title: Alterations in brain-derived neurotrophic factor in the mouse hippocampus following acute but not repeated benzodiazepine treatment.
abstract: 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.
authors.affiliation: McLean Hospital, Belmont, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Licata
authors.affiliation: New England Primate Research Center, Southborough, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Shinday
authors.affiliation: Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Huizenga
authors.affiliation: Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Shayna B
authors.initials: SB
authors.lastname: Darnell
authors.affiliation: Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Sangrey
authors.affiliation: McLean Hospital, Belmont, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.affiliation: New England Primate Research Center, Southborough, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: James K
authors.initials: JK
authors.lastname: Rowlett
authors.affiliation: Massachusetts General Hospital, Charlestown, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003975:Diazepam; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D017781:Genes, Immediate-Early / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014229:Triazolam; D000077334:Zolpidem
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D001569:Benzodiazepines; D014229:Triazolam; D000077334:Zolpidem; D003975:Diazepam