Transient plasticity of hippocampal CA1 neuron glutamate receptors contributes to benzodiazepine withdrawal-anxiety

Neuropsychopharmacology. 2004 Nov;29(11):1994-2006. doi: 10.1038/sj.npp.1300531.


Withdrawal from 1-week oral administration of the benzodiazepine (BZ), flurazepam (FZP) is associated with enhanced AMPA receptor (AMPAR)-mediated and reduced NMDA receptor (NMDAR)-mediated excitation in CA1 pyramidal neurons 2-days after cessation of FZP administration. The present study examined temporal regulation of glutamate receptor-mediated whole-cell currents in CA1 neurons from hippocampal slices prepared from 0-, 1-, 2-, and 4-day FZP-withdrawn rats in relation to expression of anxiety-like behavior during BZ withdrawal. AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude was significantly increased in CA1 neurons from 1- and 2-day FZP-withdrawn rats, while evoked NMDAR EPSC amplitude was reduced only in neurons from 2-day FZP-withdrawn rats. Withdrawal-anxiety, measured in the elevated plus-maze, was observed 1 day, but not 0, 2, or 4 days, after FZP treatment with 1-day withdrawn rats spending significantly reduced time in open arms compared to controls. CA1 neuron hyperexcitability was evident from the significant increase in the frequency of extracellular, 4-AP-induced spike discharges in slices from 1-day FZP-withdrawn rats. Systemic injection of the NMDAR antagonist MK-801 (0.25 mg/kg) on day 1 of withdrawal prevented reduced NMDAR-mediated currents in CA1 neurons from 2-day FZP-withdrawn rats, whereas AMPAR-mediated currents remained upregulated. Furthermore, MK-801 'unmasked' withdrawal-anxiety in the same 2-day FZP-withdrawn rats. Systemic injection of the AMPAR antagonist GYKI-52466 (0.5 mg/kg) at the onset of withdrawal blocked increased AMPAR-mediated currents and withdrawal-anxiety in 1-day FZP-withdrawn rats. These findings suggest that increased CA1 neuron AMPAR-mediated excitation may contribute to hippocampal hyperexcitability and expression of withdrawal-anxiety after prolonged BZ exposure via NMDAR-mediated neural circuits.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anxiety / chemically induced
  • Anxiety / metabolism*
  • Anxiety / psychology
  • Benzodiazepines / adverse effects*
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • In Vitro Techniques
  • Male
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glutamate / metabolism*
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / psychology


  • Receptors, Glutamate
  • Benzodiazepines