Neurotransmitters
Neurotransmitters
What You'll Learn
- Three NT classes — amino acids, monoamines, neuropeptides; excitatory vs inhibitory pairs
- ACh — muscarinic vs nicotinic receptors, NMJ blockade (pre vs post), anticholinesterases
- Catecholamine synthesis — TYR → L-DOPA → DA → NE → Epi; rate-limiting = tyrosine hydroxylase
- Dopamine pathways — nigrostriatal, mesolimbic, mesocortical, tuberoinfundibular; D1 vs D2
- Serotonin — raphe nuclei, 5-HT receptor subtypes, serotonin syndrome
- Glutamate — NMDA (Ca2+, Mg2+ block, glycine co-agonist), AMPA (fast EPSPs), excitotoxicity
- GABA — GABA-A (Cl−, 5 binding sites), GABA-B (K+, baclofen), GAD enzyme
- Glycine — spinal inhibition, strychnine antagonist, tetanus blocks release
HighYield Pearls
- Rate-limiting enzymes: tyrosine hydroxylase (catecholamines: DA, NE, Epi) — tryptophan hydroxylase (5HT) — GAD (GABA, B6-dependent) — ChAT (ACh)
- 4 DA pathways: nigrostriatal (motor → PD when lost), mesolimbic (reward/positive psychosis sx), mesocortical (executive/negative sx), tuberoinfundibular (inhibits prolactin → D2 block causes galactorrhea/amenorrhea)
- NMDA receptor: Ca²⁺-permeable, voltage + ligand gated, Mg²⁺ block at rest, glycine co-agonist site — blocked by ketamine, memantine, PCP, dextromethorphan, ethanol — central to LTP and excitotoxicity
- GABA-A vs GABA-B: A = ionotropic Cl⁻ channel (benzos, barbiturates, propofol, ethanol, neurosteroids); B = GPCR Gi (baclofen for spasticity, GHB)
- Disease NT pairs: AD = ↓ACh (Meynert) — PD = ↓DA + relative ↑ACh in striatum — HD = ↓GABA (medium spiny neurons) — depression = ↓5HT/NE/DA — schizophrenia = ↑mesolimbic DA + ↓mesocortical DA
- MAO selectivity: MAO-A breaks down 5HT + NE + DA (target in depression; tyramine crisis with cheese); MAO-B is DA-selective (selegiline/rasagiline for PD); COMT degrades catecholamines (entacapone for PD)
- Orexin/hypocretin: lateral hypothalamus — loss → narcolepsy type 1 with cataplexy; DORAs (suvorexant, lemborexant, daridorexant) block it for insomnia
- CGRP: migraine pathophysiology — gepants (ubrogepant, rimegepant, atogepant) and mAbs (erenumab, fremanezumab, galcanezumab, eptinezumab)
- Pyridoxine (B6)-dependent seizures: B6 is cofactor for GAD → deficiency → ↓GABA → neonatal refractory seizures responsive to IV pyridoxine
- Glycine = main spinal inhibitory NT: strychnine blocks → tetanic spasms; hyperekplexia from GLRA1 mutation; tetanus toxin blocks glycine release from Renshaw cells
🔍 Quick ReferenceReceptors / pathways · Synthesis / breakdown · Disease association
Receptors / pathways
- NMDA receptor — Mg²⁺ block + glycine co-agonist → LTP, memory, excitotoxicity; ketamine/memantine/PCP target
- α4β2 + α7 nicotinic AChR → main CNS nicotinic subtypes; α4β2 in nicotine addiction, α7 in cognition
- D1 family (D1, D5) Gs vs D2 family (D2, D3, D4) Gi → D2 block = antipsychotic effect + EPS + hyperprolactinemia
- GABA-A pentameric Cl⁻ channel → benzos, barbiturates, propofol, ethanol, neurosteroids binding sites
- 5HT3 ionotropic receptor → area postrema — ondansetron antiemetic target
- H3 autoreceptor → pitolisant inverse agonist for narcolepsy (boosts histamine wake drive)
Synthesis / breakdown
- Tyrosine → L-DOPA (TH, rate-limiting) → DA (AADC) → NE (DBH) → Epi (PNMT) → catecholamine pathway
- Tryptophan → 5-HTP (Trp hydroxylase) → 5HT (AADC) → serotonin synthesis
- Glutamate → GABA (GAD, B6-dependent) → main inhibitory NT synthesis — B6 deficiency causes seizures
- Choline + acetyl-CoA → ACh (ChAT), broken down by AChE → cholinesterase inhibitors (donepezil, rivastigmine, neostigmine, pyridostigmine)
- MAO-A vs MAO-B; COMT → monoamine degradation — selegiline/rasagiline (MAO-B), entacapone/tolcapone (COMT)
- AADC deficiency → infantile combined DA + 5HT deficiency (treatable inborn error)
Disease / drug association
- Nucleus basalis of Meynert ACh loss → Alzheimer disease — cholinesterase inhibitors
- Substantia nigra pars compacta DA loss → Parkinson disease; tuberoinfundibular block → galactorrhea
- Strychnine blocking glycine; GLRA1 mutation → tetanic spasms; hereditary hyperekplexia
- Orexin/hypocretin neuron loss in lateral hypothalamus → narcolepsy type 1 with cataplexy; DORAs for insomnia
- CGRP release from trigeminal afferents → migraine — gepants and CGRP mAbs
- Riluzole reducing glutamate release → ALS (only NT-targeted disease-modifying therapy)
