Electrophysiological characterization of functionally distinct 5-hydroxytryptamine receptors on guinea-pig submucous...

Intracellular recordings were made from neurons of the guinea-pig submucous plexus and the actions of 5-hydroxytryptamine on the postsynaptic membrane and on evoked synaptic potentials were examined. 5-Hydroxytryptamine produced two types of direct postsynaptic responses: (1) A depolarization associated with a fall in input resistance was observed in all cells. Voltage-clamp and ion substitutions showed that this depolarization resulted primarily from an inward sodium current. This response could be as brief as 30 ms; it showed desensitization and was selectively abolished by 0.2-2 microM ICS 205-930. (2) A depolarization (or inward current) associated with a decreased conductance was observed in about 50% of neurons, usually after the first response was blocked by ICS 205-930. This response was due to a decreased potassium conductance; the minimum time course of this response was 8-10 s. It did not show desensitization and was not sensitive to blockade by currently available antagonists of 5-hydroxytryptamine, nicotinic and/or muscarinic receptors. Higher concentrations of 5-hydroxytryptamine were required to produce the sodium conductance increase than the potassium conductance decrease; 2-methyl-5-hydroxytryptamine was equally effective in producing these responses. 5-Hydroxytryptamine also caused a barrage of "spontaneous" nicotinic excitatory post-synaptic potentials which were sensitive to tetrodotoxin. This response desensitized, was blocked by ICS 205-930 and is presumed to reflect excitation of other cholinergic cell bodies in the plexus by the sodium conductance increase mechanism described. The evoked nicotinic excitatory postsynaptic potential and the adrenergic inhibitory postsynaptic potential were decreased by 5-hydroxytryptamine; a portion of this inhibition showed desensitization and was blocked by ICS 205-930 as well as by the muscarinic receptor antagonists, atropine and pirenzepine. The ICS 205-930-insensitive portion of this inhibition could not be attributed to activation of 5-hydroxytryptamine-1 or 5-hydroxytryptamine-2 receptors. Thus, the following conclusions are drawn: 5-hydroxytryptamine excites submucous plexus neurons by activating two distinct 5-hydroxytryptamine receptors. Activation of the 5-hydroxytryptamine-3 receptor (sensitive to ICS 205-930) produces a depolarization mediated by an increased sodium conductance. The same effect occurring in other cholinergic cell bodies initiates action potentials which are responsible for the 5-hydroxytryptamine-induced release of acetylcholine.(ABSTRACT TRUNCATED AT 400 WORDS)