Neurotransmitters

Also known as: neurotransmitter, neuromodulators, acetylcholine, ACh, glutamate, GABA, glycine, dopamine, serotonin, 5-HT, noradrenaline, histamine, substance P, endorphins

Chemical messengers released from presynaptic terminals that act on specific receptors of target cells. They include amino acids (glutamate, GABA, glycine), acetylcholine, monoamines (dopamine, noradrenaline, adrenaline, serotonin, histamine), neuropeptides, purines, gases and lipid messengers.

Chemical Synapse

Overview

A classical neurotransmitter must meet four criteria. It is synthesised in the neuron. It is released in a Ca²⁺-dependent way upon stimulation. It acts on specific receptors to mimic the effect of nerve stimulation. And it has a mechanism for inactivation. Small-molecule transmitters are made locally in the terminal and stored in small clear vesicles. Neuropeptides are synthesised in the soma, transported to the terminals, stored in large dense-core vesicles and released with higher-frequency firing, often as co-transmitters. Each transmitter can act on multiple receptor subtypes, so its effect depends on the receptor, not the molecule.

Functionally, glutamate is the main excitatory transmitter of the CNS. GABA (brain) and glycine (spinal cord and brainstem) are the main inhibitory transmitters. The monoamines and acetylcholine are neuromodulators. They arise from small brainstem and basal forebrain nuclei but project diffusely, setting the brain's arousal, mood, attention and motivation. Most psychoactive drugs act on these systems.

Catecholamine synthesis: tyrosine → (tyrosine hydroxylase, rate-limiting) → L-DOPA → (aromatic L-amino-acid/DOPA decarboxylase) → dopamine → (dopamine β-hydroxylase, inside vesicles) → noradrenaline → (PNMT, induced by cortisol in the adrenal medulla) → adrenaline. Catecholamines are degraded by MAO and COMT to homovanillic acid (from dopamine) and vanillylmandelic acid (from noradrenaline and adrenaline). Serotonin is made from tryptophan (tryptophan hydroxylase, then decarboxylase) and degraded by MAO-A to 5-HIAA.

Parts & subdivisions

Glutamate
The principal excitatory CNS transmitter. Receptors: ionotropic AMPA (fast Na⁺/K⁺), NMDA (Ca²⁺-permeable; needs glycine or D-serine as co-agonist and depolarisation to relieve the Mg²⁺ block; a coincidence detector for LTP and memory), kainate, and metabotropic mGluR1–8. Cleared by astrocytic transporters. Excess causes excitotoxicity (Ca²⁺ overload) in stroke, trauma and ALS. Drugs: ketamine and memantine (NMDA antagonists); riluzole reduces glutamate release.
GABA (γ-aminobutyric acid)
The main inhibitory transmitter of the brain, made from glutamate by glutamic acid decarboxylase (GAD; needs vitamin B6). GABA-A is a Cl⁻ channel potentiated by benzodiazepines (increase opening frequency), barbiturates (increase opening duration), alcohol, propofol and neurosteroids. GABA-B is a GPCR that opens K⁺ channels; baclofen is the agonist, used for spasticity. Reduced in Huntington disease. B6 deficiency (isoniazid) causes seizures.
Glycine
The main inhibitory transmitter of the spinal cord and brainstem (Renshaw cells, Ia inhibitory interneurons), acting via strychnine-sensitive Cl⁻ channels. Strychnine blocks the receptors and tetanus toxin blocks release, both causing spasms. Glycine is also the NMDA co-agonist.
Acetylcholine (ACh)
Made from choline and acetyl-CoA by choline acetyltransferase, and hydrolysed in the cleft by acetylcholinesterase; choline is taken back up, which is the rate-limiting step. Released at the NMJ (nicotinic N_M), at all autonomic ganglia (N_N), by parasympathetic postganglionic fibres and sympathetic fibres to sweat glands (muscarinic M1–M5), and in the CNS from the nucleus basalis of Meynert (cortex; memory and attention, lost in Alzheimer disease) and the pedunculopontine nuclei (arousal, REM sleep).
Dopamine
Four pathways. Nigrostriatal (substantia nigra pars compacta → striatum: movement; degenerates in Parkinson disease). Mesolimbic (VTA → nucleus accumbens: reward and addiction; overactive in the positive symptoms of schizophrenia). Mesocortical (VTA → prefrontal cortex: cognition; underactive in negative symptoms). Tuberoinfundibular (arcuate nucleus → pituitary portal blood: inhibits prolactin, so D2 blockers cause hyperprolactinaemia). Receptors D1 and D5 (Gs) and D2–D4 (Gi).
Noradrenaline (norepinephrine)
The transmitter of most sympathetic postganglionic neurons, acting on α1, α2, β1, β2 and β3 receptors. In the CNS it arises from the locus coeruleus in the dorsal pons, projecting diffusely for arousal, vigilance, attention and the stress response. Cleared by the noradrenaline transporter (NET) and degraded by MAO and COMT. Targeted by SNRIs, tricyclics and clonidine (α2 agonist).
Serotonin (5-hydroxytryptamine)
Synthesised from tryptophan in the raphe nuclei of the brainstem, projecting widely: mood, sleep–wake, appetite, pain modulation (raphe magnus → dorsal horn) and nausea (5-HT3 receptors in the area postrema and gut vagal afferents; ondansetron). About 90% of the body's serotonin is in gut enterochromaffin cells. Reduced in depression (SSRIs). Excess causes serotonin syndrome (clonus, hyperthermia, agitation).
Histamine
CNS histamine comes from the tuberomammillary nucleus of the posterior hypothalamus and promotes wakefulness. This is why first-generation H1 antihistamines, which cross the BBB, are sedating.
Neuropeptides
Substance P (pain, via NK1 receptors; dorsal horn), endogenous opioids (β-endorphin, enkephalins and dynorphin acting on μ, δ and κ receptors; analgesia via the PAG and dorsal horn), orexin/hypocretin (lateral hypothalamus, wakefulness; lost in narcolepsy type 1), neuropeptide Y (feeding), CGRP (migraine; anti-CGRP drugs), VIP (gut and vasodilation) and somatostatin.
Gases (NO, CO, H₂S)
Nitric oxide is made on demand by NO synthase (Ca²⁺/calmodulin-activated), diffuses freely, including retrogradely, and activates guanylyl cyclase, raising cGMP. It mediates vasodilation, penile erection (nitrergic parasympathetic fibres; PDE5 inhibitors prolong it), gut relaxation and plasticity.
Purines (ATP, adenosine)
ATP is co-released with ACh and noradrenaline and acts on P2X (ion channel) and P2Y receptors. Adenosine acts on A1 and A2A receptors, accumulates with wakefulness and promotes sleep. Caffeine is an adenosine-receptor antagonist.
Endocannabinoids
Anandamide and 2-arachidonoylglycerol are lipid messengers synthesised on demand by the postsynaptic neuron. They act retrogradely on presynaptic CB1 receptors to suppress transmitter release. THC mimics them.
Disease associations (summary)
Alzheimer: ↓ ACh. Parkinson: ↓ dopamine (↑ relative ACh). Huntington: ↓ GABA, ↓ ACh. Depression: ↓ serotonin, ↓ noradrenaline. Schizophrenia: ↑ mesolimbic dopamine. Anxiety: ↓ GABA, ↓ serotonin. Myasthenia gravis: anti-nicotinic AChR antibodies. Narcolepsy: ↓ orexin.

