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Neurotransmitters: A Comprehensive Reference

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Overview: What Is a Neurotransmitter?

1. Synthesized in the neuron
2. Stored in presynaptic vesicles
3. Released in a Ca²⁺-dependent manner upon stimulation
4. Act on specific postsynaptic receptors
5. Have a defined mechanism of inactivation (reuptake, enzymatic degradation, or diffusion)

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PART I: CATECHOLAMINES

Catecholamine Biosynthesis - Shared Pathway

Phenylalanine → Tyrosine (liver, phenylalanine hydroxylase)
                    ↓ Tyrosine hydroxylase (TH) [RATE-LIMITING STEP]
                    + tetrahydrobiopterin (BH4) cofactor
               L-DOPA
                    ↓ Aromatic amino acid decarboxylase (AADC)
               Dopamine
                    ↓ Dopamine-β-hydroxylase (DBH) [inside vesicles]
               Norepinephrine
                    ↓ Phenylethanolamine-N-methyltransferase (PNMT) [cytoplasmic]
               Epinephrine

• Tyrosine hydroxylase requires tetrahydrobiopterin (BH4) as cofactor. Its synthesis depends on GTP-cyclohydrolase-1.
• Key regulation: TH is subject to feedback inhibition by dopamine and norepinephrine (end-product inhibition).
• DBH is unique - it is the only step that occurs inside synaptic vesicles rather than in the cytoplasm.
• PNMT is cytoplasmic; only neurons in the C1, C2, C3 regions of the medulla and the adrenal medulla express it.
• PKU (phenylketonuria): mutation in phenylalanine hydroxylase gene - phenylalanine accumulates, causing severe mental retardation.

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1. DOPAMINE (DA)

Molecular Structure

• Chemical name: 3,4-dihydroxyphenethylamine
• Formula: C₈H₁₁NO₂; MW = 153.18 g/mol
• Structure: A catecholamine with a catechol ring (benzene ring with two adjacent hydroxyl groups at positions 3 and 4) and an ethylamine side chain (-CH₂-CH₂-NH₂)
• Key structural features: The catechol moiety is essential for receptor binding; the amine group can be protonated at physiological pH (pKa ~8.9), making it largely cationic

         HO    CH₂—CH₂—NH₂
          |
    HO   [benzene ring]

Dopaminergic Pathways (Kaplan & Sadock, p. 418-420)

Vesicular Storage and Release

• Dopamine is packaged into vesicles by VMAT-2 (vesicular monoamine transporter 2) in the CNS.
• Reserpine blocks VMAT, depleting dopamine stores.
• Amphetamines reverse VMAT action, mobilizing dopamine from vesicles into the cytoplasm and then the synapse.
• Release is triggered by action potential → Ca²⁺ influx → SNARE complex-mediated exocytosis (using synaptobrevin/VAMP and SNAP-25).

Metabolism/Inactivation

• Reuptake via the dopamine transporter (DAT) - the primary termination mechanism
• MAO (monoamine oxidase) - mitochondrial; converts DA to DOPAC (3,4-dihydroxyphenylacetic acid) via oxidative deamination
• COMT (catechol-O-methyltransferase) - methylates to 3-methoxytyramine (3-MT); acts mainly extracellularly
• Final product: Homovanillic acid (HVA) = DOPAC + COMT action; measured in CSF and urine as DA metabolite marker

Dopamine Receptors

Signal Transduction Mechanisms

• D1/D5 (Gs pathway): Gs → adenylate cyclase → ↑cAMP → PKA activation → phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) → modulation of ion channels, gene expression via CREB
• D2/D3/D4 (Gi pathway): Gi → ↓adenylate cyclase → ↓cAMP; also activates K⁺ channels (hyperpolarization) and inhibits voltage-gated Ca²⁺ channels

Dopamine Receptor Agonists

Dopamine Receptor Antagonists

• Schizophrenia: Hyperdopaminergic activity in mesolimbic (positive symptoms); hypodopaminergic in mesocortical (negative/cognitive symptoms)
• Parkinson's disease: Loss of nigrostriatal dopamine neurons (>70% lost before symptoms appear)
• Reward/addiction: Mesolimbic pathway; drugs of abuse all increase nucleus accumbens DA
• ADHD: Dysregulation in mesocortical DA (methylphenidate, amphetamines increase DAT-mediated reuptake blockade or DA release)

