PART 1 — Big picture + Loewi + what “chemical synapse” actually does (zero-omission)

1) Core idea: nerves as “biologic transducers”

• POINT: Nerve terminals convert an electrical signal (action potential) into a chemical signal (released transmitter).
• Logic: AP arrives → terminal Ca²⁺ rises → vesicles fuse → chemical crosses synaptic cleft → receptors convert it back into an electrical/biochemical change in the next cell.

2) Otto Loewi experiment (why it proved chemical neurotransmission)

• Observation proven: Stimulating a nerve can release a diffusible chemical that changes organ function.
• Setup:
• Two frog hearts:
• Heart A = innervated (has vagus/sympathetic supply)
• Heart B = denervated (no innervation)
• Both perfused with saline via cannulas.
• Vagus stimulation result:
• Stimulate vagus of Heart A → heart rate slows
• Transfer saline effluent from Heart A → Heart B → Heart B also slows
• Therefore: vagus released a chemical into saline → Loewi called it “vagusstoff”
• Later identified as acetylcholine (ACh)
• Sympathetic stimulation result:
• Stimulate sympathetic of Heart A → heart rate increases
• Transfer effluent to Heart B → Heart B rate increases
• Conclusion: Nerve terminals release chemicals that reproduce nerve effects on the target organ.

3) Common steps at ALL chemical synapses (the “pipeline”)

Regardless of mediator, synaptic transmission follows the same big sequence:

1. Synthesis of transmitter
• usually in nerve terminal (depends on transmitter type; peptides are an exception—see later)
2. Storage
• packaged into synaptic vesicles
3. Release (triggered by nerve impulses)
• AP → Ca²⁺ influx → exocytosis into synaptic cleft
4. Receptor action
• transmitter binds receptors on:
• postsynaptic membrane (neuron / muscle / gland)
• sometimes presynaptic membrane too (feedback control)
5. Termination of transmitter action
• diffusion away
• reuptake into nerve terminal (major for many)
• enzymatic degradation
6. Regulation + drugs
• Every step can be modulated physiologically and altered by drugs
• Big implication: drugs can affect somatic & autonomic motor activity AND also emotion/behavior/brain functions

4) Neuromodulators (what they are)

• Some neuron-released chemicals have little/no direct effect alone
• But they change the effect of transmitters (amplify/shape/limit)

→ these are neuromodulators

PART 2 — Chemistry of transmitters + how we identify them + major classes

1) How transmitters/enzymes are localized in tissues (2 key methods)

• Immunohistochemistry
• Use antibodies against a substance (transmitter/enzyme), labeled
• Apply to brain/tissue → antibody binds → locate label with light/electron microscopy
• In situ hybridization histochemistry
• Localizes mRNA for synthesizing enzymes or receptors
• Useful for mapping where synthesis machinery / receptors are expressed

2) Two major transmitter classes

A) Small-molecule transmitters

Includes:

• Amino acids: glutamate, GABA, glycine
• Acetylcholine
• Monoamines: norepinephrine, epinephrine, dopamine, serotonin
• ATP

B) Large-molecule transmitters (neuropeptides)

Examples:

• substance P, enkephalins, vasopressin, and many others
• Key rule: neuropeptides are usually co-localized with a small-molecule transmitter

PART 3 — Receptors (this is the “why effects differ”) + the 5 themes

Core principle

• Effect of a mediator depends more on the receptor subtype than the mediator itself.

Five “intro themes” you MUST keep straight

Theme 1 — One ligand → many receptor subtypes

• Example: norepinephrine acts on α1, α2, β1, β2, β3
• Logic: same transmitter, different receptors → different responses in different tissues

Theme 2 — Presynaptic receptors exist (not only postsynaptic)

• Autoreceptor: presynaptic receptor for the same transmitter
• usually inhibits further release (feedback control)
• example: NE on presynaptic α2 → ↓ further NE secretion
• Heteroreceptor: presynaptic receptor whose ligand is a different chemical
• example: NE acting on a receptor on a cholinergic terminal → inhibits ACh release
• Note: presynaptic receptors can sometimes facilitate release too

Theme 3 — Two giant receptor families

1. Ionotropic (ligand-gated channels)
• ligand binds → channel opens → fast conductance change
• time: milliseconds
• key for fast synaptic transmission
2. Metabotropic (GPCR, 7-TM)
• ligand binds → G-protein → second messenger
• second messenger modulates voltage-gated channels / intracellular signaling
• generally slower, longer-lasting modulation

