Key idea: For boards, think in terms of: NT → major nucleus → main pathway → function → clinical + drugs.
| Class | Examples | Key Features |
|---|---|---|
| Excitatory (fast) | Glutamate, Aspartate | Main CNS excitatory NT; ionotropic (AMPA, NMDA) & metabotropic receptors |
| Inhibitory (fast) | GABA (CNS), Glycine (spinal cord) | Main CNS & spinal inhibitory NTs; Cl⁻ or K⁺ mediated |
| Monoamines | Dopamine, NE, Serotonin | Slow modulators; small nuclei with diffuse projections; psychiatric & movement disorders |
| Cholinergic | Acetylcholine (ACh) | Cortex, hippocampus, neuromuscular junction, autonomic ganglia |
| Neuropeptides | Substance P, Enkephalins, Endorphins, Orexin, CRH, etc. | Co-transmitters; slow, modulatory; often G-protein coupled receptors |
Most fast EPSPs = glutamate (AMPA); most fast IPSPs = GABAA (CNS) or glycine (spinal cord/brainstem). Monoamines & peptides modulate, but do not usually mediate the primary fast synaptic transmission.
| Step | Physiology | Key Drugs/Toxins |
|---|---|---|
| 1. AP arrival | Action potential → depolarization of presynaptic terminal | Na⁺ channel blockers (phenytoin, carbamazepine, lidocaine) |
| 2. Ca²⁺ influx | Voltage-gated Ca²⁺ channels open → Ca²⁺ entry | Ca²⁺ channel blockers (gabapentin, pregabalin; some anesthetics) |
| 3. Vesicle fusion | SNARE complex mediates vesicle fusion and exocytosis | Botulinum toxin: cleaves SNAREs (↓ ACh release) |
| 4. NT binding | NT diffuses across cleft → binds receptors | Receptor agonists/antagonists (benzos @ GABAA, ketamine @ NMDA, etc.) |
| 5. Termination | Reuptake, enzymatic breakdown, diffusion |
Reuptake inhibitors: SSRIs, SNRIs, TCAs (SERT/NET) Enzyme inhibitors: MAOIs, COMT inhibitors, AChE inhibitors |
Electrical synapses: Gap junctions; fast, bidirectional; found in some brainstem nuclei, hypothalamus, and early development.
Most clinically used CNS drugs act at the synapse, NOT at the axon: receptors, transporters, enzymes, or vesicle release machinery.
| Receptor | Type | Key Features | Clinical/Drugs |
|---|---|---|---|
| AMPA | Ionotropic (Na⁺/K⁺) | Fast EPSPs; majority of excitatory transmission | Targeted indirectly by many anticonvulsants |
| NMDA | Ionotropic (Ca²⁺/Na⁺) | Voltage & ligand dependent (Mg²⁺ block); central to plasticity & excitotoxicity |
Antagonists: ketamine, PCP, memantine Implicated in stroke, TBI, epilepsy |
| Kainate | Ionotropic | Less prominent; modulates excitability | Experimental agonists used to induce seizures in models |
| mGluRs | Metabotropic | Pre- and postsynaptic modulation, slow effects | Targets for experimental epilepsy/psychiatric drugs |
Metabolism: Glutamate–glutamine cycle between neurons and astrocytes (astrocytes clear glutamate via EAAT transporters).
Ischemia → ↓ ATP → failed Na⁺/K⁺ pump → depolarization → massive glutamate release → NMDA-mediated Ca²⁺ influx → neuronal death. This cascade underlies many neuroprotective strategies.
| Receptor | Type | Effect | Key Drugs |
|---|---|---|---|
| GABAA | Ionotropic (Cl⁻ channel) | Fast inhibition (hyperpolarization via Cl⁻ influx) |
Benzodiazepines, barbiturates, zolpidem General anesthetics, alcohol (potentiation) |
| GABAB | Metabotropic (G-protein) | Opens K⁺ channels, ↓ Ca²⁺ → slow inhibition | Baclofen: GABAB agonist (spasticity) |
Metabolism: Synthesized from glutamate by glutamic acid decarboxylase (GAD); broken down by GABA transaminase.