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2. NOREPINEPHRINE (NE) / NORADRENALINE

Molecular Structure

• Chemical name: (R)-(-)-4-(2-amino-1-hydroxyethyl)benzene-1,2-diol
• Formula: C₈H₁₁NO₃; MW = 169.18 g/mol
• Structure: Identical to dopamine but with a hydroxyl group at the β-carbon of the ethylamine side chain (added by DBH inside vesicles)
• Stereochemistry: The naturally active form is the L-(−)-isomer (levorotatory)

Noradrenergic Pathways

• Locus coeruleus (LC) in the pons: the primary noradrenergic nucleus; sends projections to virtually the entire CNS (cortex, hippocampus, cerebellum, spinal cord). Involved in arousal, attention, stress responses
• Lateral tegmentum: Projects to limbic areas; involved in emotion and autonomic regulation
• Peripheral: Postganglionic sympathetic neurons release NE at all organs except sweat glands (which use ACh)

Synthesis, Storage, Release (Ganong's, p. 157)

• NE synthesis follows the catecholamine pathway through dopamine
• DBH converts dopamine → NE inside synaptic vesicles (unique among NT synthesis steps)
• After release, NE is terminated primarily by reuptake via NET (norepinephrine transporter) - the most important mechanism
• Tricyclic antidepressants (TCAs) and SNRIs block NET → ↑synaptic NE
• Cocaine also blocks NET (explains cardiovascular toxicity)

Adrenergic Receptors

NE/Adrenergic Agonists

NE/Adrenergic Antagonists

Metabolism of Catecholamines

• MAO (MAO-A and MAO-B): Intraneuronal; catalyzes oxidative deamination
• COMT: Extraneuronal; catalyzes O-methylation
• NE → via MAO → DHPG (3,4-dihydroxyphenylglycol), via COMT → normetanephrine; final product = VMA (vanillylmandelic acid)
• MAO inhibitors (MAOIs): phenelzine, tranylcypromine, selegiline (MAO-B selective) - used in depression, Parkinson's

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3. EPINEPHRINE (Adrenaline)

Molecular Structure

• Chemical name: (R)-4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol
• Formula: C₉H₁₃NO₃; MW = 183.20 g/mol
• Structure: NE with an additional N-methyl group on the amine (added by PNMT)
• The N-methyl group increases β-receptor affinity

CNS and Peripheral Roles

• Brain epinephrine neurons are concentrated in medullary C1, C2, C3 cell groups; project to LC, dorsal raphe, hypothalamus, nucleus accumbens.
• Primarily a hormone from the adrenal medulla (80% of adrenal output), but also functions as a CNS neurotransmitter.
• Broader receptor action than NE: acts on α1, α2, β1, β2, β3 receptors.

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PART II: SEROTONIN (5-Hydroxytryptamine, 5-HT)

Molecular Structure

• Chemical name: 5-hydroxytryptamine
• Formula: C₁₀H₁₂N₂O; MW = 176.21 g/mol
• Structure: An indolethylamine - an indole ring (bicyclic: benzene fused with pyrrole) with a hydroxyl group at position 5 and an ethylamine (-CH₂-CH₂-NH₂) side chain
• Precursor: L-tryptophan (essential amino acid, dietary)

Synthesis Pathway

L-Tryptophan
     ↓ Tryptophan hydroxylase (TPH) [RATE-LIMITING STEP; requires BH4]
         TPH1 (peripheral/enterochromaffin cells)
         TPH2 (brain/neurons)
5-Hydroxytryptophan (5-HTP)
     ↓ Aromatic amino acid decarboxylase (AADC)
5-Hydroxytryptamine (Serotonin)
     ↓ MAO-A (mainly) + aldehyde dehydrogenase
5-Hydroxyindoleacetic acid (5-HIAA) [urinary metabolite - measured in carcinoid syndrome]

