Chronic benzodiazepine administration alters hippocampal CA1 neuron excitability: NMDA receptor function and expression

B. J. Van Sickle, A. S. Cox, K. Schak, L. John Greenfield, E. I. Tietz

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Rats are tolerant to benzodiazepine (BZ) anticonvulsant actions two days after ending one-week administration of the BZ, flurazepam (FZP). Concurrently, GABAA receptor-mediated inhibition is reduced and AMPA receptor-mediated excitation is selectively enhanced in CA1 pyramidal neurons in hippocampal slices. In the present study, the effects of chronic FZP exposure on NMDA receptor (NMDAR) currents were examined in CA1 pyramidal neurons in hippocampal slices and following acute dissociation. In CA1 neurons from chronic FZP-treated rats, evoked NMDAR EPSC amplitude was significantly decreased (52%) in slices, and the maximal current amplitude of NMDA-induced currents in dissociated neurons was also significantly reduced (58%). Evoked NMDAR EPSCs were not altered following acute desalkyl-FZP treatment. Using in situ hybridization and immunohistochemical techniques, a selective reduction in NR2B subunit mRNA and protein expression was detected in the CA1 and CA2 regions following FZP treatment. However, total hippocampal NMDAR number, as assessed by autoradiography with the NMDAR antagonist, [3H]MK-801, was unchanged by FZP treatment. These findings suggest that reduced NMDAR-mediated currents associated with chronic BZ treatment may be related to reduced NR2B subunit-containing NMDARs in the CA1 and CA2 regions. Altered NMDAR function and expression after chronic BZ exposure may contribute to BZ anticonvulsant tolerance or dependence.

Original languageEnglish (US)
Pages (from-to)595-606
Number of pages12
JournalNeuropharmacology
Volume43
Issue number4
DOIs
StatePublished - Sep 1 2002

Keywords

  • CAI
  • EPSCs
  • Excitatory synapses
  • Flurazepam
  • NMDA receptor
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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