Neurotransmitter Systems Notes

Neurotransmitter Systems

Identification and History
  • Acetylcholine (ACh): First identified neurotransmitter.
    1. Discovered by Otto Loewi in 1920s.
    2. Name 'cholinergic' introduced by Henry Dale.
    3. Loewi and Dale shared the Nobel Prize in 1936.
Criteria for Neurotransmitter Classification

Four criteria for a substance to be considered a neurotransmitter:

  1. Synthesized in the neuron.
  2. Present in the presynaptic terminal and released during neuronal stimulation.
  3. Mimics the effects of neuron stimulation when applied exogenously.
  4. Has a mechanism for removal from the synapse.
Discovery Experiment by Otto Loewi
  • Conducted using two frog hearts (Heart #1 connected to vagus nerve, Heart #2 in saline).
  • Stimulation of vagus nerve caused Heart #1 to slow, which was mirrored in Heart #2 after delay.
  • Hypothesized that a substance (termed Vagusstoff, now known as ACh) was released into the fluid, affecting Heart #2.
Neurotransmitter Mechanisms
  • Feeding processes:
    • Synthesized in neuron, stored in presynaptic terminal.
    • Released upon depolarization (calcium-dependent).
    • Effects rapidly reversed via reuptake or degradation.
Techniques for Localizing Neurotransmitters
  1. Immunocytochemistry:
    • Involves injecting neurotransmitter to create antibodies, which are then labeled and used to identify neurotransmitter presence in brain tissue.
  2. In situ hybridization:
    • Utilizing labeled probes to visualize neurotransmitter mRNA in brain tissue.
  3. Electrochemical Techniques:
    • Isolating neurons, electrically stimulating them, and analyzing the release of neurotransmitters.
Experimental Techniques for Neurotransmitter Analysis
  • Mimicking synaptic activity:
    • Intracellular recordings from neurons responding to a neurotransmitter.
    • Use of microionophoresis to inject candidate neurotransmitters and observe effects.
  • Neuropharmacological analysis:
    • Use of agonists/antagonists to study receptor specificity.
  • Ligand-binding methods:
    • Identifying receptors by applying labeled ligands to localize binding sites.
Types of Receptors and Their Mechanisms
  • Ionotropic Receptors: Fast acting and ligand-gated, e.g. AMPA, NMDA (Glutamate), and GABA_A.
  • Metabotropic Receptors: Slow acting, often linked to G-protein coupled pathways, e.g. muscarinic ACh receptor.
Major Neurotransmitter Classes
  1. Amino Acid Neurotransmitters:
    • Excitatory: Glutamate (involved in learning and memory).
    • Inhibitory: GABA (tranquilizing effects) and Glycine.
  2. Monoamines:
    • Catecholamines: Dopamine (movement, reward), Norepinephrine (arousal, attention), Epinephrine.
    • Indoleamines: Serotonin (mood regulation).
  3. Peptides: Substances like enkephalins, substance P, and endorphins.
  4. Unconventional Neurotransmitters: Endocannabinoids, Nitric Oxide (NO).
Glutamate and Its Receptors
  • Major excitatory neurotransmitter in the CNS:
    • Receptors: AMPA (fast EPSP), NMDA (requires depolarization to activate), and Kainate receptors.
    • Risks: Excessive activation can lead to excitotoxicity, damage to nerve cells.
GABA as the Primary Inhibitory Neurotransmitter
  • Synthesis: Derived from glutamate via GAD.
  • GABA Receptors:
    • GABA_A: Ionotropic, Cl- channels.
    • GABA_B: Metabotropic, linked to K+ channels.
  • Role in health: Insufficient GABA can lead to seizures; GABAergic drugs are used to treat anxiety and epilepsy.
Dopamine and Its Functions
  • Roles: Motor control (Nigrostriatal system), Reward (Mesolimbic system), Hormones (Tuberoinfundibular).
  • Dopamine receptors: D1/D5 (excitatory) and D2/D3/D4 (inhibitory).
  • Parkinson's disease: Result of dopamine neuron loss; treatment involves dopamine precursors like L-DOPA.
Serotonin and Its Pathways
  • Synthesis: From tryptophan.
  • Functions: Regulates mood, sleep, pain perception; target for many antidepressants.
  • Receptor Types: Multiple subtypes linked to various functions in the brain.
Norepinephrine System
  • Roles: Involved in arousal and attention.
  • Receptors: Alpha and beta adrenergic receptors involved in various physiological responses, including stress reactions.
  • Clinical significance: Found in treatments for mood disorders and stress responses.
Integration of Neurotransmitter Systems
  • Dale's Principle: Suggests that each neuron synthesizes and releases one primary neurotransmitter, but there may be co-released neuropeptides.
  • Divergence and convergence of neurotransmitter effects can lead to complex interactions in neural signaling.