Serotonergic Pathways

• Raphe nuclei (dorsal raphe = B7, median raphe = B8) in the brainstem are the primary serotonergic cell bodies
• Project to cortex, limbic system, hippocampus, striatum, cerebellum, spinal cord
• 90%+ of body's serotonin is in enterochromaffin cells of the GI tract; 8% in platelets
• Melatonin synthesis: serotonin → (N-acetyltransferase) → N-acetylserotonin → (HIOMT) → melatonin (in pineal gland)

Vesicular Storage and Termination

• Stored in vesicles via VMAT-2 (same as catecholamines)
• Terminated primarily by SERT (serotonin transporter) reuptake
• SSRIs block SERT → ↑synaptic 5-HT → antidepressant effect
• Degraded by MAO-A → 5-HIAA

Serotonin Receptors (Kaplan & Sadock, p. 441 onwards)

Key Signal Transduction

• 5-HT2 family → Gq → PLC → IP3 (releases Ca²⁺ from ER) + DAG (activates PKC) → phosphorylation cascades
• 5-HT1 family → Gi → ↓cAMP; opens inward rectifier K⁺ channels (GIRK channels) → hyperpolarization
• 5-HT3 → rapid depolarization via cation influx (Na⁺/K⁺)

Serotonin Agonists

Serotonin Antagonists

SSRIs/SNRIs (Reuptake Inhibitors - Indirect Serotonergic Agents)

5-HT2A and Hallucination Mechanism (Kandel's Principles of Neural Science)

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PART III: ACETYLCHOLINE (ACh)

Molecular Structure

• Chemical name: 2-(acetyloxy)-N,N,N-trimethylethan-1-aminium
• Formula: C₇H₁₆NO₂⁺; MW = 146.21 g/mol (as the cation)
• Structure: An ester of choline and acetic acid
  • Choline: HO-CH₂-CH₂-N⁺(CH₃)₃
  • Acetyl group: CH₃-CO-O- esterified to the hydroxyl of choline
• Key structural feature: The quaternary ammonium group (N⁺(CH₃)₃) carries a permanent positive charge, making ACh unable to cross lipid membranes (cannot enter the CNS when given peripherally)

    O
    ‖
CH₃-C-O-CH₂-CH₂-N⁺(CH₃)₃

Synthesis and Metabolism

• Synthesis: Choline + Acetyl-CoA → ACh
  • Enzyme: Choline acetyltransferase (ChAT) - the marker enzyme for cholinergic neurons
  • Choline is derived from diet and recycled from ACh hydrolysis (high-affinity choline transporter)
  • Rate-limiting: availability of choline and acetyl-CoA
• Vesicular storage: ACh packaged by VAChT (vesicular ACh transporter)
  • Vesamicol blocks VAChT
• Termination: Unlike all other NTs, ACh is NOT terminated by reuptake. Instead:
  • Acetylcholinesterase (AChE) - at the synapse and on RBCs; hydrolyzes ACh to choline + acetate in <1 ms
  • Butyrylcholinesterase (BuChE, pseudocholinesterase) - in plasma and liver; broader substrate specificity
• Choline is recaptured by the high-affinity choline transporter (hemicholinium-3 blocks this)

Cholinergic Pathways

Acetylcholine Receptors

Nicotinic Acetylcholine Receptors (nAChR) - Kandel's Principles of Neural Science, p. 302-303

• Structure: Pentameric ion channel; each subunit has 4 transmembrane (TM) helices (M1-M4), with M2 forming the pore lining
• Muscle type (NMJ): Composed of α₁₂β₁γδ (fetal) or α₁₂β₁εδ (adult) subunits
• Neuronal type: α (α2-α10) and β (β2-β4) subunits in various combinations; e.g., α4β2 is the predominant brain subtype; α7 (homomeric) in cortex and hippocampus
• Ion permeability: Na⁺ and K⁺ (at NMJ); α7 also highly permeable to Ca²⁺
• Mechanism (Kandel's): Two ACh molecules must bind (one per α subunit) → conformational change → channel opening → net inward current (depolarization) → end-plate potential (EPP) → action potential

• Nicotine (partial agonist at most subtypes; full agonist at some)
• Succinylcholine (depolarizing NMJ blocker - acts as agonist, causes persistent depolarization → phase I block)
• Varenicline (partial agonist at α4β2 - smoking cessation)

