Which postsynaptic action of dopamine is mediated by cyclic AMP?

The experimental basis, for proposals that adenosine 3' ,5'-cyclic monophosphate (cAMP) acts as intracellular mediator of one or the other postsynaptic actions of dopamine (DA) in mammalian sympathetic ganglia, is analyzed. These synaptic actions of DA are (I) a hyperpolarizing one, as the direct transmitter for the slow-inhibitory postsynaptic potential (s-IPSP); and (II) a modulatory one, inducing an enduring enhancement of the slow-excitatory postsynaptic response (s-EPSP) to another transmitter, acetylcholine (ACh).(A) Stimulation of adenyl cyclase by DA or appropriate neural input appears generally to support either role; however, the comparative characteristics of DA and norepinephrine (NE) in relation to adenyl cyclase do not appear to be in accord with those in relation to hyperpolarizing actions. (B) Postsynaptic actions of cAMP do not support a role in DA action-I, but they are fully appropriate for DA action-II. (C) Phosphodiesterase inhibition by the relatively potent and selective agent RO-20-1724, under conditions reported to protect and increase cAMP in these ganglia, is shown not to augment the s-IPSP or DA-hyperpolarization; although theophylline does augment these responses, this effect is shown not to be attributable to an inhibition of phosphodiesterase, and it does not provide support for a role in DA action-I. Effects of these inhibitors are at least compatible with the proposed modulatory role-II for cAMP. (D) The timing of the putative chemical reactions involved in a mediation by cAMP would appear to be far too slow for the purposes of DA action-I (s-IPSP response), but it is readily accommodated by the slow onset and development of the modulatory change induced by DA action-II.The suggestion that guanosine 3', 5'-cyclic monophosphate (cGMP) may mediate the slow muscarinic depolarizing response to ACh (s-EPSP) has gained definitive experimental support. Suitable cholinergic stimulation of guanyl cyclase has been demonstrated. The postsynaptic action of cGMP in a low concentration range fits with the unique characteristics of the s-EPSP, at least for cells with normal, not already depolarized, resting membrane potentials. cGMP has also been found capable of antagonizing the modulatory action of either DA (action-II) or of cAMP, but only in a remarkably time-dependent manner.It is concluded that cAMP does not mediate the inhibitory synaptic DA action-I (s-IPSP response), but that it probably does mediate the enduring modulatory change in the s-EPSP (DA action-II). cGMP probably does mediate the production of the s-EPSP by ACh. cAMP would thus have a synergistic, rather than opposing, physiological action in relation to cGMP. A re-examination of the functional significance of related DA-activated adenyl cyclase systems in the brain is suggested.