Clinical: Vigabatrin irreversibly inhibits GABA transaminase → ↑ GABA (used in refractory epilepsy, infantile spasms).
Tetanus = loss of inhibitory glycinergic & GABAergic interneurons → disinhibited motor neurons → generalized rigidity & spasms.
| NT | Nucleus / Origin | Main Pathways & Functions | Clinical / Drugs |
|---|---|---|---|
| Dopamine |
Substantia nigra pars compacta (SNc) VTA (mesolimbic/mesocortical) Tuberoinfundibular (hypothalamus) |
Nigrostriatal: Movement Mesolimbic: Reward, psychosis Mesocortical: Motivation, cognition Tuberoinfundibular: ↓ Prolactin |
↓ Nigrostriatal: Parkinson’s disease ↑ Mesolimbic: Schizophrenia (positive symptoms) Antipsychotics = D2 antagonists; L-dopa, agonists for PD |
| Norepinephrine | Locus coeruleus (pons) |
Diffuse projections to cortex, limbic system, spinal cord Arousal, attention, stress response |
Implicated in depression, anxiety, ADHD SNRIs, TCAs, stimulants ↑ NE (and DA) |
| Serotonin (5-HT) | Raphe nuclei (midbrain → medulla) |
Mood, anxiety, sleep, pain modulation Descending pain inhibition in spinal cord |
SSRIs, SNRIs, TCAs ↑ 5-HT Triptans = 5-HT1B/1D agonists (migraine) Risk of serotonin syndrome with polypharmacy |
Metabolism: Monoamines broken down by MAO (A/B) and COMT. Metabolites include HVA (DA), VMA (NE/Epi), 5-HIAA (5-HT).
| Receptor | Family | Location | Function | Clinical |
|---|---|---|---|---|
| D1 | D1-like (Gs → ↑ cAMP) | Striatum (direct pathway), cortex | Activates direct pathway → facilitates movement | D1 agonists improve PD motor symptoms |
| D2 | D2-like (Gi → ↓ cAMP) | Striatum (indirect pathway), pituitary, VTA | Inhibits indirect pathway → facilitates movement; inhibits prolactin | Antipsychotics = D2 antagonists; D2 agonists = pramipexole, ropinirole |
| D3 | D2-like | Nucleus accumbens, VTA | Reward, motivation | Target for addiction research; pramipexole has D3 affinity |
| D4 | D2-like | Frontal cortex, amygdala | Cognition, attention | Clozapine has high D4 affinity |
| D5 | D1-like | Hippocampus, hypothalamus | Memory modulation | Less clinical relevance currently |
Key concept: D1 (direct pathway, ‘go’) and D2 (indirect pathway, ‘stop’) work together in the basal ganglia. PD = loss of dopamine → underactive D1 direct pathway + overactive D2 indirect pathway → bradykinesia.
| Receptor | Type | Location | Function | Clinical Relevance |
|---|---|---|---|---|
| 5-HT1A | Gi-coupled | Raphe nuclei (autoreceptor), hippocampus, cortex | ↓ Serotonin release (presynaptic); anxiolytic (postsynaptic) | Buspirone = 5-HT1A partial agonist (anxiety) |
| 5-HT1B/1D | Gi-coupled | Cranial blood vessels, trigeminal neurons | Vasoconstriction, ↓ CGRP release | Triptans = 5-HT1B/1D agonists (migraine abortive) |
| 5-HT2A | Gq-coupled | Cortex, platelets | Cortical excitation, platelet aggregation | Target of atypical antipsychotics (5-HT2A antagonism); hallucinogens are 5-HT2A agonists |
| 5-HT2C | Gq-coupled | Hypothalamus, limbic | Appetite, mood | Weight gain with 5-HT2C antagonists (olanzapine, mirtazapine) |
| 5-HT3 | Ligand-gated ion channel | Area postrema, vagus, GI | Emesis, visceral pain | Ondansetron = 5-HT3 antagonist (anti-emetic) |
| 5-HT4 | Gs-coupled | GI tract, CNS | GI motility, cognition | GI prokinetics |
Dopamine pathways: Nigrostriatal (movement), Mesolimbic (reward/psychosis), Mesocortical (negative symptoms), Tuberoinfundibular (prolactin). Side effect patterns of antipsychotics mirror these pathways (EPS, hyperprolactinemia, negative/cognitive symptoms).