• NMJ blockers (non-depolarizing): Tubocurarine, vecuronium, rocuronium, atracurium - competitively block postsynaptic nAChR at NMJ → muscle relaxation (reversed by neostigmine/sugammadex)
• Ganglionic blockers: Hexamethonium, trimethaphan - block ganglionic nAChR (historical antihypertensives)
• α-Bungarotoxin: Snake toxin; irreversibly blocks muscle-type nAChR (critical research tool - Kandel's lab used it to identify and isolate the nAChR)
• Mecamylamine: CNS-penetrant ganglionic blocker; research use

Muscarinic Acetylcholine Receptors (mAChR)

• Pilocarpine: M3 agonist; glaucoma (↑aqueous humor drainage), Sjögren's syndrome (dry mouth)
• Bethanechol: M3 selective; urinary retention, gastroparesis
• Carbachol: Non-selective; resistant to AChE; glaucoma
• Cevimeline: M3 agonist; Sjögren's syndrome
• Muscarine: Natural alkaloid (mushrooms); non-selective agonist - the "toxidrome" prototype

• Treatment: Atropine (large doses for muscarinic effects) + pralidoxime (2-PAM; regenerates AChE before "aging")

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PART IV: GABA (γ-Aminobutyric Acid)

Molecular Structure

• Chemical name: 4-aminobutanoic acid
• Formula: C₄H₉NO₂; MW = 103.12 g/mol
• Structure: A 4-carbon chain with an amino group at one end (C1-NH₂) and a carboxyl group at the other; the amino group is NOT on the α-carbon (unlike α-amino acids), hence GABA is a non-protein amino acid
• Charge at physiological pH: Zwitterionic (NH₃⁺ and COO⁻ groups)

H₂N-CH₂-CH₂-CH₂-COOH
(4-aminobutyric acid)

Synthesis and Degradation (GABA Shunt)

Glutamate → GABA
              ↓ Glutamate decarboxylase (GAD) [requires pyridoxal phosphate/Vitamin B6 as cofactor]
            GABA
              ↓ GABA transaminase (GABA-T) [in mitochondria]
            Succinic semialdehyde
              ↓ Succinic semialdehyde dehydrogenase
            Succinate (enters Krebs cycle)

• GAD (glutamic acid decarboxylase) is the marker enzyme for GABAergic neurons
• Pyridoxine (B6) deficiency → ↓GAD activity → ↓GABA → seizures (especially in neonates)
• GABA-T is also inhibited by vigabatrin (irreversible; anticonvulsant) → ↑GABA accumulation
• Storage: vesicular by VGAT (vesicular GABA transporter, also transports glycine)
• Reuptake: GAT-1, GAT-2, GAT-3 transporters; tiagabine blocks GAT-1 (anticonvulsant)

GABA Receptors

GABA-A Receptor (Ionotropic - Ligand-Gated Cl⁻ Channel)

• Structure: Pentameric; assembled from subunits belonging to families α(1-6), β(1-3), γ(1-3), δ, ε, θ, π, ρ(1-3)
• The most common native receptor contains 2α + 2β + 1γ subunits
• Ion selectivity: Cl⁻ (primarily); hyperpolarizing (Cl⁻ influx) → inhibitory postsynaptic potential (IPSP)
  • Exception: In early development, Cl⁻ is high intracellularly, so GABA-A is depolarizing (excitatory) in fetal/neonatal neurons
• Binding sites (multiple allosteric modulatory sites):
  • GABA binding site: Between α and β subunits
  • Benzodiazepine site: On γ subunit (between α and γ) - allosteric; increases frequency of Cl⁻ channel opening without activating the channel directly
  • Barbiturate/anesthetic site: Within the channel pore (on β subunit TM2) - increases duration of Cl⁻ channel opening; can open channel independently at high concentrations
  • Steroid (neurosteroid) site: On α and β subunits (distinct from benzodiazepine site)
  • Ethanol: Acts on a hydrophobic pocket in the TM domain (mainly δ-subunit containing receptors)
  • Picrotoxin/Bicuculline: Channel blockers and competitive antagonists respectively - convulsants

