Lecture 12

• Genetic


  • Selective breeding
  • Behavioural measurement → identify traits → selective breeding
  • Model to examine treatment effects — Wistar Kyoto Rat
  • Possibility of examining genetic/neurobiological differences
• Chronic concurrent stress


  • Modelling a known causative factor
  • Pathophysiological changes — levels of neurotransmitters, enzymes, receptors, transporters; number of cells; cell morphology — dendrites, spines; functional changes — electrophysiological; HPA axis (re)activity
  • Changes in behaviour — depressed mood, apathy, fatigue, weight change, sleep disturbance, anhedonia
  • Response to drug treatments
• Modelling chronic mild stress (CMS)


  1. Animals exposed to stressor each day (30-40 days) — inclination of home cage for 4 hrs, 15 mins restraint, nocturnal light, wet cage bedding — 2 hrs, food deprivation

  2. Reduced weight gain with CMS

  3. Reduced sucrose intake — anhedonia

  4. Effect of novel antidepressant S33005 — reversed decreased sugar intake

  5. Positive controls = imipramine + venlafaxine
• Other methods


  • Repeated restraint stress
  • Social isolation
  • Sensory deprivation (olfactory bulbectomy)
• Modelling early maternal separation (EMS)


  1. Day 1 — rat pups born

  2. Day 2-12 — separated from mother 3-4hrs on five separate occasions

  3. Rats then left to mature to adulthood — tested
• HPA axis


  • Give chronic corticosterone (in drinking water, injection, implanted pellets or osmotic pump)
  • Give chronic CRH
  • Inbred strains with high CRH levels (HAB/LAB strains)
  • Effect of cortisol on 5-HT function — high cort decreases 5-HT firing rate, high cort decreases 5-HT1A autoreceptor sensitivity
• 5-HT dysfunction

  • Deplete 5-HT using reserpine or MDMA
  • Transgenic mice under expression 5-HT receptors/transporter
• Learned helplessness-despair


  1. Rats subjected to uncontrollable + inescapable electric shocks — shuttle box setting

  2. Learned helplessness = animals fail to escape due to electric shock

  3. Repeated exposure to inescapable shock → failed escape

  4. Reversed by antidepressant treatment
• Chronic antidepressant treatment


  1. Examine effect of treatment on specific aspects of brain function/behaviour — chronic SSRI on HPA axis or 5-HT function

  2. Is this effect common across different classes of treatment — do SSRIs have the same effect as ECT

  3. Give indication of some of the long-term neurobiological effect of the drugs
• Forced swim test (FST)


  1. Rats forced to swim in confined area

  2. Attempt to escape — early trials

  3. In later trial — animals remain immobile → behavioural despair

  4. Clinically effective antidepressant agents reduce the emergence of behavioural despair and reduce immobility times
• Tail suspension test (TST) — mice only


  1. FST and TST

  2. TST — time struggling + time immobile

  3. Antidepressant are effective acutely

  4. Clinically antidepressants have delayed onset of action
• Treatment response has questionable relevance to disorder, all known antidepressants evoke this response
• 5-HT metabolism

  Constant 5-HT turnover

  A) 5-hydroxytryptamine

  B) Monoamine oxidase

  C) aldehyde

  D) Aldehyde dehydrogenase

  E) 5-hydroxyindoleacetic acid

  F) CHO

  G) COOH

  
• Forced swim test

  Clinically effective antidepressant agents reduce the emergence of behavioural despair and reduce immobility times

  A) immobility

  B) swimming/climbing

  C) immobility

  D) swimming/climbing