Mutual interactions of the presynaptic histamine H 3 and prostaglandin EP 3 receptors on the noradrenergic terminals in the mouse brain

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We studied whether interactions between the presynaptic histamine H 3 and prostaglandin EP 3 receptors on the noradrenergic neurons of the mouse brain cortex occur. Cerebral cortex slices from the mouse (and, in few experiments, from the rat) were preincubated with [ 3H]noradrenaline and then superfused with a physiological salt solution. Tritium overflow was evoked electrically, either at 0.3 or 3 Hz (2 min) (standard stimulation protocol) or at 100 Hz (eight pulses) (stimulation protocol under which almost no activation of the presynaptic α 2-adrenoceptors by endogenous noradrenaline occurs). In another set of experiments, Ca 2+ ions were introduced into Ca 2+-free K +-rich medium containing tetrodotoxin to evoke tritium overflow. The electrically-evoked tritium overflow (0.3 Hz) was inhibited by histamine or the H 3 receptor agonist imetit, acting via H 3 receptors, and by prostaglandin E 2 or the EP 3 receptor agonist sulprostone, acting via EP 3 receptors. When histamine or imetit was given first (at concentrations causing the maximum effect at H 3 receptors), the effect of prostaglandin E 2 on the evoked tritium overflow was attenuated by 5–10%. When prostaglandin E 2 or sulprostone was given first (at concentrations causing the maximum effect at EP 3 receptors), the effect of histamine or imetit on the evoked overflow was attenuated by almost 50%. The previous administration of prostaglandin E 2 also blunted the effect of histamine on the evoked tritium overflow evoked at 3 Hz; the degree of attenuation was identical when the current strength was 25 mA or was increased to 100 or 200 mA in order to partially compensate for the inhibitory effect of prostaglandin E 2 on the evoked overflow. In addition, prostaglandin E 2 attenuated the effect of histamine when tritium overflow was evoked (i) by 100 Hz, eight pulses or (ii) by Ca 2+ ions or (iii) when rat (instead of mouse) brain cortex slices were used. An interaction of prostaglandin E 2 or sulprostone with the H 3 receptor recognition site could be excluded since both prostanoids did not affect the specific binding of the H 3 agonist radioligand [ 3H]N α -methylhistamine to rat brain cortex membranes. In conclusion, mutual interactions occur between the presynaptic H 3 and EP 3 receptors involved in the inhibition of noradrenaline release in the mouse brain cortex. Pre-activation of the H 3 receptor slightly attenuates the EP 3 receptor-mediated effect whereas pre-activation of the EP 3 receptor more markedly attenuates the H 3 receptor-mediated effect. The interactions may occur between the receptors themselves or at a step behind the receptors (e.g., at the level of G proteins). The physiological significance of these interactions may be to limit the total extent of inhibition of noradrenaline release in a scenario under which both receptors are activated simultaneously.