Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L-826,266

Prostaglandin E₂ (PGE₂) and its analogue sulprostone inhibit noradrenaline and serotonin release in rodent tissues. We examined whether the receptor involved is blocked by the EP₃ antagonist L-826,266, whether such receptors also occur on central cholinergic neurones and retinal dopaminergic cells, whether PGE₂ is produced by the degradation of the endocannabinoid virodhamine and whether EP₃ receptor activation stimulates ³⁵S-GTPγS binding. Transmitter release was studied as electrically evoked tritium overflow in superfused tissues preincubated with ³H-noradrenaline (which in the guinea pig retina labels dopaminergic cells), ³H-serotonin or ³H-choline. ³⁵S-GTPγS binding, a measure of G protein activation, was studied in mouse and guinea pig hippocampal membranes. L-826,266 antagonised the effect of sulprostone on noradrenaline release in the rat cortex, yielding a Schild plot-based pA₂ value of 7.56. Apparent pA₂ values in mouse cortex and rat vas deferens (noradrenaline release) and rat cortex (serotonin release) were 7.55, 7.87 and 7.67, respectively. PGE₂ did not affect acetylcholine release in rat brain and dopamine release in guinea pig retina. In seven mice tissues, noradrenaline release was inhibited by sulprostone but not affected by virodhamine. ³⁵S-GTPγS binding was not altered by sulprostone but stimulated by the cannabinoid agonist WIN 55,212-2. Prostaglandins of the E series inhibit monoamine release via EP₃ receptors at which L-826,266 is a competitive antagonist. EP₃ receptors that inhibit transmitter release are not present on central cholinergic neurones and retinal dopaminergic cells. Virodhamine is not converted to PGE₂. An EP₃ receptor model based on ³⁵S-GTPγS binding could not be identified.