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.
Highlights
Benzodiazepines (BZs) and related drugs such as zolpidem increase GABA-mediated inhibition via positive allosteric modulation of GABAA receptors throughout the central nervous system [1]
All three drugs bind to a site on the native pentameric GABAA receptor that is situated between the γ2 subunit and an α subunit, but while the classical BZs are non-selective and will bind α1, α2, α3, or α5 subunit-containing receptors [38,39], ZP exhibits relatively selective affinity for GABAA receptors containing an α1 subunit [40,41]
This observation was confirmed with Enzyme-Linked Immunosorbant Assay (ELISA), which demonstrated a significant reduction in brain derived neurotrophic factor (BDNF) protein levels in the HIP following acute ZP and TZ [F(2,9)= 9.568, p= 0.006] (Figure 1D)
Summary
Benzodiazepines (BZs) and related drugs such as zolpidem increase GABA-mediated inhibition via positive allosteric modulation of GABAA receptors throughout the central nervous system [1] This drug class is commonly prescribed for treating anxiety, sleep, and seizure disorders, and while clinically valuable, their use can result in undesirable effects including memory impairment as well as abuse and dependence [2,3]. Given their widespread application, understanding more fully how BZs produce their effects is an important public health issue that will provide a framework for designing novel compounds to overcome their limitations as therapeutics. Network and receptor mechanisms contribute to our understanding of how BZs affect behavior, but there is a gap in our knowledge regarding the molecular substrates mediating the effects of this drug class
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