PMID- 24367698 OWN - NLM STAT- MEDLINE DCOM- 20140728 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 12 DP - 2013 TI - Alterations in brain-derived neurotrophic factor in the mouse hippocampus following acute but not repeated benzodiazepine treatment. PG - e84806 LID - 10.1371/journal.pone.0084806 [doi] LID - e84806 AB - Benzodiazepines (BZs) are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP), an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF) and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression. Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p.) injections of diazepam (10 mg/kg + 5 mg/kg) or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg), acute i.p. administration of both triazolam (0.03 mg/kg) and ZP (1.0 mg/kg) decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2) with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB) with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly. FAU - Licata, Stephanie C AU - Licata SC AD - McLean Hospital, Belmont, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Shinday, Nina M AU - Shinday NM AD - New England Primate Research Center, Southborough, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Huizenga, Megan N AU - Huizenga MN AD - Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Darnell, Shayna B AU - Darnell SB AD - Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Sangrey, Gavin R AU - Sangrey GR AD - Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Rudolph, Uwe AU - Rudolph U AD - McLean Hospital, Belmont, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Rowlett, James K AU - Rowlett JK AD - New England Primate Research Center, Southborough, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Sadri-Vakili, Ghazaleh AU - Sadri-Vakili G AD - Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America. LA - eng GR - R01 DA011792/DA/NIDA NIH HHS/United States GR - R01 AG035361/AG/NIA NIH HHS/United States GR - T32 DA015036/DA/NIDA NIH HHS/United States GR - DA011792/DA/NIDA NIH HHS/United States GR - R01 DA033795/DA/NIDA NIH HHS/United States GR - DA033795/DA/NIDA NIH HHS/United States GR - AG035361/AG/NIA NIH HHS/United States GR - P51 OD011103/OD/NIH HHS/United States GR - RR000168/OD011103/OD/NIH HHS/United States GR - P51 RR000168/RR/NCRR NIH HHS/United States GR - DA015036/DA/NIDA NIH HHS/United States GR - K26 RR000168/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20131219 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Proto-Oncogene Proteins c-fos) RN - 0 (Pyridines) RN - 12794-10-4 (Benzodiazepines) RN - 1HM943223R (Triazolam) RN - 7K383OQI23 (Zolpidem) RN - Q3JTX2Q7TU (Diazepam) SB - IM MH - Analysis of Variance MH - Animals MH - Benzodiazepines/*pharmacology MH - Blotting, Western MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Chromatin Immunoprecipitation MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Diazepam MH - Enzyme-Linked Immunosorbent Assay MH - Gene Expression Regulation/*drug effects/genetics MH - Genes, Immediate-Early/*physiology MH - Hippocampus/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Proto-Oncogene Proteins c-fos/metabolism MH - Pyridines MH - Reverse Transcriptase Polymerase Chain Reaction MH - Triazolam MH - Zolpidem PMC - PMC3868703 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2013/12/25 06:00 MHDA- 2014/07/30 06:00 PMCR- 2013/12/19 CRDT- 2013/12/25 06:00 PHST- 2013/08/22 00:00 [received] PHST- 2013/11/19 00:00 [accepted] PHST- 2013/12/25 06:00 [entrez] PHST- 2013/12/25 06:00 [pubmed] PHST- 2014/07/30 06:00 [medline] PHST- 2013/12/19 00:00 [pmc-release] AID - PONE-D-13-34712 [pii] AID - 10.1371/journal.pone.0084806 [doi] PST - epublish SO - PLoS One. 2013 Dec 19;8(12):e84806. doi: 10.1371/journal.pone.0084806. eCollection 2013.