Role of adenylate cyclase in presynaptic alpha 2-adrenoceptor- and mu-opioid receptor-mediated inhibition of [3H]noradrenaline release from rat brain cortex slices.
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 microM) in the presence of 1.2 mM Ca2+. Forskolin (10 microM), 8-bromo-cyclic AMP (300 microM), and dibutyryl-cyclic AMP (300 microM) facilitated both the electrically evoked and A 23187-induced [3H]noradrenaline release, whereas the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX, 300 microM) and 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62771, 30 microM) enhanced the electrically evoked release only. The inhibitory effects of clonidine (1 nM-1 microM) and the facilitatory effect of phentolamine (0.01-10 microM) on the electrically evoked [3H]noradrenaline release were strongly reduced in the presence of 8-bromo-cyclic AMP. Clonidine (1 microM) reduced and phentolamine (3 microM) enhanced A 23187-induced [3H]noradrenaline release, provided that the slices were simultaneously exposed to forskolin. The inhibitory effects of morphine (1 microM) and [D-Ala2-D-Leu5]enkephalin (DADLE, 0.3 microM), like that of the Ca2+ antagonist Cd2+ (15 microM), 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 mu-opioid receptors, alpha 2-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.
A N
AN
Schoffelmeer
E A
EA
Wierenga
A H
AH
Mulder
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002540:Cerebral Cortex / Q000201:enzymology*; D003000:Clonidine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010646:Phentolamine / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D020889:Rolipram
D011760:Pyrrolidinones; D011942:Receptors, Adrenergic, alpha; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D002104:Cadmium; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000001:Calcimycin; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D003994:Bucladesine; D009020:Morphine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020889:Rolipram; D003000:Clonidine; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine; D010646:Phentolamine