Abstract
The aim of this study was to investigate the pharmacological characteristics of the 5-hydroxytryptamine-(5-HT)-induced electrical response in cultured neuroblastoma N1E-115 cells of the mouse. In these cells 5-HT induces a transient membrane depolarization, which is associated with a transient inward current, that has been recorded in voltage clamp experiments on whole cells. The peak amplitude of the inward current depends on the concentration of 5-HT applied. Maximum peak inward current was evoked by 10 μM 5-HT and half maximum effect by 2 μM. Responses to 5-HT were blocked by nanomolar concentrations of selective 5-HT 3-receptor antagonists, whereas the selective agonist 2-methyl-5-HT mimicked the membrane depolarization induced by 5-HT. A number of agonists and antagonists, which are known to act on 5-HT 1-like, 5-HT 2, dopaminergic and adrenergic receptors failed to affect the response to 5-HT in neuroblastoma cells. Observed antagonistic effects of SCH 23390 [(R) − (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hemimaleate] and haloperidol are discussed. The inhibitory effect of the 5-HT 3 receptor antagonist, ICS 205–930 [(3α-tropanyl)-1H-indole-3-carboxylic acid ester] has been demonstrated. When cells were exposed to 0.1 nM ICS 205–930 the maximum evoked response was reduced by about 50%, but a surmountable shift of the concentration-response curve of 5-HT was not observed. The kinetics of the 5-HT-induced inward current remained unchanged in the presence of ICS 205–930. Recovery from the block by ICS 205–930 was very slow. The apparent non-competitive nature of this antagonism is discussed. The amplitude of the membrane depolarization evoked by ionophoretic application of 5-HT decreased in the presence of a small concentration of 5-HT. Dopamine (DA) also induced a depolarizing response in N1E-115 cells. Responses to ionophoretically applied 5-HT and dopamine were both potently desensitized by 5-HT. Dopamine induced densensitization only at much greater concentrations. It is concluded that in cultured neuroblastoma N1E-115 cells of the mouse, the 5-HT-induced membrane depolarization and the associated inward current are mediated by a single population of 5-HT 3 receptor-mediated ion channels. These cells are an appropriate in vitro model to study the molecular mechanisms underlying the functioning of 5-HT 3 receptors.
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