Module 2 Part 3: Classical and Nonclassical Neurotransmitter Systems

Vocabulary flashcards covering classical and nonclassical neurotransmitter systems, receptor subtypes, pathways, and discovery experiments.

Cholinergic system

The neurotransmitter system that uses acetylcholine (ACh) as its transmitter, featuring two sets of receptors: nicotinic and muscarinic.

Nicotinic receptors

Ionotropic ACh receptors that form a channel for small cations (e.g., $Na^+$ and $K^+$), causing membrane depolarization and fast EPSPs; found at neuromuscular junctions, in the brain, and in both autonomic nervous system divisions.

Muscarinic receptors

Slower-acting metabotropic ACh receptors belonging to the G-protein coupled family; found in the brain and parasympathetic nervous system, but NOT in the sympathetic nervous system.

Acetylcholine synthesis

The enzymatic combination of precursor chemicals choline and acetyl CoA by choline acetyltransferase (ChAT) inside cholinergic neurons to produce acetylcholine.

Basal Forebrain Cholinergic System

A major CNS area containing large ACh pools—including the nucleus basalis and medial septal diagonal band—projecting to the cortex, hippocampus, olfactory bulbs, amygdala, and brainstem to regulate learning, memory, attention, sensory processing, motivation/reward, and motor coordination.

Brainstem cholinergic neurons

A major CNS ACh system projecting to the spinal cord, cerebellum, and brainstem that plays a key role in species-specific behaviors such as sleep/wakefulness, aggression, biorhythms, ingestive behaviors, and thermoregulation.

Acetylcholine in the somatic PNS

The sole neurotransmitter used by motor neurons controlling skeletal muscle, acting on nicotinic receptors across all motor neurons originating from the spinal cord and cranial nerves.

Acetylcholine in the sympathetic ANS

The neurotransmitter used exclusively at preganglionic neurons in the sympathetic nervous system, where it acts on nicotinic receptors.

Acetylcholine in the parasympathetic ANS

The primary neurotransmitter of the parasympathetic system, utilized at BOTH preganglionic neurons (acting on nicotinic receptors) and postganglionic neurons (acting on muscarinic receptors).

Effects of ACh at parasympathetic postganglionic sites

Muscarinic receptor-mediated actions that contract smooth muscle (GI, urinary, respiratory), decrease heart rate, and dilate blood vessels to lower blood pressure.

Monoaminergic (biogenic amine) system subclasses

Two structural categories of monoamines: catecholamines (containing a catechol ring: dopamine, norepinephrine, epinephrine) and indoleamines (containing an indole ring: serotonin).

Catecholamine synthesis chain

A sequential conversion sequence wherein dopamine (DA) serves as the precursor for norepinephrine (NE), which then serves as the precursor for epinephrine (EPI).

Dopaminergic system cell numbers

The CNS contains approximately $15,000\text{--}20,000$ DA cells, making up over $50\%$ of all CNS catecholaminergic cells.

Dopamine receptors overview

G-protein coupled (metabotropic) receptors categorized into two main families based on their coupling to the second messenger cAMP: the D1 family and the D2 family.

D1 family (D1-like) dopamine receptors

Receptors including D1 and D5 subtypes that INCREASE intracellular cAMP levels, leading to excitation (via sodium channel opening) or inhibition depending on cellular context.

D2 family (D2-like) dopamine receptors

Receptors including D2, D3, and D4 subtypes that DECREASE intracellular cAMP levels by inhibiting adenylate cyclase, resulting in target neuron inhibition.

Dopamine synthesis

A two-step pathway where tyrosine is converted into DOPA (dihydroxyphenylalanine) by tyrosine hydroxylase, and DOPA is converted into dopamine by DOPA decarboxylase.

Two large DA neuron clusters in the CNS

The Ventral Tegmental Area (VTA) and the Substantia Nigra, which together give rise to three primary dopamine pathways.

Mesostriatal (nigrostriatal) pathway

A dopamine pathway originating in the substantia nigra and projecting to the striatum (caudate and putamen) that fine-tunes motor control and degenerates in Parkinson's disease.

Mesolimbic pathway

A dopamine pathway originating in the VTA and projecting to limbic structures (hippocampus, amygdala, nucleus accumbens) that mediates reward, motivation, pleasure/euphoria, and addiction.

