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        SB-334867-A antagonises orexin mediated excitation in the locus coeruleus

        Author
        Soffin, E.M.
        Evans, M.L.
        Gill, C.H.
        Harries, M.
        Benham, C.D.
        Davies, C.H.
        Attention
        2299/3507
        Abstract
        Electrophysiological recordings from identified noradrenergic locus coeruleus (LC) neurones in rat brain slices have revealed that the orexins can cause direct and reversible depolarisation of the postsynaptic membrane. Whilst it is known that the membrane depolarisation produced by orexin-A can triple the firing rate of spontaneously active LC neurones, quantitative pharmacological analysis that determines the receptor subtype(s) mediating the orexinergic response has not yet been performed. Here we demonstrate that the effects of orexin-A are five-fold more potent than orexin-B on LC neuronal excitability. We show further that the orexin receptor antagonist SB-334867-A inhibits the effects of both agonists with pKB values similar to those calculated for human OX1 receptors expressed in CHO cells. Finally, we found no evidence for tonic activation of OX1 receptors in LC noradrenergic neurones despite electron microscopic evidence that orexin terminals directly contact these neurones. These data demonstrate that SB-334867-A is a useful tool compound with which to study the physiology of OX1 receptors.
        Publication date
        2002
        Published in
        Neuropharmacology
        Published version
        https://doi.org/10.1016/S0028-3908(01)00156-3
        Other links
        http://hdl.handle.net/2299/3507
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