Neurotransmitters
Neurotransmitters
What Do You Need to Know?
- 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
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 → cortex), septal nuclei → hippocampus, 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 |
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 → (DOPA decarboxylase) → DA → (dopamine β-hydroxylase) → NE → (PNMT) → Epi
- Degradation: MAO (intraneuronal) + 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).
Dopamine
Four Pathways
| Pathway | Origin → Target | Function | Clinical |
|---|---|---|---|
| Nigrostriatal | SNc → striatum | Movement | ↓ DA = Parkinson's; D2 block = EPS |
| Mesolimbic | VTA → nucleus accumbens | Reward | ↑ DA = positive symptoms (schizophrenia) |
| Mesocortical | VTA → prefrontal cortex | Cognition | ↓ DA = negative/cognitive symptoms |
| Tuberoinfundibular | Hypothalamus → pituitary | Inhibits prolactin | D2 block → hyperprolactinemia |
D1 vs D2 Receptors
| Feature | D1-like (D1, D5) | D2-like (D2, D3, D4) |
|---|---|---|
| Mechanism | Gs → ↑ cAMP | Gi → ↓ cAMP |
| Effect | Stimulatory; activates direct pathway | Inhibitory; inhibits indirect pathway |
| Clinical | D1 agonists: PD motor improvement | D2 antagonists: antipsychotics; D2 agonists: pramipexole, ropinirole |
DA in Disease — Comparison
| Feature | Parkinson's | Schizophrenia | Huntington's |
|---|---|---|---|
| DA level | ↓↓ nigrostriatal | ↑ mesolimbic; ↓ mesocortical | Relative ↑ (loss of GABA/ACh) |
| Pathology | Loss of SNc neurons | Mesolimbic DA hyperactivity | Loss of GABAergic MSNs in caudate |
| Movement | Bradykinesia, rigidity, tremor | EPS from DA blockade (iatrogenic) | Chorea (early), rigidity (late) |
| Treatment | L-DOPA, DA agonists, MAO-B inhibitors | D2 antagonists (antipsychotics) | VMAT2 inhibitors (tetrabenazine) |
Board Pearl
Antipsychotic side effects map to pathway blockade: nigrostriatal → EPS; tuberoinfundibular → hyperprolactinemia; mesolimbic → therapeutic; mesocortical → worsens negative symptoms.
Norepinephrine
- Origin: locus ceruleus (pons) → diffuse projections to cortex, limbic, cerebellum, spinal cord
- Functions: arousal, attention, stress response, mood
- Inactivation: reuptake (NET), MAO, COMT
| Receptor | Mechanism | Key Effects |
|---|---|---|
| α1 | Gq → IP3/DAG | Vasoconstriction, mydriasis |
| α2 | Gi → ↓ cAMP | ↓ NE release (presynaptic); ↓ sympathetic outflow |
| β1 | Gs → ↑ cAMP | ↑ HR, ↑ contractility |
| β2 | Gs → ↑ cAMP | Bronchodilation, vasodilation |
- Clonidine, guanfacine: α2 agonists (HTN, ADHD) — Prazosin: α1 blocker (PTSD nightmares)
- SNRIs: block NE + 5-HT reuptake — TCAs: block NE + 5-HT reuptake (plus anticholinergic effects)
Serotonin (5-HT)
- Synthesis: tryptophan → (tryptophan hydroxylase; rate-limiting) → 5-hydroxytryptophan → 5-HT
- Origin: raphe nuclei (midbrain to medulla) → diffuse CNS projections
- Degradation: MAO-A → 5-HIAA
5-HT Receptor Subtypes
| Receptor | Type | Function / Location | Clinical |
|---|---|---|---|
| 5-HT1A | Gi | Autoreceptor (raphe); anxiolytic | Buspirone = partial agonist (anxiety) |
| 5-HT1B/1D | Gi | Cranial vasoconstriction, ↓ CGRP | Triptans = agonists (migraine) |
| 5-HT1C | Gq | Choroid plexus, appetite | Now reclassified as 5-HT2C |
| 5-HT2A | Gq | Cortical excitation, platelets | Hallucinogens = agonists; atypical antipsychotics = antagonists |
| 5-HT2C | Gq | Appetite, mood (hypothalamus) | Antagonists (olanzapine) → weight gain |
| 5-HT3 | Ionotropic (cation) | Area postrema, vagus, GI → emesis | Ondansetron = antagonist (anti-emetic) |
Serotonin Syndrome
Board Pearl
Drug combinations causing serotonin syndrome: SSRI + MAOI, SSRI + triptan, SSRI + tramadol, SSRI + linezolid.
