Role of Adenylate Cyclase in Presynaptic α2‐Adrenoceptor‐ and μ‐Opioid Receptor‐Mediated Inhibition of [3H]Noradrenaline Release from Rat Brain Cortex Slices

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Abstract
Rat brain cortex slices, prelabelled with [3H]noradrenaline, were superfused and exposed to electrical biphasic block pulses (1 Hz; 12 mA, 4 ms) or to the Ca2+ ionophore A 23187 (10 μM) in the presence of 1.2 mM Ca2+. Forskolin (10 μM), 8‐bromo‐cyclic AMP (300 μM), and dibutyryl‐cyclic AMP (300 μM) facilitated both the electrically evoked and A 23187‐induced [3H]noradrenaline release, whereas the phosphodiesterase inhibitors 3‐isobutyl‐1‐methylxanthine (IBMX, 300 μM) and 4‐(3‐cyclopentyloxy‐4‐methoxyphenyl)‐2‐pyrrolidone (ZK 62771, 30 μM) enhanced the electrically evoked release only. The inhibitory effects of clonidine (1 nM–1 μM) and the facilitatory effect of phentolamine (0.01–10 μM) on the electrically evoked [3H]noradrenaline release were strongly reduced in the presence of 8‐bromo‐cyclic AMP. Clonidine (1 μM) reduced and phentolamine (3 μM) enhanced A 23187‐induced [3H]noradrenaline release, provided that the slices were simultaneously exposed to forskolin. The inhibitory effects of morphine (1 μM) and [D‐Ala2‐D‐Leu5]enkephalin (DADLE, 0.3 μM), like that of the Ca2+ antagonist Cd2+ (15 μM), on the electrically evoked release of [3H]noradrenaline were not affected by 8‐bromo‐cyclic AMP. Moreover, morphine and DADLE did not inhibit A 23187‐induced release in the absence or presence of forskolin. These data strongly suggest that in contrast to presynaptic μ‐opioid receptors, α2‐adrenoceptors on noradrenergic nerve terminals are negatively coupled to adenylate cyclase and may thus reduce neurotransmitter release by inhibiting the feed‐forward action of cyclic AMP on the secretion process.

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