Mesocortical pathway

A dopamine pathway originating in the VTA and projecting to frontal cortical areas that regulates focus, cognition, learning, memory, and behavioral inhibition.

Tuberoinfundibular pathway

A minor fourth dopamine pathway originating in the hypothalamus and projecting to the pituitary gland to control prolactin secretion.

Dopamine and Parkinson's disease

A neurodegenerative disease targeting the mesostriatal system, characterized by loss of dark-pigmented DA cells in the substantia nigra.

Noradrenergic system

The neurotransmitter system using norepinephrine (NE) as its signaling molecule, with utilizing cells designated as noradrenergic.

Alpha adrenergic receptors

G-protein coupled noradrenergic receptors (alpha-1 and alpha-2 subtypes) primarily involved in stimulating effector cells and constricting blood vessels.

Beta adrenergic receptors

G-protein coupled noradrenergic receptors (beta-1 and beta-2 subtypes) primarily involved in relaxing effector cells and dilating blood vessels.

Norepinephrine synthesis

The enzymatic conversion of precursor dopamine into norepinephrine via dopamine-beta-hydroxylase.

Locus coeruleus

A major NE cell body cluster in the pons projecting to the cortex, limbic system, and thalamus; regulates learning, memory, attention, arousal, mood, anxiety, and aggression.

Lateral tegmental area

A major NE cell cluster in the midbrain projecting to the cerebellum, spinal cord, and hypothalamus; regulates motor coordination and feeding behavior.

Norepinephrine in the PNS

The principal neurotransmitter used by postganglionic sympathetic neurons, operating via alpha (effector stimulation/vasoconstriction) and beta (effector relaxation/vasodilation) receptors.

Serotonergic system

The neurotransmitter system utilizing serotonin (5-hydroxytryptamine, 5-HT), which was initially identified in blood serum.

Raphe nucleus

A group of $9$ diffuse midline nuclei located along the midbrain and brainstem that serves as the primary CNS site of serotonin production.

Serotonin receptors

A group of $14$ identified receptor subtypes ($\text{5-HT}_1$ through $\text{5-HT}_{14}$); all are metabotropic G-protein coupled receptors except $\text{5-HT}_3$, which is ligand-gated ionotropic.

Serotonin synthesis

Two-step pathway converting tryptophan into 5-hydroxytryptophan via tryptophan hydroxylase, which is subsequently converted to 5-hydroxytryptamine (serotonin) via 5-HT decarboxylase.

Serotonergic system functions

Involved in memory/learning (cortical), mood and emotional behaviors (limbic), regulatory functions like appetite and sleep (hypothalamic), and pain analgesia (spinal).

Amino acid neurotransmitters - two classes

Functional classes comprising excitatory amino acids (which depolarize neurons) and inhibitory amino acids (which hyperpolarize neurons).

Glutamate - overview

The most widespread amino acid and primary neurotransmitter in the CNS, present at over $50\%$ of synapses and synthesized in terminals from glutamine.

Glutamate recycling

Clearance of synaptic glutamate via EAATs into astrocytes, conversion into glutamine by glutamine synthetase, transport back to presynaptic neurons, and reconversion to glutamate.

Excitotoxicity

Neuronal death resulting from excessive stimulation caused by high concentrations of extracellular glutamate.

Other excitatory amino acids (besides glutamate)

Aspartic acid, cysteic acid, and homocysteic acid.

Glutamate distribution

Ubiquitous and evenly distributed throughout all areas of the central nervous system.

Glutamate receptors - overview

Receptor categories consisting of ionotropic types (defined by selective agonists) and $8$ metabotropic G-protein coupled types (mGluR1 through mGluR8).

NMDA receptor

An ionotropic glutamate receptor opening a voltage-dependent cation channel, playing a central role in learning, memory, and long-term potentiation (LTP).

Kainate (KA) receptor

One of three distinct ionotropic glutamate receptor subtypes identified using selective chemical agonists.

AMPA receptor

An ionotropic glutamate receptor that works in conjunction with NMDA receptors to facilitate learning and memory.

mGluR receptors

A set of $8$ G-protein coupled metabotropic glutamate receptors (mGluR1–mGluR8) categorized by the second messenger pathways they trigger.

