Lecture 9

• Tuberoinfundibular pathway


  • Hypothalamus → pituitary stalk
  • Anterior pituitary
  • DA acts as prolactin release inhibiting factor (PRIF) — tonic inhibition of lactation
• Nigrostriatal pathway


  • Substantia nigra → dorsal striatum
  • Part of extra-pyramidal motor system
  • Involved in initiation + control of movement
  • Disease — Parkinson's + Huntington's chorea
  • Normal nigrostriatal DA/ACh/GABA balance
• Mesolimbic/mesocortical pathway


  • Ventral tegmental area → ventral striatum, hipp. OR frontal cortex
  • Frontal cortex — Cognition mood/emotions
  • Ventral striatum + hippocampus — Reward, Addiction, Sensory processing
• Dopamine theory of psychosis


  • Caused by overactive DA system in the brain
  • Evidence: Amphetamine —> SCZ-like symptoms, DA R antagonists reduce SCZ symptoms, Affinity for DA receptors correlates with therapeutic efficacy
• Mechanism of action of antipsychotics


  • Affinity of antipsychotics for D2 receptors correlates with therapeutic efficacy
  • Antipsychotic drugs block D2 receptors in limbic/cortical areas
  • High affinity D2 receptor antagonists
  • Tricyclic structure
  • Affinity for other (non-DA R subtypes) — muscarinic, histamine, adrenergic receptors
• Side effects of antipsychotics


  • H1 mediated — Sedation, weight gain
  • M1 mediated — Dry mouth, blurred vision, urinary retention
  • α1 mediated — Postural hypotension
  • Nigrostrial — Extrapyramidal side effects, Tremor, muscle rigidity + loss of facial expression, Tardive dyskinesia
  • Tuberoinfundibular — Regulation of prolactin, Galactorrhoea, gynaecomastia
• Typical antipsychotics


  • Phenothiazines — Chlorpromazine (sedation), Thioridazine (anticholinergic), Fluphenazine (EPS)
  • Thioxanthenes — Flupenthixol (similar profile to phenothiazines)
  • Butyrophenones — Haloperidol (lack muscarinic and antihistamine activity, EPS is a problem)
• Atypical antipsychotics


  • Not tricyclic structure
  • Varying affinity for D2 receptor
  • Examples — Clozapine, olanzapine, risperidone, amisulpiride, quetiapine
  • Side effects — Better EPS side effect profile, Clozapine — agranulocytosis, High incidence of weight gain + metabolic syndrome, Risperidone + olanzapine — Weight gain + insulin resistance, Resultant diabetes/hyperglycaemia — CVD risk
  • Benefits — Effective for treatment in resistant patients, Better at treating -ve symptoms — lower D2 affinity, higher affinity for D3, D4 + 5-HT2A
  • Hypothesis for MOA — Much faster dissociation rate from D2 receptor (Koff) — loose binding, Drugs can be displaced by physiological phasic/bursts of DA transmission — important in DA striatal pathways, Less distortion of physiological DA signalling in striatal pathways, Cannot exclude role of 5-HT2
• Metabolic syndrome + antipsychotics — Prevalence increases with age
• L-DOPA levels in the brain

  Higher activity in SCZ patients

  
• Prolactin regulation

  Tuberoinfundibular pathway

  A) suckling

  B) Prolactin releasing factor

  C) anterior pituitary

  D) hypothalamic nuclei

  E) Prolactin

  F) Mammary tissue

  G) Dopamine

  H) Prolactin releasing inhibiting

  I) tonic

  
• Nigrostriatal ACh/DA/GABA balance


  Activity in the striatum

  A) Substantia nigra

  B) DA

  C) -ve

  D) D2

  E) ACh

  F) M1

  G) GABA

  H) +ve

  I) Striatum

  J) Output