- Vigabatrin (GABA-T inhibitor); tiagabine (GAT-1 block) → AEDs that boost GABA — vigabatrin for infantile spasms
Overview
| Category | Examples | Key Features |
|---|---|---|
| Amino acids | Glutamate, GABA, glycine, aspartate | Fast synaptic transmission; most abundant CNS NTs |
| Monoamines | DA, NE, epinephrine, 5-HT, histamine | Slow modulators; small nuclei, diffuse projections |
| Neuropeptides | Substance P, enkephalins, orexin | Co-transmitters; slow, modulatory; G-protein coupled |
- Main excitatory (CNS): glutamate — Main inhibitory (CNS): GABA — Main inhibitory (spinal): glycine
- NMJ + autonomic ganglia: ACh — Postganglionic sympathetic: NE (except sweat glands = ACh)
Electrolyte Concentrations
| Ion | Intracellular (mM) | Extracellular (mM) | Equilibrium Potential |
|---|---|---|---|
| K+ | ~140 | ~4 | −90 mV |
| Na+ | ~15 | ~145 | +60 mV |
| Ca2+ | ~0.0001 | ~2 | +120 mV |
| Cl− | ~5–15 | ~110 | −70 to −80 mV |
Acetylcholine (ACh)
- Synthesis: choline + acetyl-CoA → ACh (via ChAT); rate-limiting = choline supply
- Degradation: AChE → choline + acetate
- Key locations: basal forebrain (nucleus basalis of Meynert → cortex), medial septum / diagonal band → hippocampus, pedunculopontine + laterodorsal tegmental nuclei (PPT/LDT) → thalamus, brainstem — wake, REM sleep, DBS target for PD gait/freezing; NMJ, all autonomic ganglia, Renshaw cells, striatal interneurons
Cholinergic Receptors
| Receptor | Type | Mechanism | Location |
|---|---|---|---|
| Nicotinic (NM) | Ionotropic (Na+/K+) | Fast excitation | NMJ |
| Nicotinic (NN) | Ionotropic (Na+/K+) | Fast excitation | Autonomic ganglia, adrenal medulla, CNS |
| M1, M3, M5 | Muscarinic (Gq) | IP3/DAG → excitatory | CNS, glands, smooth muscle |
| M2, M4 | Muscarinic (Gi) | ↓ cAMP → inhibitory | Heart (↓ HR), presynaptic, CNS |
- nAChR subunit composition: Adult muscle nAChR = (α1)2β1δε; fetal/immature/denervated = (α1)2β1δγ (γ→ε perinatal switch). MG main immunogenic region (MIR) on α1. Neuronal nicotinic = α7 homomeric (CNS) and α4β2 (most abundant; nicotine addiction).
Cholinergic Agonists and Antagonists
| Drug | Action | Use |
|---|---|---|
| Bethanechol | Muscarinic agonist | Urinary retention |
| Pilocarpine | Muscarinic agonist | Glaucoma |
| Atropine | Muscarinic antagonist | Bradycardia, organophosphate poisoning |
| Benztropine | Central muscarinic antagonist | EPS, PD tremor |
| Hexamethonium | Ganglionic nicotinic blocker | Experimental |
Anticholinesterases
| Type | Examples | Use |
|---|---|---|
| Reversible | Edrophonium, pyridostigmine, neostigmine, donepezil, rivastigmine | MG diagnosis/treatment; Alzheimer's |
| Irreversible | Organophosphates (sarin, parathion) | Cholinergic crisis (SLUDGE); Tx: atropine + pralidoxime |
NMJ Blockade
| Feature | Presynaptic | Postsynaptic |
|---|---|---|
| Mechanism | ↓ ACh release | Block nicotinic receptor at endplate |
| Examples | Botulinum toxin, Lambert-Eaton, aminoglycosides, Mg2+ | Non-depolarizing: curare, vecuronium; Depolarizing: succinylcholine |
| Rep stim | Decremental; Lambert-Eaton: incremental at high rate | Decremental (non-depolarizing) |
Board Pearl
Nucleus basalis of Meynert degenerates early in Alzheimer's. AChE inhibitors (donepezil, rivastigmine) compensate for this cholinergic loss.
Catecholamine Synthesis
- Tyrosine → (tyrosine hydroxylase; RATE-LIMITING) → L-DOPA → (aromatic L-amino acid decarboxylase (AADC; also called DOPA decarboxylase) — same enzyme converts 5-HTP→5-HT and L-DOPA→dopamine; carbidopa/benserazide inhibit AADC peripherally to allow L-DOPA to cross BBB in PD) → DA → (dopamine β-hydroxylase) → NE → (PNMT) → Epi
- Degradation:
- MAO-A (intraneuronal, mitochondrial outer membrane) — preferentially metabolizes NE, 5-HT, DA; non-selective MAOI + SSRI/SNRI/linezolid/tramadol → serotonin syndrome
- MAO-B — preferentially metabolizes DA; predominant in glia and brain; MAO-B inhibitors (selegiline metabolized to amphetamine, rasagiline, safinamide) for PD — at PD doses, MAO-B selective avoids tyramine reaction (transdermal/high-dose loses selectivity)
- COMT (extraneuronal)
- Metabolites: DA → HVA; NE/Epi → VMA; 5-HT → 5-HIAA
Board Pearl
Tyrosine hydroxylase = rate-limiting step in catecholamine synthesis. Tryptophan hydroxylase = rate-limiting for serotonin. Know the metabolites: HVA (DA), VMA (NE), 5-HIAA (5-HT).
Continue reading — sign in
The full note has more clinical pearls, tables, and board-focused tips. Free account, no fee.