Albert, Anthony Paul;
(1997)
The effects of 5-hydroxytryptamine on rat dorsal vagal preganglionic motoneurones in vitro.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The dorsal motor nucleus of the vagus (DMN) is located in the dorsomedial medulla oblongata. It mainly contains dorsal vagal preganglionic neurones (DVMs) which control many autonomic functions. Immunocytochemical studies have shown that 5-hydroxytryptamine (5-HT) is present in nerve fibres and nerve terminals innervating the DMN. In addition, ligand-binding studies and in situ hybridisation studies have localised a number of 5-HT receptor subtypes in the DMN. This suggests that 5-HT may have an important role in modulating the activity of DVMs. The aim of my thesis was to examine the subthreshold effects of 5-HT on visually-identified DVMs using a thin brainstem slice preparation in combination with the whole-cell recording patchclamp configuration in current-clamp and voltage-clamp modes. In over 95 % of DVMs tested in current-clamp mode, applications of 5-HT elicited slow, prolonged excitatory effects which were dose-dependent and did not exhibit desensitization or run-down during recordings lasting over two hours. The excitatory responses to 5-HT were maintained in a media which blocked synaptic transmission indicating that the effects were mediated via postsynaptic 5-HT receptors. Furthermore, 5-HT elicited increases in baseline noise suggesting that the amine also enhanced the levels of postsynaptic potentials (PSPs) by activating presynaptic 5-HT receptors. The direct, postsynaptic excitatory effects of 5-HT were abolished or attenuated significantly (p <0.05) by the superfusion of the 5 -HT2a/2c receptor antagonists ketanserin and LY 53,857 and the 5 -HTia/2a receptor antagonist spiperone. The 5-HT1a/2a receptor antagonist pindobind.5-HTiA and the 5 -HT4 receptor antagonist GR 113808A had no effects on the excitatory responses of 5-HT. Superfusion of the 5 -HT3 receptor antagonists ICS-205-930 and MDL 7222 did not significantly (p> 0.05) attenuate the effects of 5-HT on DVMs. The excitatory effects of 5-HT on DVMs were mimicked by the 5-HT2A/2C receptor agonist α-methyl-5-HT, the 5-HTi/2 receptor agonist 5-CT and the non-selective 5-HT agonist 5-MEOT. Applications of the 5-HTg receptor agonist 2-methyl-5-HT evoked small subthreshold excitatory effects associated with increases in baseline noise. In all DVMs tested in voltage clamp mode, applications of 5-HT, α-methyl-5- HT and 5-CT evoked subthreshold inward currents that were associated with changes in three different ion currents; reductions of an outward rectifying K+ current and an inward rectifying current and the augmentation of a hyperpolarization-activated or Ih current. Combinations of the changes in the outward rectifying and Kir currents were observed in the same DVMs. The present study concludes that 5-HT elicits direct, postsynaptic subthreshold excitatory effects on DVMs via the activation of 5-HTJA receptors which are coupled to the modulation of at least three different ion channels. The mechanisms by which the 5-HT2A receptors are coupled to the ion channels, the possible physiological functions of the activation of 5 -HT2A receptors and the potential sources of 5-HT inputs onto DVMs are discussed.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The effects of 5-hydroxytryptamine on rat dorsal vagal preganglionic motoneurones in vitro |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Biological sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10106033 |
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