• Important nuance from text:
• Example: α2 receptors ↓ cAMP, BUT G-protein can also act directly on Ca²⁺ channels to inhibit NE release

Theme 4 — Receptors cluster near release sites

• Postsynaptic receptors are concentrated in clusters close to presynaptic endings
• Often due to binding/scaffolding proteins holding them in place

Theme 5 — Desensitization with prolonged exposure

• Most receptors become less responsive with sustained ligand exposure
• Two types:
• Homologous: reduced response only to that ligand
• Heterologous: reduced response to other ligands too

PART 4 — Reuptake (huge in termination + drugs)

1) What reuptake is

• Rapid transport of transmitter from synaptic cleft back into presynaptic cytoplasm
• Uses high-affinity, Na⁺-dependent membrane transporter
• Example model: NE
• NE released → taken back by NET
• some re-entered NE gets repackaged into vesicles by VMAT
• Similar membrane + vesicular transporters exist for many small transmitters

2) Why it matters clinically

• Reuptake is a major termination mechanism
• If reuptake is blocked → transmitter effect becomes stronger + longer
• Examples:
• Many antidepressants inhibit amine reuptake
• Cocaine may inhibit dopamine reuptake
• Special warning: glutamate
• Uptake into neurons + glia is critical because glutamate can act as an excitotoxin
• During ischemia/anoxia, inhibited reuptake → ↑ neuronal loss

PART 5 — Small-molecule transmitters (major exam chunk, zero-omission)

A) Excitatory & inhibitory amino acids

1) Glutamate (main excitatory transmitter)

• Status: main excitatory transmitter in brain/spinal cord
• Magnitude claim: responsible for ~75% of excitatory transmission in CNS

Synthesis: two linked pathways

1. Krebs cycle pathway
• α-ketoglutarate → glutamate via GABA transaminase (GABA-T)
2. Glutamate–glutamine cycle (neuron ↔ glia)
• glutamate released → taken up (Ca²⁺-dependent exocytosis made it enter cleft first)
• transported into glia via uptake transporter
• glia converts glutamate → glutamine via glutamine synthetase
• glutamine diffuses back to neuron terminal
• neuron converts glutamine → glutamate via glutaminase

• Transport back into neuron can occur directly too (membrane transporters)
• Vesicular packaging:
• glutamate concentrated into vesicles by vesicular glutamate transporter

Glutamate receptors

Ionotropic subtypes (3)

• AMPA
• Kainate
• NMDA

(Each named by relatively specific agonist)

Structure: ionotropic glutamate receptors are tetramers

• multiple subunits with helical domains spanning membrane 3 times + pore-forming sequence
• subunit families identified:
• AMPA: GluR1–GluR4
• Kainate: GluR5–GluR7 + KA1 + KA2
• NMDA: NR1 + NR2A–NR2D

Functional ion movement & synaptic effect

• AMPA/kainate: mainly Na⁺ influx + K⁺ efflux → fast EPSP
• AMPA usually low Ca²⁺ permeability
• missing certain subunits → ↑ Ca²⁺ permeability → can contribute to excitotoxicity
• NMDA: large Ca²⁺ influx + Na⁺ influx
• excess glutamate → NMDA Ca²⁺ entry becomes major basis of excitotoxicity

NMDA receptor — the 3 “unique” rules

1. Glycine is required
• glycine binding is essential for NMDA response to glutamate
2. Voltage-dependent Mg²⁺ block
• at normal membrane potentials: channel blocked by extracellular Mg²⁺
• block removed only if postsynaptic cell is partly depolarized (typically via adjacent AMPA/kainate activation)
3. Slower EPSP
• NMDA EPSP is slower than AMPA/kainate EPSP

Where receptors are found (distribution)

• Most CNS neurons have both AMPA and NMDA
• Kainate receptors:
• presynaptic on GABA endings
• postsynaptic at various sites; especially hippocampus, cerebellum, spinal cord
• Glia: AMPA + kainate can be in glia; NMDA only in neurons
• Hippocampus: high NMDA density
• NMDA blockade prevents long-term potentiation (LTP)
• thus NMDA likely involved in memory/learning

Metabotropic glutamate receptors (mGluR)