| Nucleus | Projection | Function | Clinical |
|---|---|---|---|
| Nucleus basalis of Meynert | Diffuse to neocortex | Attention, arousal, cortical activation | Degenerates in Alzheimer’s disease → basis for AChE inhibitors |
| Medial septal nucleus | Hippocampus | Memory, hippocampal theta rhythms | Memory impairment with cholinergic dysfunction |
| Pontine cholinergic nuclei | Thalamus, cortex | REM sleep, arousal | Sleep regulation; REM-related phenomena |
Nucleus basalis of Meynert is the key cholinergic nucleus affected early in Alzheimer’s disease. AChE inhibitors (donepezil, rivastigmine) are designed to compensate for this loss.
| Feature | Detail |
|---|---|
| Source | Tuberomammillary nucleus (TMN) of posterior hypothalamus |
| Projections | Diffuse to entire CNS (cortex, hippocampus, striatum, brainstem) |
| Primary function | Wakefulness, arousal (part of ascending arousal system) |
| H1 receptors | Gq-coupled; wakefulness; allergic responses. Blocked by first-gen antihistamines → sedation |
| H2 receptors | Gs-coupled; gastric acid secretion; minor CNS role |
| H3 receptors | Gi-coupled; presynaptic autoreceptor → ↓ histamine release. Also modulates DA, NE, ACh release |
| Pitolisant | H3 inverse agonist → ↑ histamine release → promotes wakefulness. FDA-approved for narcolepsy and OSA-related EDS |
Histamine neurons in TMN are active during wakefulness and silent during sleep — similar to NE (locus coeruleus) and 5-HT (raphe). Antihistamines cause sedation by blocking H1-mediated cortical activation.
Pitolisant (H3 inverse agonist) increases histamine release and is approved for narcolepsy. First-generation antihistamines (diphenhydramine) cause sedation via CNS H1 blockade. The tuberomammillary nucleus is the ONLY source of brain histamine.
| Peptide | Function | Clinical Relevance |
|---|---|---|
| Substance P | Pain transmission (esp. in dorsal horn); neurogenic inflammation | NK1 receptor antagonists (aprepitant) used as antiemetics |
| Endorphins/Enkephalins | Endogenous opioids; pain modulation, reward | Opioid receptors (μ, κ, δ) targeted by analgesics (morphine, fentanyl) |
| Orexin (hypocretin) | Wakefulness, appetite | Loss in narcolepsy type 1; orexin antagonists (suvorexant) for insomnia |
| CRH, ACTH, etc. | Stress axis (hypothalamic–pituitary) | Interact with mood, anxiety, neuroendocrine disorders |
Narcolepsy type 1 = loss of orexin-producing neurons in lateral hypothalamus. This is a favorite board association.
| Neurotransmitter | Major Nucleus | Main Targets | Key Disorders |
|---|---|---|---|
| Glutamate | Ubiquitous (most excitatory neurons) | Entire CNS | Stroke, epilepsy, neurodegeneration (excitotoxicity) |
| GABA | Interneurons, cerebellum, basal ganglia | CNS inhibition | Epilepsy, anxiety, spasticity |
| Dopamine | SNc, VTA | Striatum, limbic system, cortex | Parkinson’s, schizophrenia, addiction |
| Norepinephrine | Locus coeruleus | Diffuse cortical & spinal projections | Depression, anxiety, ADHD |
| Serotonin (5-HT) | Raphe nuclei | Cortex, limbic, spinal cord | Depression, anxiety, migraine, pain |
| ACh | Nucleus basalis, septal nuclei, brainstem | Cortex, hippocampus, NMJ | Alzheimer’s, myasthenia gravis, organophosphate poisoning |