• Propofol: Acts at GABA-A (β subunit) + other sites; IV anesthetic
• Etomidate: GABA-A (β2/β3); IV induction (adrenal suppression concern)
• Neurosteroids (allopregnanolone/brexanolone): Positive allosteric modulator of GABA-A at a δ-containing extrasynaptic site; brexanolone (IV allopregnanolone) approved for postpartum depression
• Alcohol: GABA-A positive modulator; NMDA antagonist
• Z-drugs (zolpidem, zaleplon, eszopiclone): BZD receptor agonists (GABA-A at α1 subunit) - more selective for sedation/sleep

GABA-B Receptor (Metabotropic - GPCR)

• Structure: Heterodimer of GABA-B1 and GABA-B2 subunits (unique among GPCRs)
• G-protein: Gi/Go
• Mechanism: ↓cAMP; ↑K⁺ conductance (GIRK - hyperpolarization); ↓Ca²⁺ conductance (presynaptic, inhibits transmitter release)
• Location: Both presynaptic (autoreceptor, reducing GABA release; also heteroreceptor on glutamatergic terminals) and postsynaptic

• Baclofen: GABA-B agonist; muscle relaxant (spasticity in MS, spinal cord injury), hiccups, alcohol use disorder; intrathecal baclofen for severe spasticity
• GHB (gamma-hydroxybutyrate): GABA-B agonist + GHB receptor agonist; Xyrem for narcolepsy/cataplexy; drug of abuse

• CGP36742, SGS742: Research tools; potential use in cognitive enhancement

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PART V: GLUTAMATE

Molecular Structure

• Chemical name: L-Glutamic acid (2-aminopentanedioic acid)
• Formula: C₅H₉NO₄; MW = 147.13 g/mol
• Structure: An α-amino acid with two carboxyl groups (α-carboxyl at C1, γ-carboxyl at C5) and an amino group at C2
• The principal excitatory neurotransmitter of the CNS; makes up >50% of all CNS synapses

HOOC-CH(NH₂)-CH₂-CH₂-COOH

Synthesis and Termination

• Synthesized from α-ketoglutarate (Krebs cycle intermediate) via transamination or from glutamine via glutaminase (glutamine-glutamate cycle)
• Glutamine-glutamate cycle: Released glutamate is taken up by astrocytes → converted to glutamine by glutamine synthetase → released to neurons → converted back to glutamate by glutaminase
• Vesicular storage by VGluT1, VGluT2, VGluT3
• Reuptake by EAATs (Excitatory Amino Acid Transporters, 1-5): EAAT1 (GLAST) and EAAT2 (GLT-1) are astrocytic; EAAT3/4 are neuronal. Riluzole (ALS drug) enhances EAAT-mediated glutamate clearance

Glutamate Receptors

Ionotropic Glutamate Receptors

1. Glutamate binding site (GluN2 subunit)
2. Co-agonist/glycine/D-serine site (GluN1 subunit) - MUST be occupied for channel opening
3. Mg²⁺ block (inside channel pore, at resting membrane potential) - removed by depolarization (voltage-dependent)
4. PCP/ketamine/dizocilpine (MK-801) site - within open channel (open-channel blockers)
5. Zinc site (inhibitory modulation; on GluN2A/B)
6. Polyamine site (spermidine, spermine - positive modulation)

1. High-frequency presynaptic stimulation → large glutamate release
2. Simultaneous AMPA-mediated depolarization → removes Mg²⁺ block from NMDA receptor
3. NMDA channel opens → Ca²⁺ influx → activates CaM kinase II, PKC, PKA
4. CaMKII phosphorylates AMPA receptors → ↑conductance; also promotes trafficking of AMPA receptors to synapse
5. CREB activation → gene expression → late-phase LTP (structural changes, new synapses)

Metabotropic Glutamate Receptors (mGluR1-8)

Glutamate Receptor Antagonists (NMDA)

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PART VI: GLYCINE

Structure and Mechanism

• Formula: C₂H₅NO₂; MW = 75.03 g/mol - the simplest amino acid
• Structure: H₂N-CH₂-COOH
• Primary inhibitory transmitter of the spinal cord and brainstem; uses glycine receptor (GlyR)
• GlyR is a pentameric Cl⁻ channel (like GABA-A); composed of α1-4 and β subunits; strychnine-sensitive
• Also serves as a co-agonist (not the primary agonist) at the NMDA receptor glycine site (GluN1)

