  binding  to  a  G  protein–coupled  receptor  in  the  brain  known  as  the  CB1  receptor.The  psychotomimetic  drugs  of  abuse,  phencyclidine  (angel  dust,  PCP)  and  ketamine,  bind  specific  sites  in  the  channel  of  the  NMDA  glutamate  receptor,  where  they  act  as  noncompetitive  NMDA  receptor  antagonists.Drugs  of  abuse  cause  addiction  by  inducing  a  range  of  molecular  and  cellular  adaptations  in  several  brain  reward  regions,  which  are  becoming  increasingly  well  known.