AbstractNeural control of the sleep-wake cycle results from the complex interaction of neurotransmitters systems, which arise from anatomically and chemically defined brain structures. Serotonergic neurons located in the dorsal raphe nucleus (DRN) are currently accepted to be wake-promoting however their precise regulation by other neurotransmitter systems during the sleep-wake cycle is currently unknown. The main aim of this study was to utilise in vitro and in vivo electrophysiological techniques in order to elucidate the intra-raphe regulation of serotonergic neurons.
In vitro, single-unit recordings from putative serotonin (5-HT) neurons revealed that these neurons fired spontaneously in acute brain slices taken from mice. Initial pharmacological investigations revealed that putative 5-HT neurons in the DRN were under regulatory control by α1-adrenoreceptors, 5-HT2 receptors, orexin receptors and histamine receptors. In vitro, patch-clamp studies were performed in order to extend the investigation of 5-HT2, orexin and histamine receptors further in the hope of understanding the cellular mechanisms responsible for their actions. Most interestingly, histamine produced a large inward current, depolarisation and excitation of putative 5-HT neurons in the DRN. Histamine was shown to mediate its effects predominantly via the H1 receptor subtype and furthermore this receptor was observed to be constitutively active in the acute brain slice.
In vivo, single unit recordings from putative 5-HT neurons were performed in order to assess the role of the H1 receptor further. Recordings were made from the DRN of anaesthetised, head-restrained rats. Pharmacological inhibition of H1 receptors reduced the firing of putative 5-HT neurons, confirming the functional activity of these receptors in the intact brain. In order to investigate the significance of H1 receptor blockade on the sleep-wake cycle, electroencephalogram (EEG) recordings were performed. EEG recordings revealed that blocking H1 receptors caused a significant increase in the amount of non-rapid eye movement (NREM) sleep. The data reported here could have important clinical implications in the discovery of novel sleep therapies which target the serotonergic and/or the histaminergic system.
|Date of Award||2014|
|Supervisor||Delia Belelli (Supervisor), Jeremy Lambert (Supervisor) & Keith A. Wafford (Supervisor)|