Neuroanatomy, Neurophysiology and Neurodevelopment · 6 min read
Neurons, Synapses and Neurotransmitter Systems
On the ANCC exam this content sits in Domain I, Scientific Foundation (about 22% of scored items), which explicitly lists neuroanatomy, neurophysiology, neurodevelopment and heritability. ANCC items tend to be precise: which pathway explains a side effect, which receptor causes orthostasis, which brain region is hypoactive in a given disorder. The AANPCB exam folds the same knowledge into Assess and Diagnose items (scientific foundations, growth and development, comorbidities) and into Plan items where you must predict a drug's effect from its receptor profile. In both exams the winning strategy is to connect structure to symptom to treatment rather than memorizing isolated facts.
This chapter reviews how neurons signal, how neurotransmitters are made, released and removed, and the receptor families that psychotropic drugs target. Boards use this material to test mechanism-of-action reasoning: if you know the synthesis and clearance steps, you can predict what a drug or a toxin will do.
The Neuron and Electrical Signaling
A neuron receives input through dendrites, integrates it in the cell body, and sends output along an axon to presynaptic terminals. Astrocytes clear glutamate and support the blood-brain barrier, oligodendrocytes myelinate central axons and microglia prune synapses during development.
The resting membrane potential is about -70 mV, maintained by the sodium-potassium ATPase. When excitatory input depolarizes the axon hillock to threshold, voltage-gated sodium channels open and sodium rushes in, producing the action potential; voltage-gated potassium channels then repolarize the membrane. Myelin allows saltatory conduction between nodes of Ranvier. At the terminal, depolarization opens voltage-gated calcium channels, and calcium influx triggers vesicle fusion and neurotransmitter release. Lamotrigine, carbamazepine, oxcarbazepine and valproate block voltage-gated sodium channels; gabapentin and pregabalin bind the alpha-2-delta subunit of calcium channels.
Synaptic Transmission and Receptor Types
Released transmitter crosses the synaptic cleft and binds postsynaptic receptors, and often presynaptic autoreceptors that act as a brake on further release. Signaling ends by reuptake through transporters (SERT for serotonin, NET for norepinephrine, DAT for dopamine), enzymatic breakdown (acetylcholinesterase in the cleft; monoamine oxidase and COMT inside or near the terminal) or diffusion.
Receptors fall into two broad families. Ionotropic (ligand-gated ion channel) receptors act in milliseconds: GABA-A (chloride channel), NMDA and AMPA glutamate receptors (cation channels), nicotinic acetylcholine receptors and the 5-HT3 receptor. Metabotropic (G-protein-coupled) receptors act more slowly through second messengers such as cAMP and phosphoinositide: dopamine D1-D5, most serotonin receptors, adrenergic, muscarinic, histamine, opioid and GABA-B receptors. Second-messenger cascades lead to gene transcription changes, which is one reason many psychotropic effects take weeks.
Monoamines: Synthesis, Location and Breakdown
Dopamine, norepinephrine and epinephrine are catecholamines built from the amino acid tyrosine. Tyrosine hydroxylase, the rate-limiting enzyme, converts tyrosine to L-dopa; dopa decarboxylase makes dopamine; dopamine beta-hydroxylase converts dopamine to norepinephrine inside vesicles. Serotonin is an indolamine built from tryptophan; tryptophan hydroxylase is rate-limiting, producing 5-hydroxytryptophan and then serotonin. Monoamines are packaged into vesicles by VMAT2, the target of valbenazine and deutetrabenazine for tardive dyskinesia.
Breakdown products appear on exams. Serotonin is metabolized to 5-HIAA; low cerebrospinal fluid 5-HIAA has been associated with impulsive aggression and violent suicide attempts. Dopamine becomes homovanillic acid (HVA), and norepinephrine becomes MHPG (and vanillylmandelic acid peripherally). MAO-A preferentially breaks down serotonin, norepinephrine and dietary tyramine; MAO-B preferentially breaks down dopamine. That is why nonselective MAO inhibitors risk tyramine hypertensive crisis, while selective MAO-B inhibition at low selegiline doses carries less dietary risk.
