3.3.1.1 Main receptor subtypes

Serotonin receptors

Serotonin (5-hydroxytryptamine, 5-HT) has 14 receptor subtypes. All are G protein-coupled except 5-HT3, the only ionotropic subtype, which is a ligand-gated cation channel.

• Early nausea on selective serotonin reuptake inhibitors (SSRIs) comes from 5-HT3 stimulation.

• Blocking 5-HT2C removes the satiety signal, so appetite and weight rise.

• Agomelatine is an agonist at MT1 and MT2 melatonin receptors and a 5-HT2C antagonist; it resynchronises circadian rhythms and releases frontal dopamine and noradrenaline.

Buspirone

• Buspirone, an azapirone anxiolytic, is a partial agonist at 5-HT1A receptors with no action at gamma-aminobutyric acid A (GABA-A) or 5-HT2A receptors.

• It is a full agonist at somatodendritic 5-HT1A autoreceptors but a partial agonist at postsynaptic 5-HT1A receptors.

• Sustained stimulation desensitises the autoreceptors and raises serotonergic firing, so anxiety falls only after weeks.

• Because of this delay it is unsuitable for single-dose situational relief; unlike a benzodiazepine, it has low dependence liability.

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Dopamine receptors

All dopamine receptors are G protein-coupled. D1 and D5 couple to stimulatory G proteins, while the D2-like family (D2, D3, D4) couples to inhibitory G proteins.

• Presynaptic D2 autoreceptors inhibit dopamine synthesis and release.

• Ropinirole is a non-ergot agonist at D2 and D3 receptors, with negligible D1 activity, used in restless legs and parkinsonism.

• Brexpiprazole, like aripiprazole, is a partial agonist at D2 and 5-HT1A receptors and an antagonist at 5-HT2A, so it rarely raises prolactin.

• Cariprazine, another D2 partial agonist, preferentially targets limbic D3 receptors.

Adrenergic receptors

• Lofexidine stimulates presynaptic alpha-2 adrenoceptors in the locus coeruleus, damping the noradrenergic overactivity of opioid withdrawal.

• Guanfacine is a selective alpha-2A agonist acting on prefrontal pyramidal neurones to strengthen attention and working memory; it is a non-stimulant treatment for attention deficit hyperactivity disorder.

Cholinergic receptors

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• M1 blockade in cortex and hippocampus impairs new learning and memory and can precipitate delirium.

• Peripheral muscarinic blockade causes dry mouth, blurred vision, constipation, urinary retention and tachycardia.

• Varenicline is a partial agonist at alpha-4 beta-2 nicotinic receptors, releasing enough mesolimbic dopamine to ease craving while blocking the reward from smoked nicotine.

GABA receptors

GABA-A receptors are pentameric chloride channels, usually built from two alpha, two beta and one gamma subunit.

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After long benzodiazepine use, abrupt stopping leaves neurones under-inhibited, causing rebound anxiety, insomnia, tremor, and at worst seizures and delirium, so doses are tapered.

• GABA-B is a G protein-coupled heterodimer of B1 and B2 subunits; it opens potassium channels and limits calcium entry, so less transmitter is released.

• Baclofen is a GABA-B agonist.

• Gamma-hydroxybutyrate (GHB, sodium oxybate) acts through GABA-B and through its own high-affinity GHB binding site.

Sigma-1 receptor

• Sigma-1 is an endoplasmic reticulum chaperone, not an opioid receptor, with neurosteroids as proposed endogenous ligands.

• Fluvoxamine is the antidepressant with sigma-1 agonism, which is linked to its antidepressant action.

• Sigma-1 amplifies nociceptive signalling, so selective antagonists are being developed as analgesics for neuropathic pain.

Other receptor families

Combined H1 and 5-HT2C blockade is associated with weight gain.