Lecture 11

• Monoamine neurotransmitters


  • 5-HT
  • NA
  • DA
  • HA
• Monoamine neurotransmitters


  • Innervation in forebrain
  • Numerous functions: mood, sleep, anxiety, cognition, reward
• Evidence for monoamine implication


  • Reserpine (hypertension) lowers mood
  • Iproniazid (Used for TB) → improves mood in depressed patients
  • Imipramine (antipsychotic analogue) → improves mood in depressed patients
  • Other drugs against depression (TCAs) → affinity for MA transporters
• Treatments for depression

  • Tricyclic antidepressants
  • Dual inhibitors of NA + 5-HT reuptake
  • Clomipramine — relatively 5-HT selective
  • Indolamine theory of depressison — decreased 5-HT function in the brain
  • Led to development of SSRIS
• 5-HT neuroanatomy

  Dorsal raphe nuclei (DRN) + Median raphe nuclei (MRN) cell bodies → long, branching axons → terminal innervate neurones in forebrain
• 1. HT receptor families


  • 5HT1
  • 5HT2
  • 5HT3
  • 5HT4
  • 5HT5
  • 5HT6
  • 5HT7
• 5-HT1 family


  • GPCRs
  • 1A,B,D = autoreceptors + postsynaptic receptors
  • 1A = 5-HT cell bodies
  • 1B+D = 5-HT terminals
  • Coupled to Gi/o → open K+ + decrease cAMP
  • Inhibitory + role in behaviours
• 5-HT neurotransmission


  1. Transporters + autoreceptors

  2. Postsynaptic receptors
• 5-HT2 family

  • Postsynaptic GPCRs
  • Coupled to Gq/11 → phospholipase C → incr. IP3 + DAG
  • Stimulatory/excitatory
  • Mood, anxiety, atypical antipsychotics → affinity for 5-HT2A
  • Role in behaviours(?) 2A agonists → hallucinogenic/psychedelic, 2A antagonists → incr. slow wave sleep, 2C agonists → anxiogenic
• 5-HT3 receptors


  • Pentameric ligand cation channel (ionotropic receptor)
  • Excitatory
  • Role in behaviour(?) emesis → modulate release of ACh
  • Antagonists = antiemetics
• Lower 5-HIAA in CSF in depression, suicide + impulsive aggression → MAO candidate for genetic cause
• Lowered 5-HIAA by maternal deprivation → early life adversity
• Relationship between [5-HIAA]CSF and central 5-HT NT questionable
• Endocrine response to 5-HT drugs


  ACTH → cortisol+prolactin released in response to 5-HT neurotransmission
• Attenuated 5-HT1A hypothermic response


  In depressed patients
• 5-HT1A binding reduced


  In depressed patients
• Serotonin transporter (SERT) decreased


  In depression
• 5-HTT polymorphism


  • Linked polymorphic region → 5-HTTLPR
  • Tandem repeat in 5' regulatory promoter region
  • Low/moderate expression associated with — affective disorders, stress susceptibility, eating disorders, etc
  • Increased risk w/ adult/childhood stress
• 5-HT function compromised → maybe 5-HT1A
• Overactive HPA axis (raised cortisol + reduced feedback)
• HPA/5-HT interaction


  CORT → 5-HT function
• Early life events can compromise 5-HT function + HPA axis
• Microbiota influences shaping + modulation of gut-brain axis
• Microbiota has significant impact on processes related to NT synth, myelination of neurones in PFC + development of amygdala + hippocampus
• Intestinal bac = source of vitamins, deficiency = antidepressant response + exacerbation of depressive symptoms
• Dysregulation in innate + adaptive immune response → depressed patients
• Inflammation = critical disease modifier → promoting susceptibility to depression
• Controlling inflammation → therapeutic benefit
• 5-HT neurotransmission

  Autoreceptors + transporters

  A) 5-HTT

  B) 5-HT1A

  C) 5-HT1B

  D) 5-HT neurone

  E) 5-HT1A

  F) 5-HTT

  
• 5-HT postsynaptic receptors

  5-HT1A function important

  A) 5-HT1A

  B) 5-HT1B

  C) 5-HT1D

  D) 5-HT2A

  E) 5-HT2C

  F) 5-HT3