A research pharmacologist tests a new drug that selectively blocks H3 receptors in the CNS. What would be the expected pharmacological effects?

• A Sedation and increased appetite due to blocked H3 receptors on histaminergic neurons reducing histamine release
• B Bronchoconstriction due to blocking H3 heteroreceptors on airway parasympathetic nerves, increasing ACh release
• C Increased wakefulness, reduced appetite, and increased histamine release from hypothalamic tuberomammillary neurons due to removal of autoreceptor inhibition ✓
• D Peripheral vasodilation due to blocked H3 heteroreceptors on sympathetic noradrenergic neurons reducing norepinephrine release

Explanation

H3 receptors are presynaptic autoreceptors predominantly in the CNS (hypothalamus) and heteroreceptors that inhibit the release of histamine and other neurotransmitters (dopamine, NE, ACh, serotonin). H3 autoreceptors on histaminergic cell bodies (tuberomammillary nucleus) and terminals reduce histamine synthesis (by inhibiting histidine decarboxylase via Ca2+-calmodulin pathway) and release. Blocking H3 receptors removes this inhibitory feedback, increasing histamine release and action at postsynaptic H1/H2 receptors. Since central histamine is pro-wakefulness and anorectic, H3 antagonism would promote wakefulness and reduce appetite. H3 antagonists (e.g., pitolisant) are used in narcolepsy. This is the opposite of H1 antihistamine effects (sedation, weight gain).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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