• Activation leads to either:
• ↑ IP3/DAG (and signaling)
• or ↓ cAMP
• 8 subtypes known
• Locations:
• Presynaptic: mGluR 2–4, 6–8
• Postsynaptic: mGluR 1 and 5
• Roles:
• synaptic plasticity (hippocampus, cerebellum)
• presynaptic mGluR autoreceptors in hippocampus limit glutamate release
• Genetics note:
• mGluR1 knockout → severe motor incoordination + spatial learning deficits

Postsynaptic density (PSD)

• Excitatory synapse hallmark: thick postsynaptic area = PSD
• PSD contains:
• ionotropic glutamate receptors
• signaling proteins
• scaffolding proteins
• cytoskeletal proteins
• mGluRs lie adjacent to PSD (not in PSD core)

Pharmacology (glutamate)

• Many agonists/antagonists exist, clinical use still “early” historically because glutamate identified as NT only in 1970s
• Example development area:
• NMDA antagonists via intraspinal/extradural routes for chronic pain

Clinical Box: Excitotoxins (must-know mechanism)

• Normal state: extracellular glutamate kept micromolar by Na⁺-dependent uptake into neurons/glia (despite millimolar intracellular)
• Excess glutamate occurs with ischemia, anoxia, hypoglycemia, trauma
• Mechanism of death:
• massive Ca²⁺ influx (esp via NMDA) → neuronal death
• Research use:
• microinject excitotoxins to destroy cell bodies while sparing nearby axons
• Stroke logic:
• infarct core dies
• surrounding penumbra: partial ischemia → membrane gradients fail → astrocytes can’t clear glutamate (Na⁺ gradient collapse) → glutamate accumulates → excitotoxic death in penumbra
• Implicated diseases:
• ALS, Parkinson disease, Alzheimer disease

Therapeutic highlights (from text):

• Riluzole: voltage-gated channel blocker, may antagonize NMDA → slows ALS progression modestly
• Memantine: NMDA antagonist used to slow decline in Alzheimer disease
• Amantadine: NMDA antagonist; with levodopa improves function in Parkinson disease

2) GABA (major inhibitory mediator)

• Role: major inhibitory mediator in brain; mediates pre- and postsynaptic inhibition
• Synthesis: glutamate → GABA via glutamate decarboxylase (GAD)
• Metabolism: mainly via transamination:
• GABA → succinic semialdehyde → succinate (enters TCA)
• enzyme: GABA-T
• Reuptake: active reuptake via GABA transporter
• Vesicle loading:
• VGAT loads GABA and glycine into vesicles

GABA receptors (3 subtypes)

1. GABA_A
2. GABA_B
3. GABA_C

Distribution:

• GABA_A and GABA_B widely distributed CNS
• GABA_C mainly retina in adult vertebrates

Ionotropic vs metabotropic

• GABA_A and GABA_C: ionotropic Cl⁻ channels
• Cl⁻ entry → fast IPSP
• GABA_B: GPCR
• via G-proteins:
• Gi inhibits adenylyl cyclase → opens K⁺ channels
• Go inhibits/delays Ca²⁺ influx
• mediates presynaptic inhibition + slow postsynaptic inhibition

Receptor structure details

• GABA_A: pentamer built from many subunit options:
• 6 α, 4 β, 4 γ, 1 δ, 1 ε
• common synaptic form: 2α + 2β + 1γ
• dendrite/axon/soma receptors may use δ/ε instead of γ
• GABA_C: simpler pentamer of ρ subunits (3 ρ’s in combinations)

Background “noise control”

• Chronic low-level stimulation of GABA_A aided by interstitial GABA
• Function: reduces incidental “noise” → improves CNS signal-to-noise ratio

Pharmacology of GABA synapses (must-know)

• Benzodiazepines (eg diazepam): potentiate GABA_A Cl⁻ conductance → anxiolytic, muscle relaxant, anticonvulsant, sedative
• bind to α subunits of GABA_A
• Barbiturates (phenobarbital): anticonvulsant via ↑ GABA_A inhibition + suppress AMPA excitation
• anesthetic barbiturates (thiopental, pentobarbital, methohexital) act as GABA_A agonists + neuromodulators
• brain regional differences correlate with GABA_A subtype variation
• Many inhaled anesthetics (as per text): act more by inhibiting NMDA/AMPA, not by increasing GABA activity