- Triad: mental status changes + autonomic instability (hyperthermia, tachycardia) + neuromuscular hyperactivity (clonus, hyperreflexia)
- vs NMS: serotonin syndrome = rapid onset, clonus, hyperreflexia; NMS = slow (days), lead-pipe rigidity, bradyreflexia
- Tx: stop offending agent + cyproheptadine (5-HT2A antagonist) + benzodiazepines + supportive
Clinical Pearl
The key differentiator: clonus and hyperreflexia (serotonin syndrome) vs lead-pipe rigidity and bradyreflexia (NMS). Serotonin syndrome develops within hours; NMS over days.
Glutamate
| Receptor | Ion | Key Features | Drugs/Clinical |
|---|---|---|---|
| AMPA | Na+ | Fast EPSPs; majority of excitatory transmission | Perampanel (antagonist, epilepsy) |
| NMDA | Ca2+, Na+ | Voltage + ligand gated; Mg2+ block; requires glycine co-agonist; LTP, excitotoxicity | Ketamine, PCP, memantine (antagonists) |
| Kainate | Na+, K+ | Modulates excitability | Experimental seizure models |
| mGluRs | — | Metabotropic; slow modulation | Experimental targets |
- Excitotoxicity: ischemia → ↓ ATP → depolarization → glutamate flood → NMDA Ca2+ influx → neuronal death
- Anti-NMDA receptor encephalitis: Ab vs NR1 subunit; young woman → psychiatric symptoms → seizures → orofacial dyskinesias → autonomic instability; associated with ovarian teratoma
Board Pearl
NMDA receptor is a coincidence detector: requires membrane depolarization (Mg2+ block relief) AND glutamate + glycine binding simultaneously. This is fundamental to LTP and memory.
GABA
- Synthesis: glutamate → (GAD, requires vitamin B6) → GABA
- Degradation: GABA transaminase; vigabatrin = irreversible inhibitor → ↑ GABA (infantile spasms; side effect: visual field constriction)
| Feature | GABA-A | GABA-B |
|---|---|---|
| Type | Ionotropic (Cl− channel) | Metabotropic (Gi) |
| Effect | Fast IPSPs (Cl− influx) | Slow IPSPs (K+ efflux, ↓ Ca2+) |
| Drugs | BZDs, barbiturates, zolpidem, alcohol | Baclofen (spasticity) |
GABA-A — 5 Binding Sites
| Site | Agent | Effect |
|---|---|---|
| GABA | GABA, muscimol | Opens Cl− channel |
| Benzodiazepine | Diazepam, lorazepam, midazolam | ↑ Frequency of Cl− opening (requires GABA; ceiling effect) |
| Barbiturate | Phenobarbital, thiopental | ↑ Duration of Cl− opening (can open WITHOUT GABA → no ceiling → fatal OD) |
| Neurosteroid | Allopregnanolone | Positive allosteric modulator |
| Picrotoxin | Picrotoxin | Blocks Cl− channel → convulsant |
- Huntington's: loss of GABAergic MSNs in caudate → relative DA excess → chorea
- Anti-GAD antibodies: stiff-person syndrome, cerebellar ataxia, temporal lobe epilepsy
Board Pearl
BZDs increase FREQUENCY; barbiturates increase DURATION of Cl− channel opening. Barbiturates can open the channel without GABA → no ceiling effect → respiratory depression/death. BZDs require GABA → safer.
Glycine
- Main inhibitory NT in spinal cord and lower brainstem
- Ionotropic Cl− channel receptor (similar to GABA-A)
- Renshaw cells: glycinergic interneurons mediating recurrent inhibition of motor neurons
- Dual role: also a mandatory co-agonist at NMDA receptors
- Strychnine: competitive glycine receptor antagonist → muscle spasms, opisthotonus
- Tetanus toxin: blocks glycine + GABA release (cleaves synaptobrevin) → disinhibited motor neurons → rigidity, trismus
Clinical Pearl
Both strychnine and tetanus produce spinal disinhibition but differ in mechanism: strychnine blocks the glycine receptor directly; tetanus prevents presynaptic release of glycine/GABA by cleaving VAMP/synaptobrevin.
