Stéphanie Perreau-Lenz1,2, Laura-Sophie Hoelters3, Sarah Leixner3, Carla Sanchis-Segura4, Anita Hansson3, Ainhoa Bilbao3, Rainer Spanagel3. 1. Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. stephanie.perreau-lenz@sri.com. 2. SRI Biosciences, Division of SRI International, Center for Neuroscience, 333 Ravenswood Avenue, Menlo Park, CA, 94025, USA. stephanie.perreau-lenz@sri.com. 3. Central Institute for Mental Health, Institute of Psychopharmacology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 4. Area de Psicobiologia, Universitat Jaume I, Castelló, Spain.
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 physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1 Brdm1 mutant 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, Per1 Brdm1 mutant 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 Per1 Brdm1 mutant 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.
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 physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1 Brdm1 mutant 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, Per1 Brdm1 mutant 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 Per1 Brdm1 mutant 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: Xiangning Xue; Wei Zong; Jill R Glausier; Sam-Moon Kim; Micah A Shelton; BaDoi N Phan; Chaitanya Srinivasan; Andreas R Pfenning; George C Tseng; David A Lewis; Marianne L Seney; Ryan W Logan Journal: Transl Psychiatry Date: 2022-03-26 Impact factor: 7.989