3) Glycine

• Has both excitatory and inhibitory roles in CNS
• Excitatory-support role: binds NMDA receptors → increases NMDA sensitivity to glutamate
• may spill into interstitial fluid in spinal cord → can facilitate pain via dorsal horn NMDA
• Direct inhibitory role: especially brainstem + spinal cord
• increases Cl⁻ conductance (fast inhibition)
• antagonist: strychnine
• strychnine toxicity (convulsions/muscular hyperactivity) shows importance of postsynaptic inhibition
• Glycine inhibitory receptor:
• Cl⁻ channel, pentamer with:
• ligand-binding α subunit
• structural β subunit

Spinal inhibition neuron types (3 groups)

1. neurons secreting glycine only → transporter GLYT2
2. neurons secreting GABA only → enzyme marker GAD
3. neurons secreting both glycine + GABA
• have both GLYT2 + GAD
• interestingly may package glycine + GABA in same vesicles

4) Acetylcholine (ACh)

Where ACh is used (full list as given)

• Neuromuscular junction
• Autonomic ganglia
• Postganglionic parasympathetic neuro-effector junctions
• Some postganglionic sympathetic neuro-effector junctions
• All neurons that exit CNS (as per text list):
• cranial nerves, motor neurons, preganglionic neurons
• Central cholinergic systems:
• basal forebrain complex (septal nuclei + nucleus basalis) → hippocampus + neocortex
• pontomesencephalic cholinergic complex → dorsal thalamus + forebrain
• Functions implicated: sleep-wake regulation, learning, memory

Storage & synthesis machinery

• ACh stored in small clear synaptic vesicles in high concentration
• Synthesis in terminal:
• choline + acetyl-CoA → ACh via choline acetyltransferase (ChAT)
• Choline uptake:
• Na⁺-dependent choline transporter CHT
• Vesicle loading:
• vesicle-associated transporter VAT
• Release:
• AP → Ca²⁺ influx → ACh exocytosis

Termination: hydrolysis (not reuptake)

• Must be removed rapidly for repolarization
• Hydrolysis in synaptic cleft:
• ACh → choline + acetate via acetylcholinesterase (AChE)
• aka true/specific cholinesterase
• clustered in postsynaptic membrane
• fast enough to explain rapid Na⁺ conductance changes during transmission
• Other cholinesterases:
• plasma “pseudocholinesterase” hydrolyzes ACh but differs from AChE
• influenced by endocrine factors + liver function variation

ACh receptors

Two main types (pharmacologic basis):

1. Muscarinic (M)

• muscarine mimics ACh actions on smooth muscle/glands
• metabotropic GPCR
• 5 subtypes: M1–M5
• Distribution highlights from text:
• M1, M4, M5 in CNS
• M2 in heart
• M3 on glands + smooth muscle
• M1 also on autonomic ganglia (modulates transmission)

1. Nicotinic (N)

• nicotine mimics ACh in sympathetic ganglia + skeletal muscle
• ionotropic ligand-gated cation channel superfamily (includes GABA_A, glycine receptors, and some glutamate receptors)
• Each receptor is 5 subunits forming central channel → Na⁺ and other cations pass → depolarization
• Subunit types: α, β, γ, δ, ε (encoded by different genes)
• Subtypes:
• NM (neuromuscular junction): 2α + 1β + 1δ + (γ or ε)
• NN (CNS + autonomic ganglia): only α + β
• Each α has a binding site:
• needs ACh binding on both α subunits → conformational change → channel opens
• Neuronal nicotinic receptors have high Ca²⁺ permeability
• many located presynaptically on glutamate terminals → facilitate glutamate release

Cholinergic pharmacology points explicitly mentioned

• Hemicholinium blocks CHT (choline uptake)
• Vesamicol blocks VAT (ACh into vesicle)
• Botulinum toxin prevents ACh release

PART 6 — Monoamines + ATP + peptides + “other transmitters” (still zero-omission, but grouped)

1) Norepinephrine & epinephrine

• NE is transmitter at most sympathetic postganglionic endings
• Stored in small dense-core (granulated) vesicles
• NE & epinephrine secreted by adrenal medulla
• epinephrine is not the mediator at postganglionic sympathetic endings
• Sympathetic postganglionic neurons have multiple varicosities along axon; each can secrete NE