Other Neurotransmitters
Histamine
- Tuberomammillary nucleus (posterior hypothalamus) — only source of brain histamine
- H1 (Gq): wakefulness; blockade → sedation — H3 (Gi): autoreceptor; pitolisant (H3 inverse agonist) approved for narcolepsy
NT–Neuropeptide Co-transmitter Pairs
| Neurotransmitter | Co-released Neuropeptide | Location |
|---|---|---|
| ACh | VIP | Parasympathetic postganglionic |
| NE | Neuropeptide Y | Sympathetic postganglionic |
| Dopamine | CCK | Mesolimbic neurons |
| Serotonin | Substance P, TRH | Raphe nuclei |
| GABA | Enkephalin, dynorphin | Striatal MSNs |
| Glutamate | Substance P, CGRP | Dorsal horn afferents |
Opioid Receptors
| Receptor | Endogenous Ligand | Effects | Drugs |
|---|---|---|---|
| Mu (μ) | β-endorphin, enkephalins | Analgesia, euphoria, respiratory depression, miosis, constipation | Morphine, fentanyl; naloxone (antagonist) |
| Delta (δ) | Enkephalins | Spinal analgesia, mood modulation | Antidepressant/analgesic contribution |
| Kappa (κ) | Dynorphin | Analgesia, dysphoria, sedation, diuresis | Butorphanol; dysphoria limits use |
Substance P
- Pain transmission in dorsal horn (C fibers); NK1 receptor — aprepitant (NK1 antagonist) for chemotherapy-induced nausea
Board Pearl
Narcolepsy type 1 = loss of orexin-producing neurons in lateral hypothalamus (undetectable CSF orexin-A). Suvorexant (orexin antagonist) is used for insomnia — opposite mechanism.
Quick Reference
NT Summary Table
| NT | Rate-Limiting Step | Nucleus | Function | Key Disorders |
|---|---|---|---|---|
| Glutamate | Glutaminase | Ubiquitous | Main excitatory | Stroke, epilepsy, anti-NMDAR encephalitis |
| GABA | GAD (B6) | Interneurons, striatum | Main CNS inhibitory | Epilepsy, Huntington's, stiff-person |
| Glycine | — | Spinal cord, brainstem | Spinal inhibition | Strychnine, tetanus, hyperekplexia |
| DA | Tyrosine hydroxylase | SNc, VTA | Movement, reward | PD, schizophrenia, Huntington's |
| NE | Tyrosine hydroxylase | Locus ceruleus | Arousal, attention | Depression, anxiety, ADHD |
| 5-HT | Tryptophan hydroxylase | Raphe nuclei | Mood, sleep, pain | Depression, migraine, serotonin syndrome |
| ACh | Choline supply | Nucleus basalis | Memory, NMJ | Alzheimer's, MG, Lambert-Eaton |
| Histamine | Histidine decarboxylase | TMN | Wakefulness | Narcolepsy (pitolisant) |
Board Cheat Sheet
- Parkinson's: ↓ DA (SNc → striatum)
- Alzheimer's: ↓ ACh (nucleus basalis)
- Depression: ↓ NE and 5-HT
- Schizophrenia: ↑ mesolimbic DA, ↓ mesocortical DA
- Huntington's: ↓ GABA/ACh in striatum → relative ↑ DA → chorea
- MG: Ab vs postsynaptic nicotinic AChR — Lambert-Eaton: Ab vs presynaptic Ca2+ channels
- Stiff-person: anti-GAD Ab → ↓ GABA
- BZDs: ↑ frequency — Barbiturates: ↑ duration of Cl− opening
- Triptans: 5-HT1B/1D agonists — Buspirone: 5-HT1A agonist
- Anti-NMDAR encephalitis: young woman, psychiatric → dyskinesias → look for ovarian teratoma
References
- Bhatt A. Ultimate Review for the Neurology Boards. 3rd ed. Demos Medical; 2016. Chapter 1.
- Blumenfeld H. Neuroanatomy Through Clinical Cases. 3rd ed. Sinauer; 2021.
- Purves D, et al. Neuroscience. 6th ed. Oxford University Press; 2018.
- Ropper AH, et al. Adams and Victor's Principles of Neurology. 12th ed. McGraw-Hill; 2023.