28 - Neuromodulators

Question 1

Monoamines

Answer 1

• Dopamine
• Serotonin
• Norepinephrine
• Histamine

Monoamines go through reuptake to be used again.

Does not include ACh because it’s destroyed by hydrolysis, not through reuptake

Question 2

Chatecholamine

Answer 2

• Dopamine and norepinephrine
• Derived from tyrosine
• Are also monoamines, so they undergo reuptake

Question 3

Nueormodulator Derivision

Answer 3

• Dopamine: tyrosine
• Norepinephrine: tyrosine
• Serotonin: tryptophan
• Histamine: decarboxylation of histidine
• Aceytlcholine: acetyl-CoA and choline

Question 4

Mood + Behavior Neuromodulators

Answer 4

DA, NE, 5HT

Question 5

Dopamine Receptor, Functions, Pathways

Answer 5

• Receptor: GCPR
• Functions: mood/behavior, BG motor, reward
  
  • Works with 5HT to modulate impulsiveity, aggression, cognition
• Pathways
  
  • SNc > BG (dorsal striatum)
    
    • Nigrostriatal
  • VTA > NAc (circuits, reward)
    
    • Mesolimbic
  • VTA > vmPFC (valence) via MFB
    
    • Mesocortical
  • Arcuate nucleus > median eminence via tuberoinfundubular pathway

Question 6

Dopamine Antipsychotic Side Effects per Pathway

Answer 6

• Mesolimbic: VTA > NAc
  
  • No side effects; this is the main target
• Nigrostriatal (SNc > BG)
  
  • Extrapyramidal: dystonia (muscle contractions) and akathisia (restlessness)
  • Tardive dyskinesia: repetitive movements (irreversible)
• Mesocortical: VTA > vmPFC
  
  • Negative and cognitive symptoms
• Tuberoinfundibular: Arc Nuc > Med Eminence
  
  • Hyperprolactinemia: menstrual irreguarity, osteoporosis, sexual dysfunction

Question 7

Schizophrenia

Answer 7

• Dopamine problem
• Inhibition of MAO, COMT (catabolizes DA) = psychotic symptoms
• Overactivity of mesolimbic pathway (VTA > NAc) = positive symptoms (hallucinations, delusions)
• Underactivity of mesolimbic pathway (VTA > NAc) = negative symptoms (blunted affect, apathy) and cognitive symptoms

Question 8

Raphe Nuclei

Answer 8

• Serotonin
• Two systems:
  
  • Dorsal Raphe System (Ascending)
    
    • Medial forebrain bundle
    • Signal-to-noise ratio
  • Raphespinal System (desceding)
    
    • Raphe obscurus: CPGs in SC
    • Raphe magnus: analgesia
      
      • Uses PAG, enkephalin
    • Raphe pallidus: thermogenesis

Question 9

Serotonin Syndrome

Answer 9

• Life-threatening
• Caused by hyperserotonergic state associated with high doses of serotonergic drugs
• When combinations of serotonergic agents are used together or when antidepressants are changed without an adequate washout period between drugs
• Symptoms:
  
  • Cognitive effects: mental confusion, hypomania, agitation, headache, coma
  • Autonomic effects: shivering, sweating, fever, hypertension, tachycardia, nausea, diarrhea
  • Somatic effects: myoclonus/clonus (muscle twitching), hyperreflexia, tremor, insomnia

Question 10

Ketamine

Answer 10

• suppresses bursting activity in lateral habenula by increasing NMDA receptor activity (SSRIs increase BDNF which increases NMDA receprot afibity) for glutamate
• Lateral habenula burst signals requires NMDARs (glutamate), so when there’s less, it does not burst
• So now DA can be released for rapid response to MDD

Question 11

Locus Coeruleus

Answer 11

• Releases NE
• Pons
• Gap junctions: fast
• Excited by novel stim
• Control fight or flight
• Phasic release = attention, learning
• Tonic release = sympathethic nervous system

Question 12

ADHD

Answer 12

• NE
• Increased tonic firing rate of LC neurons
• Prevents shift to phasic responses characteristic of forced attention

Question 13

Panic Disorder

Answer 13

• LC is long associated, because stressors activate the LC-NE system and drugs that enhance LC activity elicit panic in susceptible individuals
• However, direct stimulation of the human LC does not induce panic
• So LC is not panic, is just part of the story

Question 14

ACH Neurons

Answer 14

• Mesopontine Cholinergic Neurons
  
  • Pons to thalamus to cortex
  • Forced maintenance of attention
• Substantia Innominata (septal nuclei + NBM)
  
  • ACH: spatial, declarative memory
  • GABA: disinhibition
  • ACH + GABA:
    
    • Cortical arousal (potentiation)
    • Selective attention
    • Cortical plasticity (learning, mem)

Question 15

Ascending Arousal Systems

Answer 15

• Indirect
  
  • Mesopontine ACH > thalamus > via reticular nunclei for synchronic signaling > cortex
  • Active during wakefulness and REM sleep
• Direct
  
  • Input:
    
    • Substantia innominata: ACh/GABA
    • TMN: histamine
    • LC: NE
    • Dorsal raphe nuclei: 5HT
  • Active during wakefulness and NON-REM
• Brainstem Control:
  
  • VLPO of hypothalamus: sleep
    
    • SCN helps win
  • Direct ascending arousal system: awake
    
    • LHA (orexin) helps win