2.5.1.2 Basic pharmacology of noradrenaline, serotonin, dopamine, GABA, acetylcholine and excitatory amino acids

Transmitter classes

• Catecholamines are dopamine, noradrenaline and adrenaline only. They share a catechol nucleus (a benzene ring with two adjacent hydroxyl groups) and are made from tyrosine.

• Histamine and the indoleamines are not catecholamines.

• Biogenic amines are formed by decarboxylating an amino acid, so they are a wider group than the catecholamines.

• Amino acid transmitters, such as glycine and aspartate, are released as the amino acid itself.

Other transmitters

• Nitric oxide is not stored in vesicles. Neuronal nitric oxide synthase makes it on demand after calcium activates the enzyme through calmodulin, and oxidises L-arginine to nitric oxide and citrulline.

• Narcolepsy type 1, with cataplexy, follows loss of orexin (hypocretin) neurones in the lateral hypothalamus. A very low cerebrospinal fluid (CSF) orexin confirms it.

Monoamine synthesis

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Monoamine breakdown

• Monoamine oxidase (MAO) degrades dopamine, noradrenaline and serotonin inside the presynaptic terminal, on the outer mitochondrial membrane, by oxidative deamination.

• Catechol-O-methyltransferase (COMT) inactivates dopamine and noradrenaline themselves by O-methylation.

• Dopamine is inactivated by three enzymes together: MAO-A, MAO-B and COMT.

Each enzyme is told apart by its reaction: synthesis uses hydroxylation and decarboxylation, MAO uses oxidative deamination, COMT uses O-methylation, and acetylcholinesterase uses ester hydrolysis.

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• The COMT gene lies at 22q11.2. In prefrontal cortex, where dopamine transporters are few, COMT does much of the dopamine clearing, which links it to working memory and psychosis risk.

• Amphetamine-type stimulants enter the terminal through monoamine transporters, displace transmitter from vesicles and drive the transporters backwards, releasing dopamine, noradrenaline and serotonin.

• MAO inhibitors differ from stimulants: they prevent breakdown inside the terminal rather than forcing release.

Noradrenaline

• Locus coeruleus noradrenaline drives arousal, vigilance, attention and stress responses.

• Noradrenaline is the transmitter at most sympathetic nerve endings, whereas adrenaline acts mainly as a hormone.

• Presynaptic alpha-2 autoreceptors restrain noradrenaline release. Clonidine and lofexidine stimulate them, calming the noradrenergic overactivity of opioid withdrawal.

Dopamine

Arvid Carlsson won a Nobel Prize for showing that dopamine is a transmitter in its own right, not only a step on the way to noradrenaline.

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Dopamine drives motivation and reward; it is not the satiety signal.

Receptors

All five dopamine receptors are G-protein-coupled; none is ionotropic.

• D2 autoreceptors on dopamine terminals are inhibitory and restrain further dopamine release.

Clinical links

• Tardive dyskinesia is thought to reflect striatal dopamine receptor supersensitivity after long-term blockade.

• Vesicular monoamine transporter 2 (VMAT2) inhibitors such as tetrabenazine stop dopamine being packed into vesicles and deplete it; they have the best evidence in tardive dyskinesia.

• Neuroleptic malignant syndrome is attributed to abrupt dopamine blockade in the striatum and hypothalamus after a potent D2 antagonist.

Serotonin

Raphe neurones project widely to brain and spinal cord.

• 5-HT3 is the only ionotropic serotonin receptor, a pentameric cation channel passing mainly sodium and potassium. The 5-HT1, 2, 4, 5, 6 and 7 families are G-protein-coupled.

• Fenfluramine curbed appetite by releasing serotonin.

• The 5-HT2 family mediates the insomnia and agitation of early SSRI treatment, whereas 5-HT3 mediates the nausea.

• Low CSF 5-HIAA marks reduced central serotonin turnover in suicidal behaviour, impulsive aggression and depression, notably after violent or impulsive suicide attempts. It is a research finding, not a diagnostic test.

• Obsessive-compulsive disorder is treated with an SSRI or clomipramine, which act mainly by blocking serotonin reuptake, often at higher doses and over a longer trial than in depression.

Acetylcholine

• Acetylcholine is the transmitter inside every autonomic ganglion, sympathetic and parasympathetic; the divisions differ only at the postganglionic ending.

• Choline acetyltransferase joins acetyl coenzyme A and choline in the terminal. Its cortical and hippocampal activity falls as the nucleus basalis of Meynert degenerates, tracking cognitive decline.

