Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons

Article Article scientifique Article Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons eng 2011 author Uschakov Aaron 679688 author Grivel Jérémy 509986 author Cvetkovic Lopes Vesna 135729 author Bayer Laurence 529638 author Bernheim Laurent 22268 author Jones Barbara E author Muhlethaler Michel 26428 author Serafin Mauro 23317 e16672 10.1371/journal.pone.0016672 21347440 1932-6203 We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA) of hypocretin/orexin (hcrt/orx) neurons was changed to an inhibition following sleep deprivation (SD). Here we describe that in control condition (CC), i.e. following 2 hours of natural sleep in the morning, the α(2)-adrenergic receptor (α(2)-AR) agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC), it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK) channels. Since concentrations of clonidine up to a thousand times (100 µM) higher than those effective in SDC (100 nM), were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABA(B) agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α(2)-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α(2)-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α(2)-ARs associated with GIRK channels is normally down-regulated (or desensitized) in hcrt/orx neurons to only become available for their inhibition following sleep deprivation. Adrenergic alpha-2 Receptor Agonists/pharmacology Animals Brain/pathology Calcium/metabolism Clonidine/pharmacology G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism Intracellular Signaling Peptides and Proteins/metabolism Membrane Potentials/drug effects Neurons/drug effects/metabolism/pathology Neuropeptides/metabolism Norepinephrine/metabolism Rats Rats, Sprague-Dawley Receptors, Adrenergic, alpha-2/metabolism Sleep Deprivation/metabolism/pathology Dewey 616.8 53 Département de neurosciences fondamentales 21A false 166 Culture Primaire de myoblastes humains 208 170 Mécanismes impliqués dans la régulation des états de veille et de sommeil 213 PloS one 6 2 08ba79be-f6b6-450f-ae78-502edd101715 Article (Published version) Public 2011_Uschakov_SleepDeprivation_PlosOne.pdf 772591 application/pdf CC BY openAccess Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales

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Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons	PloS one			2011	705	376

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Cvetkovic Lopes, Vesna