The role of serotonin and histamine receptors in the regulation of the sleep-wake cycle

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Regulation of the sleep-wake cycle relies on the interaction of a number of transmitter systems along two main pathways, one relying on the thalamus for the transmission of sensory inputs to the cerebral cortex whereas the other bypasses the thalamus to activate both cortical and lateral hypothalamic neurones. This latter pathway originates from monaminergic neurones including the serotonergic and noradrenergic neurones of the dorsal raphe (DR) and locus coeruleus (LC) respectively. Both monaminergic nuclei in tandem with the histaminergic tuberomammilary nucleus (TMN- Haas et al. 2008) fire at high frequency during wakefulness. Conversely, all three groups of neurones slow down and almost stop firing during NREM and REM sleep respectively (Saper et al. 2001). The switch between the awake and sleep state is dependent upon inhibition of the TMN neurones, a large component of which originates from the 'sleep promoting' GABAergic neurones of the VLPO. These neurones, in a reverse scenario, fire at a high frequency during sleep and are innervated by both the LC and the DR. While neurotransmitter modulation of the thalamic mediated arousal system has been subject to extensive investigation (Llinas & Steriade, 2006; Franks, 2008), the mechanisms and neuronal inputs regulating the hypothalamic sleep centres are only beginning to be elucidated (Saper et al 2005). In particular, the role played by both GABAergic and glutamatergic transmission in the excitability of both TMN and DR and the molecular identity of the receptors underpinning regulation of their activity have received limited attention. Similarly, although 5-HT and histamine can profoundly affect the excitability of the TMN and DR neurones (Eriksson et al. 2001; Barbara et al. 2002), the specific molecular mechanisms underpinning histaminergic regulation of serotonergic transmission and serotonergic regulation of histaminergic transmission in the wake-sleep cycle are yet to be fully understood. Nevertheless, the interaction of these two neurotransmitters is likely to be clinically significant, because H1R antagonists and selective 5-HT antagonist (e.g.of the 5-HT2AR and 5HT6R classes) promote sleep both in animals and in humans (Morairty e tal. 2008:; Landolt et al. 1999). Using an approach previously utilised to better understand the molecular mechanisms underpinning the thalamic actions of GABAAR active hypnotic agents (Belelli et al. 2005), we have recently investigated the role of GABAergic and serotonergic mechanisms in the regulation of DR activity (Maguire, Lambert and Belelli unpublished). The proposed project intends to extend this line of research and employ selective pharmacological tools in combination with transgenic mice and electrophysiological techniques applied to rodent brain slices to: 1) characterise inhibitory and excitatory transmission in both DR and TMN neurones 2) investigate the actions of 5-HT and histamine receptor modulation upon the activity of both DR and TMN. 3) utilize EEG recording in combination with in vitro electrophysiological techniques to elucidate the role played by 5-HT and histamine receptors in sleep-wake control. References: 1. Barbara A, Aceves J & Arias-Montano JA (2002). Brain Res. 954, 247-255. 2. Belelli D, Peden DR, Rosahl TW, Wafford KA & Lambert JJ (2005). J.Neurosci. 25, 11513-11520. 3. Eriksson KS, Stevens DR & Haas HL (2001) Neuropharmacology 40, 345-351. 4. Franks NP (2008). Nat.Rev.Neurosci. 9, 370-386. 5. Haas HL, Sergeeva OA & Selbach O (2008). Physiol Rev. 88, 1183-1241. 6. Landolt HP, Meier V, Burgess HJ, et al. (1999). Neuropsychopharmacology 21, 455-466. 7. Llinas RR & Steriade M (2006). J.Neurophysiol. 95, 3297-3308. 8. Morairty SR, Hedley L, Flores J, Martin R & Kilduff TS (2008). Sleep 31, 34-44. 9. Saper CB, Chou TC & Scammell TE (2001). Trends Neurosci. 24, 726-731. 10. Saper CB, Scammell TE & Lu J (2005). Nature 437, 1257-1263.