ORIGINAL INVESTIGATION mPer1 promotes morphine-induced locomotor sensitization and conditioned place preference via histone deacetylase activity Stéphanie Perreau-Lenz 1,2 & Laura-Sophie Hoelters 1 & Sarah Leixner 1 & Carla Sanchis-Segura 3 & Anita Hansson 1 & Ainhoa Bilbao 1 & Rainer Spanagel 1 Received: 5 April 2016 /Accepted: 6 February 2017 # Springer-Verlag Berlin Heidelberg 2017 Abstract Rationale 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 Per1 Brdm1 null 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 Per1 Brdm1 mutant mice did not show any difference in morphine antinociception, tolerance development, nor in phys- ical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sen- sitization and CPP were significantly impaired in Per1 Brdm1 mutant mice. Because a very similar dissociation between tolerance and dependence vs. sensitization and CPP was recent- ly observed after the co-administration of morphine and the HDAC inhibitor sodium butyrate (NaBut), we studied a possi- ble link between mPer1 and HDAC activity. As opposed to WT controls, Per1 Brdm1 mutant mice showed significantly en- hanced striatal global HDAC activity within the striatum when exposed to a locomotor-sensitizing morphine administration regimen. Furthermore, the administration of the HDAC inhib- itor NaBut restored the ability of morphine to promote locomo- tor sensitization and reward in Per1 Brdm1 mutant mice. Conclusions Our results reveal that although the mPer1 gene does not alter morphine-induced antinociception nor with- drawal, it plays a prominent role in the development of morphine-induced behavioral sensitization and reward via in- hibitory modulation of striatal HDAC activity. These data suggest that PER1 inhibits deacetylation to promote drug- induced neuroplastic changes. Keywords Addiction . Clock genes . Opioids . HDAC . Mice . CPP . Behavioral sensitization . Epigenetic . Sodium butyrate . Per1 Abbreviations HDAC Histone deacetylase CPP Conditioned place preference Per1 Period 1 NaBut Sodium butyrate Introduction In the past decade, clock genes have been shown to possess other properties than simply acting as circadian core self-regulators sustaining a functional circadian clock Electronic supplementary material The online version of this article (doi:10.1007/s00213-017-4574-0) contains supplementary material, which is available to authorized users. * Stéphanie Perreau-Lenz stephanie.perreau-lenz@sri.com 1 Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany 2 SRI Biosciences, Division of SRI International, Center for Neuroscience, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA 3 Area de Psicobiologia, Universitat Jaume I, Castelló, Spain Psychopharmacology DOI 10.1007/s00213-017-4574-0