Stimulation of adenylate cyclase in relation to dopamine-induced long-term enhancement (LTE) of muscarinic depolarization in the rabbit superior cervical ganglion

Abstract

Dopamine (DA) induction of the long-term enhancement (LTE) of the slow muscarinic depolarizing response to methacholine (MCh), equivalent to the slow EPSP (S-EPSP), was previously found to be mimicked by exogenous cyclic AMP (cAMP) in the rabbit superior cervical ganglion (SCG). DA-induced LTE of the S-EPSP was shown to be depressed by some DA antagonists. We now show that DA (15 μM), its analog, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), and a D2 receptor antagonist, metoclopramide, each can induce both LTE of MCh depolarization and an increase in ganglionic cAMP. Conversely, antagonists of DA-induced LTE also depress DA-induced rises in cAMP; these antagonists include haloperidol (1 μM), both (+) and (-) enantiomers of butaclamol (0.7-7 μM), flupenthixol (1 μM), and (+)-R-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol (SCH-23390) (7 μM). The selective D2 antagonists sulpiride (10 μM) and domperidone (10 μM) affect neither DA action. Alpha-2 adrenergic agonists (α-methyl-norepinephrine and clonidine) produce no LTE; α-antagonist dihydroergotamine (35 μM) does not affect either DA action, although it can completely block the hyperpolarizing response to DA or other catecholamines. Beta-antagonist propranolol (5 μM) partially depresses DA-induced rises in cAMP but has no effect on the DA-induced LTE. (Butaclamol and propranolol in combination can completely block the cAMP rise induced by DA). Beta-agonist isoproterenol can induce appreciable LTE of MCh depolarization, but this LTE is not depressed by propranolol (10 μM). Isoproterenol can elicit a substantial rise in cAMP. We conclude that LTE of slow muscarinic depolarizing responses is induced via activation of a DA receptor that is coupled to adenylate cyclase and resembles, but is not identical to, D1 receptors described in the brain. The induction of LTE by isoproterenol may reflect an ability to activate this DA receptor to some extent, rather than its additional activation of a β-receptor. In contrast to the cAMP produced at the DA receptor, cAMP formed via activation of β-receptors in this ganglion appears to be ineffective for inducing LTE of muscarinic responses.