Neurotransmitter Systems

• Targets for Drug Action

  • Receptors
  • Ion channels
  • Enzymes
  • Transporters
• Receptors


  • Sensing elements
  • Responsible for chemical communications
  • Coordinate the functions and responses for the endogenous mediators
• Agonists


  Substances that bind to and activate a receptor
• Antagonists


  Substances that bind to and block a receptor
• Ion Channels


  • Gateways in the cell membranes
  • Control in and outs of particular ions
  • Direct or in direct interactions
• Benzodiazepines


  • Facilitate the opening of GABA-A receptors by neurotransmitter GABA
  • Alteration of expression of ion channels (Gabapentin)
• Enzymes


  • Drug molecules are substrate analogues that act as competitive inhibitors
  • Drug molecules are false substrates – Formation of abnormal/non-functional products that affect normal metabolic pathway
  • Prodrug – inactive drug
• Transporters


  • Transporter protein controls the movement of ions or polar organic molecules across the cell membrane
  • E.g. neurotransmitters at nerve terminals
  • E.g. cocaine blocks uptake of monoamine (dopamine, norepinephrine & serotonin) neurotransmitters
• Most of these targets have multiple molecular isoforms
• Results in subtle differences in functions and pharmacology
• Current neuroactive drugs are non-specific
• Bind to different targets (multiple receptors, transporters & ion channels)
• The relationship between pharmacological profile and therapeutic effect remains largely unclear
• The relationship between pharmacological profile and its therapeutic effect remains unclear
• Slowly developing secondary responses to the primary drug-target interactions (drug addiction, drug tolerance/dependence)
• Amino Acid Neurotransmitters


  • Excitatory – Glutamate
  • Inhibitory – GABA
  • Mixed – Glycine
• Receptors are widely expressed throughout CNS
• Primary mechanisms to regulate neuronal activity
• Drugs targeting these receptors have widespread actions on the brain – more side effects
• GABA Receptors Subtypes


  • GABA-A (Ligand Gated Ion Channels)
  • GABA-B (G Protein Coupled)
• GABA-A (Ligand Gated Ion Channels)


  • Located in post synaptic terminals
  • Selectively permeable to CI (reduce postsynaptic excitability)
  • Pentamers (2 alpha, 2 beta and 1 gamma) – 19 different subunits are identified
  • Receptors containing different subunits showed differential sensitivity to drugs
  • Subtle differences in physiological and pharmacological properties
• GABA-B (G Protein Coupled)


  • Located in pre and post synaptic terminals
  • Inhibit voltage gated Ca2+ channels (reduce the release of neurotransmitters)
  • Open the potassium channels (reduce post synaptic excitability)
• GABA is the major inhibitory neurotransmitter
• Formation of GABA from glutamate is catalysed by GAD enzymes
• GABA synthesised neurons in the brain
• Approximately 20% of CNS neurons are GABAergic
• Most are short interneurons
• 30% of synapsed in the CNS use GABA as neurotransmitters
• All neurons are sensitive to its inhibitory effect
• Other Neurotransmitters & Modulators

  • Noradrenaline
  • Dopamine
  • Serotonin
  • Acetylcholine
• Noradrenergic Pathway in CNS

  • Cell bodies of noradrenergic neurons are found in pons and medulla
  • Most prominent cluster in locus coeruleus
  • Approximately 10,000 neurons in humans
  • Project axons into medial forebrain bundle
  • Give rise nerve terminals throughout the cortex, hippocampus, thalamus, hypothalamus, and cerebellum
  • All adrenoreceptors are G Protein Coupled Receptors
• Alpha 1 Receptors


  • Expressed in postsynaptic neurons and glial cells
  • Induce neuronal excitation
  • Functions: motor control, cognition and fear
• Alpha 2 Adrenoceptors


  • Expressed in noradrenergic neurons (in both somatodendritic and nerve terminals)
  • Functions as inhibitory autoreceptors
  • Induce neuronal inhibition
  • Functions: blood pressure control, sedation and analgesia
• Beta 1 Adrenoceptors


  • Expressed postsynaptically
  • Induce neuronal excitation
  • Functions: learning and memory, and mood
• Beta 2 Adrenoceptors


  • Expressed postsynaptically
  • Induce neuronal excitation
  • Functions: learning and memory, and mood
• Functional Importance of Noradrenergic Pathways in CNS

  • Arousal System
  • Mood
  • Cognition
  • Reward Pathway & Drug Addiction
  • BP Control
• Dopamine Pathways


  • Synthesis of dopamine - Tyrosine > dopa > Dopamine
  • Dopaminergic neurons lack dopamine βhydroxylase: no conversion to noradrenaline
  • Two functionally distinct families: D1-like (D1 & D5) and D2-like (D2-4)
• D1 Receptor


  • Increase cAMP by Gs-coupled activation of adenylyl cyclase and activate protein kinase A (PKA)
  • Expressed in striatum, limbic system, thalamus and hypothalamus
• D5 Receptor


  • Increase cAMP and activate PKA
  • Expressed in hippocampus and hypothalamus
• D2 Receptor


  • Decrease cAMP by Gi-coupled inhibition of adenylyl cyclase
  • Inhibit calcium channels + activate potassium channels
  • Expressed pre- and postsynaptically in neurons in striatum and olfactory tubercle