• Strychnine: Competitive antagonist at glycine receptor → uninhibited motor neuron firing → tetanic spasms (rat poison)

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PART VII: HISTAMINE

Structure and Receptors (Kaplan & Sadock, p. 450-451)

• Formula: C₅H₉N₃; MW = 111.15 g/mol
• Structure: Imidazole ring (5-membered ring with two nitrogens) attached to an ethylamine chain
• Synthesis: L-Histidine → Histamine (by histidine decarboxylase, requires B6 cofactor)
• CNS source: Tuberomammillary (TMN) nucleus of the posterior hypothalamus
• Function: Wakefulness/arousal, appetite regulation, cognition
• Degradation: Histamine methyltransferase (brain); diamine oxidase (periphery)

• First-generation (CNS-penetrant): Diphenhydramine (Benadryl), chlorpheniramine, promethazine - sedating (block H1 in brain); also have anticholinergic effects
• Second-generation (non-sedating): Cetirizine, loratadine, fexofenadine - do not cross BBB
• H3 inverse agonists: Pitolisant (Wakix) - approved for narcolepsy (increases histamine, ACh, DA, NE release in cortex)

• Ranitidine (withdrawn), famotidine, cimetidine - reduce gastric acid; used for peptic ulcer, GERD

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Summary Table: Receptor Signal Transduction

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Key References Used

1. Kandel ER, Koester JD, Mack SH, Siegelbaum SA - Principles of Neural Science, 6th Edition (2021) - Chapters on NMJ, nicotinic ACh receptor structure/function, synaptic transmission, LTP. [Textbook available in library as ISBN 9781259642241]
2. Sadock BJ, Sadock VA, Ruiz P - Kaplan & Sadock's Comprehensive Textbook of Psychiatry, 10th Edition - Chapters 1.7 and 1.6 on catecholamines, serotonin, GABA, glutamate, histamine, neuropeptides (pp. 418-530). [ISBN 9781975175733]
3. Brunton LL, Hilal-Dandan R, Knollmann BC - Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th Edition - Dopamine agonist/antagonist pharmacology. [ISBN 9781264258079]
4. Katzung BG - Basic and Clinical Pharmacology, 16th Edition - Parkinson's pharmacology, dopamine agonists. [ISBN 9781260463309]
5. Barrett KE, Barman SM, Brooks HL, Yuan JX-J - Ganong's Review of Medical Physiology, 26th Edition - Catecholamine synthesis, catabolism, adrenergic pharmacology. [ISBN 9781260122404]
6. Rodwell VW, Bender DA, Botham KM et al. - Harper's Illustrated Biochemistry, 32nd Edition - Tyrosine hydroxylase and catecholamine biosynthesis.
7. Siegel GJ, Albers RW, Brady S, Price DL - Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (Siegel's) - Referenced throughout for molecular mechanisms of receptor-channel coupling, second messenger systems, and GABA receptor pharmacology.

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• The NMDA receptor is the brain's "coincidence detector" - it requires BOTH presynaptic activity (glutamate) AND postsynaptic depolarization (to relieve Mg²⁺ block) - the molecular basis of Hebb's rule ("cells that fire together, wire together") and thus learning and memory (LTP).
• Benzodiazepines ↑ frequency of Cl⁻ channel opening; Barbiturates ↑ duration - both require GABA; at very high barbiturate doses, the channel opens without GABA (explains lethality in overdose vs. BZD safety).
• The catecholamine synthesis pathway is a single linear sequence: the key drug targets are tyrosine hydroxylase (rate-limiting; blocked by metyrosine), AADC (blocked by carbidopa at periphery), DBH (blocked by disulfiram), VMAT (blocked by reserpine), MAO (blocked by MAOIs), COMT (blocked by entacapone/tolcapone).
• Kandel's key insight at the nicotinic synapse: Two ACh molecules must bind one alpha subunit each → conformational change through all 5 subunits → M2 helices rotate to open the pore → Na⁺ enters, K⁺ exits, net depolarization. This is the basis of all ionotropic receptor pharmacology.