title: mPer1 promotes morphine-induced locomotor sensitization and conditioned place preference via histone deacetylase activity.
abstract: BACKGROUND
  Previous studies have shown that repeated exposure to drugs of abuse is associated with changes in clock genes expression and that mice strains with various mutations in clock genes show alterations in drug-induced behaviors.
  
  
  OBJECTIVE
  The objective of this study is to characterize the role of the clock gene mPer1 in the development of morphine-induced behaviors and a possible link to histone deacetylase (HDAC) activity.
  
  
  METHODS
  In Per1Brdm1null mutant mice and wild-type (WT) littermates, we examined whether there were any differences in the development of morphine antinociception, tolerance to antinociception, withdrawal, sensitization to locomotion, and conditioned place preference (CPP).
  
  
  RESULTS
  Per1Brdm1mutant mice did not show any difference in morphine antinociception, tolerance development, nor in physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1Brdm1mutant mice. Because a very similar dissociation between tolerance and dependence vs. sensitization and CPP was recently observed after the co-administration of morphine and the HDAC inhibitor sodium butyrate (NaBut), we studied a possible link between mPer1 and HDAC activity. As opposed to WT controls, Per1Brdm1mutant mice showed significantly enhanced striatal global HDAC activity within the striatum when exposed to a locomotor-sensitizing morphine administration regimen. Furthermore, the administration of the HDAC inhibitor NaBut restored the ability of morphine to promote locomotor sensitization and reward in Per1Brdm1mutant mice.
  
  
  CONCLUSIONS
  Our results reveal that although the mPer1 gene does not alter morphine-induced antinociception nor withdrawal, it plays a prominent role in the development of morphine-induced behavioral sensitization and reward via inhibitory modulation of striatal HDAC activity. These data suggest that PER1 inhibits deacetylation to promote drug-induced neuroplastic changes.
authors.affiliation: Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. stephanie.perreau-lenz@sri.com.|SRI Biosciences, Division of SRI International, Center for Neuroscience, 333 Ravenswood Avenue, Menlo Park, CA, 94025, USA. stephanie.perreau-lenz@sri.com.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Perreau-Lenz
authors.affiliation: Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Laura-Sophie
authors.initials: LS
authors.lastname: Hoelters
authors.affiliation: Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Leixner
authors.affiliation: Area de Psicobiologia, Universitat Jaume I, Castelló, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Sanchis-Segura
authors.affiliation: Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Hansson
authors.affiliation: Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.affiliation: Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004361:Drug Tolerance / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D056950:Period Circadian Proteins / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D056572:Histone Deacetylase Inhibitors; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D009270:Naloxone; D009020:Morphine; D006655:Histone Deacetylases
keywords: Addiction; Behavioral sensitization; CPP; Clock genes; Epigenetic; HDAC; Mice; Opioids; Per1; Sodium butyrate