• Acetylcholinesterase ends acetylcholine's action by hydrolysis in the synaptic cleft into choline and acetate, and choline is recycled. Monoamines are cleared by reuptake instead.

• Butyrylcholinesterase (plasma cholinesterase) is made in the liver, found in plasma and glia, also hydrolyses acetylcholine, and clears suxamethonium.

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Receptors

• Nicotinic receptors are fast ligand-gated cation channels. Nicotine acts on them directly, not on muscarinic receptors.

• Alpha-4-beta-2 nicotinic receptors on VTA dopamine neurones drive dopamine release in the nucleus accumbens, the basis of nicotine reinforcement.

• Varenicline is a partial agonist at alpha-4-beta-2 receptors, so it eases craving while blunting the reward of a cigarette.

• Muscarinic receptors are G-protein-coupled (M1 to M5).

• Designer receptors exclusively activated by designer drugs (DREADDs) are mutated human muscarinic receptors. The inhibitory hM4Di, from M4, is activated by clozapine-N-oxide; the excitatory hM3Dq comes from M3.

Clinical links

• Acetylcholine underlies attention, learning, memory, arousal and sleep; hyoscine, a muscarinic antagonist, causes amnesia.

• Alzheimer's disease is a cholinergic disorder, not a dopamine one: basal forebrain cholinergic loss is the basis of cholinesterase inhibitor treatment.

• Dementia with Lewy bodies has a deeper cholinergic deficit than Alzheimer's disease. The National Institute for Health and Care Excellence (NICE) recommends donepezil or rivastigmine.

• Delirium is modelled as cholinergic deficiency, and anticholinergic burden is one of its strongest precipitants in older people.

GABA and glycine

• GABA is the major inhibitory transmitter of the adult brain and hyperpolarises the postsynaptic neurone. Glycine is inhibitory mainly in the spinal cord and brainstem.

• Glutamic acid decarboxylase (GAD) makes GABA from glutamate in one step, with pyridoxal phosphate (vitamin B6) as cofactor.

• Stiff person syndrome is the classic disorder of antibodies to GAD, usually GAD65. GABA inhibition is lost, so motor neurones fire continuously.

• The GABA shunt clears GABA after uptake. GABA transaminase moves its amino group onto alpha-ketoglutarate to give succinic semialdehyde, which succinic semialdehyde dehydrogenase converts to succinic acid.

• Vigabatrin blocks GABA transaminase irreversibly and raises brain GABA.

Receptors

• GABA-A is a pentameric chloride channel. Alpha, beta and gamma assemblies carry the benzodiazepine site at the alpha-gamma interface, and subunit composition changes drug response.

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• Benzodiazepines, barbiturates and alcohol all potentiate GABA-A, which relieves anxiety. Abrupt withdrawal lowers the seizure threshold, so long-acting benzodiazepines such as chlordiazepoxide treat alcohol withdrawal.

• GABA-B is metabotropic; it reduces transmitter release and increases potassium conductance. Baclofen is its clinically used agonist.

• The glycine receptor is an ionotropic chloride channel. Strychnine blocks it and removes inhibition of motor neurones.

• Huntington's disease is a disorder of GABAergic striatal circuitry, because the GABAergic medium spiny projection neurones degenerate first.

Glutamate

• Glutamate is the principal fast excitatory transmitter of the brain. Its ionotropic receptors (AMPA, kainate and N-methyl-D-aspartate, NMDA) depolarise the neurone, unlike slow metabotropic modulators or fast inhibitory GABA.

• The NMDA receptor needs glutamate plus an obligatory co-agonist, glycine or D-serine, which binds the GluN1 subunit at a site separate from the glutamate site.

• Depolarisation relieves the NMDA receptor's magnesium block, letting calcium in to drive plasticity.

• Ketamine is an uncompetitive NMDA antagonist that blocks the open channel at the phencyclidine (PCP) site, the basis of its dissociative effects.

• The NMDA hypofunction model of schizophrenia rests on cortical GABAergic interneurones needing NMDA drive; blocking it disinhibits cortex. It is one proposed link, not a complete account.

• Astrocytes take up glutamate with a co-transported proton, and glutamine synthetase amidates it with ammonium to form glutamine, which returns to neurones.

• Excess glutamate activation during impaired energy supply causes excitotoxic injury.

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G-protein coupling

Comparison across the six systems