Glutamatergic system function

Mediates sensory/motor signal transmission, information processing, synaptic plasticity, learning/memory, and neuroendocrine function; excessive activity can provoke seizures or excitotoxicity.

GABA (gamma-aminobutyric acid)

The primary inhibitory amino acid transmitter in the CNS, utilized at $25\text{--}40\%$ of synapses in the cerebral cortex, hippocampus, and substantia nigra.

Other inhibitory amino acids (besides GABA)

Glycine, taurine, and beta-alanine.

GABA-A receptors

Fast-acting ionotropic, ligand-gated $Cl^-$ channel receptors that mediate rapid neuronal inhibition.

GABA-B receptors

Metabotropic G-protein coupled receptors that produce slow inhibitory postsynaptic responses by inhibiting $Ca^{2+}$ channels and opening $K^+$ channels.

GABA-C receptors

Ionotropic $Cl^-$ channel receptors with distinct subunit structures, located primarily within the retina.

GABA synthesis

The enzymatic conversion of the principal excitatory neurotransmitter glutamate into GABA by glutamic acid decarboxylase (GAD).

GABAergic system function

Serves as the neural 'brakes' by filtering sensory input, reducing anxiety, suppressing seizure activity, inhibiting memory formation, and inducing sedation/hypnosis.

One neuron-one neurotransmitter dogma

An outdated neural principle claiming each neuron synthesizes and releases only a single neurotransmitter, disproven by co-transmission discoveries.

Neuropeptides - definition

Short amino acid chains accepted as neurotransmitters that differ from classical small-molecule transmitters in synthesis, storage, and duration of action.

Neuropeptide synthesis

Ribosomal translation of pre-pro-peptide precursors in the cell body, kinesin transport of packaged vesicles down the axon, and intra-vesicular enzymatic cleavage into active neuropeptides.

How neuropeptides act at the synapse

Modulation of postsynaptic sites via G-protein coupled receptors to amplify or attenuate classical neurotransmitter actions and regulate presynaptic release rates.

Classes of neuropeptides

Functional families comprising opioid peptides (endorphins, enkephalins), gut-brain peptides, Substance P, and pituitary hormones (vasopressin, oxytocin).

Neuropeptides vs. classical neurotransmitters

Neuropeptides are large molecules stored in large vesicles ($90\text{--}250\,\text{nm}$) with slow, prolonged effects; classical transmitters are small molecules in small vesicles ($40\text{--}60\,\text{nm}$) with rapid, brief actions.

Neuroendocrine system

A regulatory communication system utilizing hormones secreted by neuroendocrine or endocrine cells into the bloodstream under hypothalamic and pituitary control.

Posterior pituitary (neurohypophysis)

Pituitary section directly controlled by hypothalamic axons, releasing vasopressin and oxytocin directly into nearby blood vessels upon action potential arrival.

Anterior pituitary (adenohypophysis)

Pituitary section controlled indirectly by hypothalamic releasing hormones, which trigger secretion of tropic hormones into the bloodstream to act on distant target glands.

Gaseous neurotransmitters - overview

Non-stored signaling gases synthesized on demand—including hydrogen sulfide ($H_2S$), nitric oxide ($NO$), and carbon monoxide ($CO$)—that modulate synaptic plasticity.

Nitric oxide (NO)

A gaseous retrograde neuromodulator involved in memory, analgesia, and blood vessel regulation that can elevate dopamine release but cause cell damage if continually generated.

Lipid transmitters

Endogenous cannabinoids (e.g., anandamide, 2-AG) synthesized on demand that act as retrograde messengers regulating mood, appetite, memory, motor control, and homeostatic functions.

Neurotransmission and drug action - key insight

Historical understanding of transmitter systems developed primarily through investigating how pharmacological agents selectively interact with synaptic receptors.

Otto Loewi and the discovery of chemical neurotransmission

1921 experiment by Austrian scientist Otto Loewi providing the first definitive proof that nerves alter target organs via chemical signal release.

Loewi's two-heart experiment

A fluid-connected two-chamber preparation demonstrating that fluid transferred from a vagus-stimulated slowing heart caused an isolated second heart to slow down as well.

Vagusstoff

The original name given by Otto Loewi to the chemical mediator released during vagus nerve stimulation, later identified as acetylcholine.