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.

Do Benzodiazepines Plus Fluvoxamine Cause a Rapid Increase in Serum Brain-derived Neurotrophic Factor or Clinical Improvement in Major Depressive Disorder Patients?

“…Thus, we can know the efficacy of antidepressants or/ and benzodiazepines from the changing the serum BDNF level. Acute administration of both triazolam and zolpidem resulted in reductions in BDNF protein and c-fos protein expression in the hippocampus [13]. Acute, but not chronic, administration of zolpidem specifically reduced exon IV-containing BDNF transcripts with concomitant increases in the association of methyl CpG-binding protein 2 with the BDNF gene promoter IV region and the association of the phosphor-cAMP response element-binding protein with BDNF gene promoter I region [13].…”

“…Acute administration of both triazolam and zolpidem resulted in reductions in BDNF protein and c-fos protein expression in the hippocampus [13]. Acute, but not chronic, administration of zolpidem specifically reduced exon IV-containing BDNF transcripts with concomitant increases in the association of methyl CpG-binding protein 2 with the BDNF gene promoter IV region and the association of the phosphor-cAMP response element-binding protein with BDNF gene promoter I region [13]. Several other researchers have reported that diazepam-induced c-fos expression increased or did not change in rodent brain tissue or cell lines [21].…”

“…The effects of benzodiazepine on BDNF expression, however, remain controversial. Several reports have found decreased [13], increased [14,15] or unchanged levels of BDNF and/or c-fos. To the best of our knowledge, no studies have compared BDNF levels between patients taking antidepressants with benzodiazepines and those taking antidepressants alone.…”

Effects of oral temazepam on slow waves during non-rapid eye movement sleep in healthy young adults: A high-density EEG investigation

“…As an antidepressant, ketamine also increases BDNF in responders compared to non-responders (Haile et al, 2014), and a positive relationship between slow wave parameters (SWA and amplitude) and change in BDNF among responders has also been demonstrated (Duncan et al, 2012). Because benzodiazepines have been shown to reduce BDNF in prior studies (Huang and Hung, 2009; Huopaniemi et al, 2004; Licata et al, 2013), although speculative, these agents may be antithetical to the antidepressant effects of ketamine, through reductions in slow wave activity, incidence, and morphology via reductions in this neurotrophic factor. Thus, further research that clarifies whether there is a causal link between reductions in slow waves and decline in BDNF induced by these drugs, and whether co-administration of benzodiazepines prior to sleep blunts the therapeutic response to ketamine, may help clarify the relationships between cortical plasticity, sleep slow waves, and the mechanisms underlying the thymoleptic properties of ketamine.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Acute BZ treatments might thus strongly prevent neuroplasticity. In addition, Licata et al (2013) found that single doses of triazolam and zolpidem reduced BDNF in the mouse HC, but unexpectedly a 7-day twice daily treatment with diazepam or zolpidem failed to change BDNF expression. However, concurrent 2-to 3-week diazepam treatment prevents the stimulation of neurogenesis by fluoxetine in normal rats (Wu and Castren, 2009) and in socially isolated anxious rats (Sun et al, 2013).…”