Central Nervous System Neuropharmacology

Question 1

ACh: synthesis, storage, release, termination, receptors/trasduction mechanisms

Answer 1

• synth: catalyzed by choline acetyl transferase
• storage: in vesicles by vesicle-associated transporter (VAT
• release: AP ==> Ca²⁺ release ==> fusion of vesicle
• termination: degraded by AChE
• receptors
  
  • muscarinic
    
    • M₁ - M₃ = G_q ==> stimulate PLC = excitatory
    • M₂ - M₄ = G_i/o ==> inhibits adenylyl cyclase = inhibitory
  • nicotinic: N_N ==> ionotropic

Question 2

ACh: CNS location & function

Answer 2

• location: produced @ cell bodies @ brain stem & basal forebrain
  
  • project into cebral cortex and hippocampus
• fxn: coordinate movement and cognitive fxns
  
  • e.g. motivation, memory, learning

Question 3

ACh: pathophysiology

Answer 3

• Alzheimer’s disease
• Parkinson’s disease
• Schizophrenia

Question 4

Monoamines: examples

Answer 4

• Catecholamines
  
  • Dopamine
  • Norepinephrine
• Indoleamines
  
  • Serotonin

Question 5

Catecholamine (DA & NE): synthesis, storage, release, termination,

Answer 5

• synth: rate-limited tyrosine hydroxylase (TH)
• storage: in vesicles by vesicle-monoamine transporter (VMAT) & protected from MOA (monoamine oxidase)
• release: AP ==> Ca²⁺ release ==> fusion of vesicle
• termination: reuptake by presynaptic transporters
  
  • DAT (Dopamine transporter)
  • NET (NE transporter)
• receptors
  
  • NE
    
    • a₁ = G_q ==> stimulate PLC = excitatory
    • a₂ = G_i/o ==> inhibits adenylyl cyclase = inhibitory
    • b₁ = G_s==> stimulate adenylyl cyclase
    • b₂ = G_s ==> stimulate adenylyl cyclase
  • dopamine
    
    • D₁ = G_s ==> stimulate adenylyl cyclase
    • D₂ = G_i/o ==> inhibit adenylyl cyclase

Question 6

NE/DA: CNS location & function

Answer 6

• location:
  
  • DA = substantia nigra => nestriatum pathway; ventral tegmental area => limbic cortex and frontel cortex; hypothalamus => pituitary
  • NE = cell bodies in pons/brainstem => all levels of brain
• fxn:
  
  • DA = voluntary movement; reward-related behaviors; working memory & attention
  • NE = arousal, attention, vigilance, sleep-wake cycle; fear/anxiety; mood/emotion; modulate afferent pain

Question 7

NE: pathophysiology

Answer 7

• Mania
• Depression
• Anxiety disorders
• ADHD

Question 8

Indoleamine (5HT): synthesis, storage, release, termination, receptors/trasduction mechanisms

Answer 8

• synth: rate-limited = tryptophan hydroxylase (TpH)
• storage: in vesicles by vesicle-monoamine transporter (VMAT) & protected from MOA (monoamine oxidase)
• release: AP ==> Ca²⁺ release ==> fusion of vesicle
• termination: reuptake by presynaptic transporters
  
  • SERT (serotonin transporter)
• receptors
  
  • 5HT₄ = G_s ==> stimulate adenylyl cyclase
  • 5HT3 = ionotropic = excititatory
  • 5HT_{1A, 1B, 1D} = G_i/o ==> inhibits adenylyl cyclase = inhibitory
  • 5HT_{2A, 2B, 2C} = G_q ==> stimulate PLC = excitatory

Question 9

Indoleamine (5HT): CNS location & function

Answer 9

• location: produced @ cell bodies @ raphe regions of pons/upper brain stem
  
  • project into all levels of brain
• fxn:
  
  • sleep, arousal, attention
  • emotion/mood
  • pain pathways
  • eating/drinking behaviors

Question 10

Serotonin: pathophysiology

Answer 10

• depression
• anxiety disorders
• schizophrenia
• eating disorders

Question 11

NE/DA: CNS location & function

Answer 11

• location:
  
  • DA = substantia nigra => nestriatum pathway; ventral tegmental area => limbic cortex and frontel cortex; hypothalamus => pituitary
  • NE = cell bodies in pons/brainstem => all levels of brain
• fxn:
  
  • DA = voluntary movement; reward-related behaviors; working memory & attention
  • NE = arousal, attention, vigilance, sleep-wake cycle; fear/anxiety; mood/emotion; modulate afferent pain

Question 12

DA: receptors/trasduction mechanisms

Answer 12

• dopamine
  
  • D₁ = G_s ==> stimulate adenylyl cyclase
  • D₂ = G_i/o ==> inhibit adenylyl cyclase

Question 13

NE: receptors/trasduction mechanisms

Answer 13

• a₁ = G_q ==> stimulate PLC = excitatory
• b₂ = G_s ==> stimulate adenylyl cyclase
• b₁ = G_s==> stimulate adenylyl cyclase
• a₂ = G_i/o ==> inhibits adenylyl cyclase = inhibitory

Question 14

DA: pathophysiology

Answer 14

• schizophrenia
• Parkinson’s disease
• OCD
• ADHD
• drug abuse

Question 15

GABA: synthesis, termination, & receptors

Answer 15

• synth: intertwined w/glutamate via GAD
• termination: reuptake via GABA transporter
• receptors:
  
  • GABA_A: Opens ligand-gated Cl^- channel (ionotropic) ==> IPSP
  • GABA_B: G_i/o ==> inhibits adenylyl cyclase

Question 16

GABA: drug action targets

Answer 16

• Benzodiazepines ==> bind GABA_A receptors to facilitate GABA binding ==> increased inhibition @ postsynaptic cell
• Tiagabine ==> inhibits reuptake of GABA
• Vigabatrin ==> inhibits degradation by GABA-T

Question 17

GABA: CNS location & function

Answer 17

• location: high concentration @ brain/spinal cord
• fxn: major inhibitory transmitter in CNS

Question 18

GABA: Pathophysiology

Answer 18

• generalized anxiety disorders
• seizure disorders
• sleep disorders
• alcohol abuse & withdrawal

Question 19

Glutamate: synthesis & storage/release/termination

Answer 19

• synthesis: glutamine ==> glutamate
• termination:
  
  • reuptake by neuronal glutamate transporter
  • uptake by glial cell transporter ==> glutamate ==> glutamine by gultamine synthetase ==> neuron

Question 20

Glutamate: Receptors/transduction mechanisms

Answer 20

• Ionotropic receptors
  
  • NMDA: Increase Ca++ influx
  • AMPA: Increase Na+ and Ca++ influx
  • Kainate: Increase Na+ influx
• Metabotropic receptors:
  
  • R1-R5 (Group I): Gq ==> stimulation of PLC
  • R2-R3 (Group II): Gi/o ==> inhibition of adenylyl cyclase activity-inhibit VSCC-activate K+channels
  • R4-R6-R7-R8 (Group III): Gi/o  inhibition of adenylyl cyclase activity-inhibit VSCC

Question 21

Glutamate: Pathophysiology

Answer 21

• epilepsy
• ischemic brain damage
• addiction
• schizophrenia