title: Reduced sleep and low adenosinergic sensitivity in cacna1a R192Q mutant mice.
abstract: OBJECTIVE
  Adenosine modulates sleep via A(1) and A(2A) receptors. As the A(1) receptor influences Ca(V)2.1 channel functioning via G-protein inhibition, there is a possible role of the Ca(V)2.1 channel in sleep regulation. To this end we investigated transgenic Cacna1a R192Q mutant mice that express mutant Ca(V)2.1 channels that are less susceptible to inhibition by G-proteins. We hypothesized that Cacna1a R192Q mice could show reduced susceptibility to adenosine, which may result in a sleep phenotype characterized by decreased sleep.
  
  
  METHODS
  R192Q mutant and littermate wild-type mice were subjected to a 6-h sleep deprivation, treatment with caffeine (a non-specific adenosine receptor antagonist which induces waking), or cyclopentyladenosine (CPA, an A(1) receptor specific agonist which induces sleep).
  
  
  RESULTS
  Under baseline conditions, Cacna1a R192Q mice showed more waking with longer waking episodes in the dark period and less non-rapid eye movement (NREM) sleep, but equal amounts of REM sleep compared to wild-type. After treatment with caffeine R192Q mice initiated sleep 30 min earlier than wild-type, whereas after CPA treatment, R192Q mice woke up 260 min earlier than wild-type. Both results indicate that Cacna1a R192Q mice are less susceptible to adenosinergic input, which may explain the larger amount of waking under undisturbed baseline conditions.
  
  
  CONCLUSIONS
  We here show that adenosinergic sleep induction, and responses to caffeine and CPA, are modified in the R192Q mutant in a manner consistent with decreased susceptibility to inhibition by adenosine. The data suggest that the A(1) receptor modulates sleep via the Ca(V)2.1 channel.
authors.affiliation: Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. tom.de_boer@lumc.nl
authors.forename: Tom
authors.initials: T
authors.lastname: Deboer
authors.forename: Hester C
authors.initials: HC
authors.lastname: van Diepen
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: Van den Maagdenberg
authors.forename: Johanna H
authors.initials: JH
authors.lastname: Meijer
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002110:Caffeine; D000697:Central Nervous System Stimulants; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D012892:Sleep Deprivation / Q000139:chemically induced / Q000175:diagnosis / Q000378:metabolism*; D012894:Sleep Stages / Q000187:drug effects; D012895:Sleep, REM / Q000502:physiology; D012965:Sodium Chloride / Q000008:administration & dosage
chemical_list: D000697:Central Nervous System Stimulants; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D002110:Caffeine; C048599:N(6)-cyclopentyladenosine; D012965:Sodium Chloride; D000241:Adenosine