Central NE/Epi systems

• NE neurons = noradrenergic
• “Adrenergic” should be reserved for epinephrine neurons
• NE cell bodies in locus coeruleus + other pontine/medullary nuclei
• Projections from locus coeruleus:
• descend to spinal cord
• enter cerebellum
• ascend to hypothalamic nuclei, thalamus, basal telencephalon, neocortex
• NE acts mainly as neuromodulator in those regions

Catecholamine biosynthesis (tyrosine pathway)

• Catecholamines formed by hydroxylation + decarboxylation of tyrosine
• Tyrosine sources:
• from phenylalanine (some)
• mostly dietary
• Tyrosine uptake into neurons: Na⁺-dependent carrier
• Enzymes:
• tyrosine → DOPA via tyrosine hydroxylase (rate-limiting)
• DOPA → dopamine via DOPA decarboxylase (amino acid decarboxylase)
• Feedback inhibition:
• tyrosine hydroxylase inhibited by dopamine + NE

Vesicle steps (key special rule)

• dopamine transported into vesicle by VMAT
• dopamine → NE in vesicle via dopamine β-hydroxylase
• Special fact: NE is the only small-molecule transmitter synthesized inside synaptic vesicles (rather than made in cytoplasm then loaded)

Epinephrine formation (when PNMT exists)

• some CNS neurons + adrenal medulla cells have PNMT
• NE leaves vesicle → converted to epinephrine in cytoplasm → re-enters vesicles for storage

Termination/catabolism

• Removed by:
• binding postsynaptic receptors
• binding presynaptic receptors
• reuptake
• catabolism
• Reuptake via NET is major termination for NE
• Denervation hypersensitivity explanation:
• cut noradrenergic neurons → terminals degenerate → lose NET → less clearance → more NE available from other sources → exaggerated effect

MAO vs COMT

• Oxidation by MAO (outer mitochondrial surface; abundant in nerve endings)
• Methylation by COMT (widely distributed; liver/kidney/smooth muscle; in brain: in glia + small in postsynaptic neurons; none in presynaptic noradrenergic neurons)
• Two metabolism patterns:
• extracellular NE/Epi mostly O-methylated → urinary normetanephrine/metanephrine reflect secretion rate
• further oxidation yields VMA (major urinary metabolite)
• in noradrenergic terminals: intracellular MAO makes deaminated derivatives (3,4-dihydroxymandelic acid + glycol) → then O-methyl derivatives (including VMA and MHPG)

α & β adrenoceptors (subtypes + signaling + locations)

• Both NE and Epi act on α and β receptors
• NE higher affinity for α
• Epi higher affinity for β
• GPCR subtypes:
• α1A, α1B, α1D
• α2A, α2B, α2C
• β1–β3
• Signaling:
• α1 → Gq → PLC → IP3 + DAG → ↑ Ca²⁺ release + PKC activation → often excitatory
• α2 → Gi → ↓ adenylyl cyclase → ↓ cAMP
• also opens GIRK K⁺ channels → hyperpolarization
• inhibits neuronal Ca²⁺ channels
• presynaptic α2 = autoreceptor → ↓ NE release
• β → Gs → ↑ adenylyl cyclase → ↑ cAMP
• Locations:
• α1: smooth muscle + heart
• α2: CNS + pancreatic islets + nerve terminals
• β1: heart + renal JG cells
• β2: bronchial smooth muscle + skeletal muscle
• β3: adipose

Noradrenergic pharmacology points (explicit)

• Metyrosine blocks tyrosine hydroxylase (rate-limiting step)
• Reserpine blocks VMAT (dopamine into vesicle)
• Bretylium / guanethidine prevent NE release
• Cocaine + TCAs block NET
• Indirect sympathomimetics:
• release stored transmitter (amphetamines, ephedrine)

2) Dopamine

• In some brain regions synthesis stops at dopamine → dopamine is released
• Reuptake via Na⁺ + Cl⁻-dependent dopamine transporter
• Metabolized by MAO + COMT → inactive products (e.g., DOPAC + HVA), mostly sulfate conjugation

Dopaminergic systems (major)

• Nigrostriatal: substantia nigra → striatum; motor control
• Mesocortical/mesolimbic (as described): ventral tegmental area → nucleus accumbens + limbic subcortical areas; reward/addiction; psychiatric relevance
• PET finding mentioned:
• dopamine receptors decline steadily with age in basal ganglia; loss greater in men

