Neurotransmitters

1⃣ From electric to chemical — How the idea changed

• ⚗ Loewi’s “Dream Experiment” (1921 → Nobel 1936)

  • Frog hearts in separate baths, connected by solution.

  • Stimulating the vagus nerve of Heart A slowed it → fluid transferred → Heart B also slowed.

  • 🧠 Conclusion: a chemical (“Vagusstoff”) mediated transmission — first proof of neurotransmission.

• 🔹 Replaced the old belief that nerves communicated purely electrically.

• ⚠ Electrical synapses exist (gap junctions), but most human signaling is chemical.

Flowchart:

Nerve impulse → Ca2+ influx → Vesicle fusion → Neurotransmitter release → Receptor activation → Response → Termination

2️⃣ The synapse — structure & components

• Presynaptic terminal: vesicles, Ca²⁺ channels, mitochondria.

• Synaptic cleft: ~20–30 nm gap filled with extracellular matrix.

• Postsynaptic membrane: receptor clusters anchored by scaffolding proteins (PSD-95, etc.).

• 🧠 Each synapse functions as a microchemical factory — release, reception, removal.

3⃣ Vesicle release mechanism (Bernard Katz, Nobel 1970)

• Katz & del Castillo used electrophysiology on frog neuromuscular junction.

  • Discovered miniature end-plate potentials (MEPPs) → each corresponds to one vesicle (quantal release).

• SNARE complex (later discovery): synaptobrevin + syntaxin + SNAP-25 mediate vesicle fusion.

• ⚗ Botulinum & tetanus toxins cleave SNAREs → block ACh release → paralysis.

4⃣ Neurotransmitter criteria (Sir Henry Dale & Loewi)

A substance is a true neurotransmitter if:

1. Synthesized/stored in the presynaptic neuron.

2. Released upon depolarization (Ca²⁺-dependent).

3. Exogenous application mimics nerve stimulation.

4. Specific termination mechanism exists.

5⃣ Classes of neurotransmitters and examples

6⃣ Acetylcholine (ACh) as prototype

• Synthesized by choline acetyltransferase from choline + acetyl-CoA.

• Stored in vesicles by VAChT (vesicular ACh transporter).

• Released → binds to nicotinic (AChR, ionotropic) or muscarinic (M1–M5, GPCR) receptors.

• Terminated by acetylcholinesterase (AChE) in synaptic cleft.

• ⚗ Drugs/toxins:

  • Botulinum toxin: blocks release (flaccid paralysis).

  • Nerve gases & organophosphates: inhibit AChE → excess ACh → muscle spasm, toxicity.

  • Neostigmine: reversible AChE inhibitor → therapeutic in myasthenia gravis.

7⃣ Catecholamines (dopamine, norepinephrine, epinephrine)

Flowchart:

Tyrosine → (Tyrosine hydroxylase) → DOPA → (DOPA decarboxylase) → Dopamine
    ↓ (Dopamine β-hydroxylase)
  Norepinephrine
    ↓ (PNMT)
  Epinephrine

• Stored in vesicles via VMAT2.

• Termination: reuptake (DAT/NET) + enzymatic degradation (MAO, COMT).

• 🧠 Clinical relevance:

  • Cocaine & amphetamines: block or reverse DAT → ↑ synaptic dopamine.

  • MAO inhibitors: prevent degradation → used in depression, Parkinson’s.

  • β-blockers: antagonize β-adrenergic receptors (post-synaptic).

8⃣ Serotonin (5-HT)

• Synthesized from tryptophan → 5-hydroxytryptophan → 5-HT.

• Reuptake via SERT; degraded by MAO-A.

• ⚗ Clinical examples:

  • SSRIs (fluoxetine, sertraline): block SERT → ↑ 5-HT availability → antidepressant.

  • MDMA (ecstasy): reverses SERT → massive 5-HT release.

  • Triptans: 5-HT₁ agonists used in migraine.

9⃣ Glutamate and GABA — balance of excitation and inhibition

• Glutamate: main excitatory transmitter.

  • Receptors: AMPA, NMDA, kainate (ionotropic) + mGluR (metabotropic).

  • ⚠ Excess = excitotoxicity (neuron death in stroke).

• GABA: main inhibitory transmitter.

  • Synthesized from glutamate via glutamic acid decarboxylase (GAD).

  • Receptors: GABAₐ (Cl⁻ channel), GABA_b (G-protein).

  • Benzodiazepines, barbiturates: enhance GABAₐ action (anxiolytic, sedative).

🔟 Synaptic plasticity and modulation

• Short-term: vesicle depletion, receptor desensitization.

• Long-term: changes in gene expression, receptor density.

• ⚗ Example: Long-term potentiation (LTP) in hippocampus — basis for learning.

  • Requires NMDA receptor Ca²⁺ influx → activates kinases → AMPA receptor insertion.

• 🧠 Many psychiatric drugs target synaptic plasticity pathways.

1⃣1⃣ Neuropeptides and co-transmission

• Often released with small-molecule transmitters.

• Substance P: pain pathways.

• Endorphins: act on opioid receptors; analgesic and euphoric.

• Vasopressin/oxytocin: modulate social behavior, stress.

1⃣2⃣ Termination mechanisms (summary)

1⃣3⃣ Receptor types & signaling overview

• Ionotropic (fast): ligand-gated ion channels (e.g., nicotinic AChR, GABAₐ, AMPA).

• Metabotropic (slow): GPCRs (e.g., muscarinic AChR, mGluR, β-adrenergic).

• Second-messenger links: same G-protein and cAMP/IP₃/DAG systems described in earlier lecture.

• ⚠ Drug selectivity depends on receptor subtype & distribution.

1⃣4⃣ Drugs and clinical examples (high-yield)

1⃣5⃣ Integration — how neurotransmission fits cell signaling

Flow overview:

Electrical impulse (AP)
      ↓
Voltage-gated Ca2+ channels open
      ↓
Ca2+ triggers vesicle fusion (SNARE)
      ↓
NT released → binds postsynaptic receptors
      ↓
Receptor activates ion channel or G-protein cascade
      ↓
Signal terminated by degradation/reuptake/diffusion

• 🧠 Reuses same molecular logic as hormonal signaling → fast localized version.

1⃣6⃣ Big names & dates timeline

1⃣7⃣ Closing takeaways

• 🔹 Neurotransmission is a chemical language of the nervous system.

• 🧠 Core pattern: Synthesis → Storage → Release → Receptor activation → Termination.

• ⚗ Drugs and toxins exploit each step for therapeutic or toxic ends.

• ⚠ Understanding these steps bridges neurobiology and pharmacology — from synaptic vesicles to psychiatric medication.