Reserpine lowers blood pressure and was historically associated with a high incidence of depressive illness. Which molecular mechanism accounts for both these effects?

• A Competitive antagonism at peripheral alpha-1 and central 5-HT receptors
• B Blockade of neuronal norepinephrine release at sympathetic postganglionic terminals without depletion of serotonin
• C Inhibition of dopa decarboxylase reducing synthesis of all monoamines
• D Irreversible inhibition of vesicular monoamine transporter, depleting norepinephrine and serotonin stores ✓

Explanation

Reserpine binds irreversibly to VMAT2, the transporter that packages monoamines into synaptic vesicles, so newly synthesised norepinephrine and serotonin are degraded by cytosolic enzymes instead of being stored. Depletion of central serotonin and catecholamines explains the depression, while peripheral noradrenergic depletion lowers blood pressure. Option B describes guanethidine, whose depletion is essentially limited to the peripheral sympathetic neuron and spares central monoamines.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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