Dopamine receptors

• 5 cloned, grouped:
• D1-like: D1, D5 → ↑ cAMP
• D2-like: D2, D3, D4 → ↓ cAMP
• Overstimulation of D2 may contribute to schizophrenia pathophysiology
• D3 highly localized to nucleus accumbens
• D4 higher affinity for clozapine than other dopamine receptors

3) Serotonin (5-HT)

• Highest concentration:
• blood platelets
• GI tract (enterochromaffin cells + myenteric plexus)
• CNS: raphe nuclei project widely (hypothalamus, limbic, neocortex, cerebellum, spinal cord)

Synthesis + handling

• From essential amino acid tryptophan
• Rate-limiting: tryptophan → 5-hydroxytryptophan via tryptophan hydroxylase
• Then → serotonin via aromatic L-amino acid decarboxylase
• Loaded into vesicles by VMAT
• Reuptake by SERT
• Inactivation: MAO → 5-HIAA (principal urinary metabolite; index of serotonin metabolism)
• CNS vs peripheral enzyme gene difference:
• CNS tryptophan hydroxylase differs from peripheral; different gene
• knockout TPH1 (peripheral) affects peripheral serotonin more than brain serotonin

Serotonin receptors

• 7 receptor classes: 5-HT1 to 5-HT7
• All GPCR except 5-HT3 (ionotropic)
• Multiple subtypes in 5-HT1 and 5-HT2 groups as listed
• Some presynaptic, some postsynaptic
• Functional notes included:
• 5-HT2A: platelet aggregation + smooth muscle contraction
• 5-HT2C knockout mice: obesity (↑ food intake despite leptin response) + prone to fatal seizures
• 5-HT3: GI tract + area postrema; linked to vomiting
• 5-HT4: GI secretion + peristalsis; also in brain
• 5-HT6/7 in brain throughout limbic; 5-HT6 has high affinity for antidepressants

Pharmacology note

• TCAs inhibit SERT (like NET effects)
• SSRIs (fluoxetine) widely used for depression

4) Histamine

• CNS cell bodies: tuberomammillary nucleus (posterior hypothalamus)
• Projections: widespread (cortex + spinal cord)
• Also found:
• gastric mucosa cells
• mast cells (heparin-containing), plentiful at body surfaces and in pituitary lobes
• Made by decarboxylation of histidine
• Receptors:
• H1, H2, H3 in periphery + brain
• H3 mostly presynaptic → inhibits release of histamine/other transmitters via G-protein
• H1 activates PLC; H2 increases cAMP
• H4 (newly described in text) may regulate immune cells
• Linked functions (diffuse system, not fully known):
• arousal, sexual behavior, BP, drinking, pain thresholds, pituitary hormone secretion regulation

5) ATP

• Often co-localized and co-released (eg from noradrenergic sympathetic postganglionic vesicles)
• Identified as neurotransmitter; mediates rapid synaptic responses in ANS + fast response in habenula
• Receptors:
• P2X: ligand-gated ion channels
• P2Y and P2U: GPCR
• Widespread distribution incl dorsal horn → role in sensory transmission
• P2X antagonists under development for chronic pain

PART 7 — Neuropeptides (large-molecule transmitters) + key examples

1) Substance P

• 11-aa peptide
• Member of tachykinins family; shared C-terminal motif described in text
• Receptors: neurokinin receptors NK1–NK3 (GPCR)
• Substance P preferred ligand for NK1 in CNS → ↑ IP3/DAG
• High concentrations:
• primary afferent endings in dorsal horn → likely mediator at first pain synapse
• nigrostriatal system (levels proportional to dopamine)
• hypothalamus (possible neuroendocrine role)
• Peripheral actions:
• skin injection → redness + swelling
• probable mediator of axon reflex
• involved in intestinal peristalsis
• NK-1 antagonists mentioned:
• antidepressant activity
• antiemetic use in chemotherapy patients

2) Opioid peptides

• Discovery logic: morphine receptors exist → search endogenous ligands → enkephalins found
• Enkephalins:
• met-enkephalin, leu-enkephalin (pentapeptides)
• Locations/effects:
• GI + many brain areas
• substantia gelatinosa; analgesia if injected into brainstem
• decrease intestinal motility
• Metabolism:
• enkephalinase A (splits Gly-Phe)
• enkephalinase B (splits Gly-Gly)
• aminopeptidase (splits Tyr-Gly)