Function

Carry signals across chemical synapses (fast transmission).
Modulate neuronal excitability, mood, arousal, attention and reward (neuromodulation).
Mediate autonomic control of viscera, glands and blood vessels.
Mediate synaptic plasticity underlying learning and memory.

Physiology: Termination of action is transmitter-specific. ACh is hydrolysed by acetylcholinesterase within milliseconds. Monoamines, glutamate and GABA are removed by Na⁺-coupled reuptake transporters (DAT, NET, SERT, EAATs, GATs) and then repackaged into vesicles by VMAT or VGLUT, or degraded by MAO and COMT. Neuropeptides are cleared by peptidases and diffusion, so their actions last longer. Dale's principle, as modernised: a neuron releases the same set of transmitters, often a small molecule plus peptides, at all its terminals.

Clinical significance

Parkinson disease therapy and the BBB

Dopamine does not cross the blood–brain barrier, but its precursor L-DOPA does, via the LAT1 transporter. Carbidopa inhibits peripheral DOPA decarboxylase but does not cross the BBB, so more levodopa reaches the brain and peripheral side-effects such as nausea and hypotension fall. MAO-B inhibitors (selegiline) and COMT inhibitors (entacapone) prolong dopamine action.

Antipsychotics and extrapyramidal effects

D2 antagonists treat positive symptoms of psychosis via the mesolimbic pathway. Blocking nigrostriatal D2 receptors causes extrapyramidal effects (acute dystonia, akathisia, parkinsonism, tardive dyskinesia), and blocking tuberoinfundibular D2 receptors causes hyperprolactinaemia (galactorrhoea, amenorrhoea). Neuroleptic malignant syndrome is a rare, life-threatening reaction.

Anticholinergic toxicity

Muscarinic blockade (atropine, tricyclics, antihistamines) causes "dry as a bone, red as a beet, hot as a hare, blind as a bat, mad as a hatter, full as a flask" (urinary retention), with tachycardia. The antidote in severe cases is physostigmine.

Mnemonics

Catecholamine synthesis

"Try Lovely Dark Night Expressos": Tyrosine → L-DOPA → Dopamine → Noradrenaline (norepinephrine) → Epinephrine (adrenaline).

Test yourself

Thermoregulatory sweating is mediated by sympathetic postganglionic fibres that release:

Noradrenaline acting on α1 receptors
Adrenaline acting on β2 receptors
Acetylcholine acting on muscarinic (M3) receptors
Dopamine acting on D1 receptors

Answer: Acetylcholine acting on muscarinic (M3) receptors

Eccrine sweat glands are the classic exception: their sympathetic postganglionic fibres are cholinergic. This is why anticholinergic poisoning causes hot, dry skin ("dry as a bone").

Parkinson disease results from degeneration of:

Cholinergic neurons of the nucleus basalis
GABAergic neurons of the caudate nucleus
Dopaminergic neurons of the substantia nigra pars compacta
Noradrenergic neurons of the locus coeruleus only

Answer: Dopaminergic neurons of the substantia nigra pars compacta

Loss of nigrostriatal dopamine reduces the D1-excited direct (go) pathway and disinhibits the D2-inhibited indirect pathway. The GPi then over-inhibits the thalamus, causing bradykinesia. In Huntington disease, by contrast, the caudate (striatal) neurons degenerate.