title: Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons.
abstract: 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.
authors.affiliation: Département de Neurosciences fondamentales, Centre Médical Universitaire, Genève, Switzerland.
authors.forename: Aaron
authors.initials: A
authors.lastname: Uschakov
authors.forename: Jeremy
authors.initials: J
authors.lastname: Grivel
authors.forename: Vesna
authors.initials: V
authors.lastname: Cvetkovic-Lopes
authors.forename: Laurence
authors.initials: L
authors.lastname: Bayer
authors.forename: Laurent
authors.initials: L
authors.lastname: Bernheim
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Jones
authors.forename: Michel
authors.initials: M
authors.lastname: Mühlethaler
authors.forename: Mauro
authors.initials: M
authors.lastname: Serafin
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D012892:Sleep Deprivation / Q000378:metabolism* / Q000473:pathology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D018341:Receptors, Adrenergic, alpha-2; D003000:Clonidine; D002118:Calcium; D009638:Norepinephrine