Precursors (multiple)

• Proenkephalin:
• contains 4 met-enkephalins + 1 leu-enkephalin + octapeptide + heptapeptide
• Proopiomelanocortin (POMC):
• contains β-endorphin (31 aa) with metenkephalin at amino end
• β-endorphin secreted into bloodstream by pituitary too
• Prodynorphin:
• contains leuenkephalin residues + dynorphin/neoendorphin
• dynorphins found in duodenum and posterior pituitary/hypothalamus; β-neoendorphins in hypothalamus

Opioid receptors

• Three classes: μ, κ, δ (text says subclasses exist but genes for one subtype each identified/characterized)
• All GPCR; all inhibit adenylyl cyclase
• Channel effects:
• μ: ↑ K⁺ conductance → hyperpolarize central neurons + primary afferents
• κ and δ: close Ca²⁺ channels
• Physiologic effect table highlights (as given):
• μ: supraspinal/spinal analgesia, respiratory depression, constipation, euphoria, sedation, ↑ GH & prolactin secretion, miosis
• κ: analgesia, diuresis, sedation, miosis, dysphoria
• δ: analgesia (text table shows this)

3) Other polypeptides (examples + receptor notes)

• Somatostatin:
• brain roles: sensory input, locomotor activity, cognition
• hypothalamus: GH-inhibiting hormone into portal system
• pancreas: inhibits insulin + other hormones
• GI tract: inhibitory regulator
• receptors: SSTR1–SSTR5 (GPCR inhibiting adenylyl cyclase)
• SSTR2: cognitive effects + GH inhibition
• SSTR5: inhibition of insulin secretion
• Vasopressin + oxytocin:
• hormones AND present in neurons projecting to brainstem/spinal cord
• Other peptides present in brain:
• bradykinin, angiotensin II, endothelin
• GI hormones also in brain:
• VIP, CCK-4/CCK-8
• CCK receptors: CCK-A and CCK-B
• CCK-8 binds both; CCK-4 binds CCK-B
• gastrin, neurotensin, galanin, GRP also in GI + brain
• many of these receptors cloned as GPCR
• CGRP:
• present in CNS/PNS, GI, CVS, urogenital
• co-localized with substance P or ACh
• injection causes vasodilation
• produced from calcitonin gene via alternative splicing:
• thyroid splicing → calcitonin mRNA
• brain splicing → CGRP mRNA
• CGRP implicated in migraine pathophysiology (trigeminal release)
• acts via two types of metabotropic CGRP receptors
• Neuropeptide Y:
• abundant in brain + autonomic nervous system
• receptors: Y1–Y8 (except Y3 are GPCR)
• effects: mobilize Ca²⁺ + inhibit adenylyl cyclase
• CNS: increases food intake → Y1/Y5 antagonists may treat obesity
• periphery: vasoconstriction
• presynaptic heteroreceptor on sympathetic terminals → reduces NE release

PART 8 — Other transmitters (NO + endocannabinoids)

1) Nitric oxide (NO)

• Also made in brain (besides endothelium EDRF)
• Made from arginine via NO synthase (one of three forms; neuronal form in brain)
• Activates guanylyl cyclase
• Gas → crosses membranes easily → binds directly to enzyme target
• Not stored in vesicles; synthesized on demand at postsynaptic sites
• Can diffuse to nearby sites on neuron
• Trigger pathway noted:
• NMDA activation → Ca²⁺ influx → activates neuronal NO synthase
• Proposed roles:
• retrograde signal enhancing presynaptic glutamate release
• synaptic plasticity → memory/learning

2) Endogenous cannabinoids

• Two identified: 2-arachidonyl glycerol (2-AG) and anandamide
• Not stored in vesicles; synthesized rapidly after depolarization with Ca²⁺ influx
• Act on cannabinoid receptor CB1 (high affinity for Δ9-THC)
• CB1 mainly presynaptic terminals
• decreases cAMP via G-protein pathway
• common in central pain pathways + cerebellum, hippocampus, cortex
• CB1 agonists: euphoria + anti-nociception
• CB1 antagonists: enhance nociception
• act as retrograde messengers: travel back to presynaptic CB1 → inhibit further transmitter release
• CB2 cloned:
• mainly peripheral
• agonists don’t cause CB1-type euphoria; possible chronic pain treatment potential