| Transmitter | Main source nuclei | Key functions | Clinical links |
|---|---|---|---|
| Dopamine | Substantia nigra, ventral tegmental area, hypothalamus | Reward, motivation, movement, prolactin inhibition | Psychosis (excess mesolimbic), Parkinson disease, ADHD, addiction |
| Norepinephrine | Locus coeruleus (pons) | Arousal, attention, vigilance, fight or flight | Anxiety, PTSD hyperarousal, depression, withdrawal states |
| Serotonin | Raphe nuclei (brainstem) | Mood, anxiety, sleep, appetite, impulse control, pain | Depression, anxiety, OCD, serotonin syndrome |
| Acetylcholine | Nucleus basalis of Meynert, brainstem | Memory, attention, REM sleep, muscle contraction | Alzheimer disease, delirium, anticholinergic toxicity |
| Histamine | Tuberomammillary nucleus (hypothalamus) | Wakefulness, appetite | H1 blockade causes sedation and weight gain |
| GABA | Widespread interneurons | Main inhibitory transmitter | Anxiety, seizures, alcohol and benzodiazepine effects |
| Glutamate | Widespread pyramidal neurons | Main excitatory transmitter, learning, plasticity | Excitotoxicity, ketamine, memantine, schizophrenia models |
| Orexin (hypocretin) | Lateral hypothalamus | Stabilizes wakefulness | Loss in narcolepsy type 1; target of orexin antagonists |
GABA and Glutamate
Glutamate is the brain's main excitatory transmitter, and GABA, made from glutamate by glutamic acid decarboxylase, is the main inhibitory one. The balance between them governs seizure threshold, anxiety and sedation.
The GABA-A receptor is a chloride channel with separate binding sites. Benzodiazepines are positive allosteric modulators that increase the frequency of channel opening only when GABA is present, which gives them a safety ceiling when taken alone. Barbiturates increase the duration of opening and can open the channel directly at high doses, which explains their lethality. Alcohol enhances GABA-A function and inhibits NMDA receptors; chronic use downregulates GABA-A and upregulates NMDA receptors, so abrupt cessation produces a hyperexcitable state with tremor, seizures and delirium. Z-drugs (zolpidem, eszopiclone, zaleplon) bind the benzodiazepine site with selectivity for alpha-1-containing receptors, giving hypnotic effect with less anxiolysis. Neuroactive steroids are also GABA-A positive allosteric modulators: oral zuranolone is approved for postpartum depression, while IV brexanolone, the first drug approved for it, is no longer marketed in the United States.
The NMDA receptor is unusual: it needs glutamate plus a co-agonist (glycine or D-serine) and depolarization to expel a magnesium ion blocking the channel. Calcium entry through NMDA receptors drives long-term potentiation, the cellular basis of learning, but excessive calcium entry causes excitotoxic injury. Ketamine and esketamine block NMDA receptors, producing a glutamate surge through AMPA receptors that rapidly promotes synaptogenesis. Memantine is a low-affinity, uncompetitive NMDA antagonist that dampens pathologic excitation in moderate to severe Alzheimer disease. Phencyclidine (PCP) is an NMDA antagonist that can produce both positive and negative psychotic symptoms, which supports the glutamate hypofunction model of schizophrenia.
Acetylcholine, Histamine and Neuropeptides
Acetylcholine is synthesized from choline and acetyl-CoA by choline acetyltransferase and destroyed by acetylcholinesterase. Cholinergic projections from the nucleus basalis of Meynert to the cortex degenerate early in Alzheimer disease, which is the rationale for cholinesterase inhibitors (donepezil, rivastigmine, galantamine). Muscarinic receptors mediate parasympathetic effects; blocking them produces the anticholinergic toxidrome (dry mouth, constipation, urinary retention, blurred vision, tachycardia, confusion). Delirium in older adults is strongly linked to anticholinergic burden. Xanomeline is a newer exception that stimulates central M1 and M4 muscarinic receptors to treat schizophrenia, paired with trospium to block peripheral muscarinic effects.
Histamine from the tuberomammillary nucleus promotes wakefulness. H1 antagonism by diphenhydramine, hydroxyzine, quetiapine, mirtazapine, olanzapine, low-dose doxepin and many TCAs produces sedation and increased appetite.
Key Takeaways
- Tyrosine hydroxylase (catecholamines) and tryptophan hydroxylase (serotonin) are the rate-limiting synthesis enzymes; VMAT2 packages monoamines into vesicles.
- MAO-A degrades serotonin, norepinephrine and tyramine; MAO-B degrades dopamine; HVA, MHPG and 5-HIAA are the main metabolites.
- Benzodiazepines increase GABA-A opening frequency; barbiturates increase duration and can open the channel directly.
- NMDA receptors need glutamate, a co-agonist and relief of magnesium block; ketamine, esketamine, memantine and PCP all act here.
- Side effects follow receptors: H1 (sedation, weight), alpha-1 (orthostasis), muscarinic (anticholinergic effects and delirium).
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