PART 9 — The tables & clinical boxes (captured, not omitted)

A) Co-localization examples (small transmitter + peptide)

Key pairings included in the text:

• Glutamate ↔ substance P
• GABA ↔ CCK, enkephalin, somatostatin, substance P, TRH
• Glycine ↔ neurotensin
• ACh ↔ CGRP, enkephalin, galanin, GnRH, neurotensin, somatostatin, substance P, VIP
• Dopamine ↔ CCK, enkephalin, neurotensin
• NE ↔ enkephalin, NPY, neurotensin, somatostatin, vasopressin
• Epinephrine ↔ enkephalin, NPY, neurotensin, substance P
• Serotonin ↔ CCK, enkephalin, NPY, substance P, VIP

B) Receptor pharmacology table (big idea summary)

• Ionotropic examples:
• AMPA/kainate/NMDA (glutamate)
• GABA_A (Cl⁻)
• glycine receptor (Cl⁻)
• nicotinic ACh receptors (cation channel)
• 5-HT3 (cation channel)
• Metabotropic examples:
• mGluRs (IP3/DAG or ↓cAMP)
• muscarinic receptors (M1–M5)
• adrenoceptors (α/β)
• most serotonin receptors

C) Clinical Box 7–2 PKU (captured fully)

• PKU: inborn error; severe cognitive impairment; ↑ phenylalanine + keto acid derivatives
• Usually due to phenylalanine hydroxylase mutation (chromosome 12 long arm)
• Cognitive impairment mainly from phenylalanine accumulation (catecholamines still formed from tyrosine)
• Can also be due to BH4 deficiency
• BH4 needed for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase
• thus BH4 deficiency → catecholamine + serotonin deficiencies + hyperphenylalaninemia
• causes hypotonia, inactivity, developmental problems
• BH4 also needed for NO synthesis → deficiency may reduce NO + increase oxidative stress
• Newborn screening practiced (regions listed) and dietary treatment should start before 3 weeks to prevent intellectual disability
• Treatment:
• low phenylalanine diet (restrict high-protein foods)
• BH4 deficiency: BH4 + levodopa + 5-hydroxytryptophan + low phenylalanine diet
• sapropterin (synthetic BH4) approved for some PKU cases

D) Clinical Box 7–3 Schizophrenia (captured)

• Symptoms: positive (hallucinations, delusions, racing thoughts) + negative (apathy, low spontaneity/motivation, difficulty with novelty)
• Prevalence: ~1–2% worldwide
• Multifactorial: genetic/biologic/cultural/psychologic
• Dopamine focus:
• attention initially on limbic D2 overstimulation
• amphetamine induces psychosis-like state (releases dopamine + NE)
• D2 receptors said elevated; antipsychotic efficacy correlates with D2 block for many drugs
• newer drugs can work with limited D2 binding; may involve D4 receptor abnormalities hypothesis
• Treatment notes:
• typical antipsychotics listed
• atypicals in 1990s; clozapine effective but risk agranulocytosis
• other atypicals listed (no agranulocytosis mentioned)

E) Clinical Box 7–4 Major depression (captured)

• NIMH figure in text: ~21 million adults in US (as written)
• Median onset age ~32; more prevalent in women
• Symptoms list included (mood, anhedonia, appetite/sleep changes, restlessness, fatigue, worthlessness, concentration issues, suicidal thoughts)
• Typical vs atypical depression features noted
• Monoamine evidence: NE, serotonin, dopamine implicated
• Hallucinogens and 5-HT2 receptor link:
• LSD = 5-HT2 agonist; discovered by accidental exposure
• psilocin, DMT are tryptamine derivatives
• mescaline and phenylethylamine hallucinogens; may bind 5-HT2
• MDMA causes serotonin release then depletion → euphoria then later depression/concentration issues
• Treatment:
• typical depression: SSRIs (fluoxetine) effective; also used for anxiety
• atypical depression: SSRIs often ineffective → MAOIs (phenelzine, selegiline)
• tyramine hypertensive crisis foods listed
• bupropion: atypical antidepressant; resembles amphetamine; increases serotonin + dopamine in brain; used for smoking cessation