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

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receptor-mediated whole-cell currents in CAI neurons from hippocampal slices prepared from 0-, 1-, 2-, and 4-day FZP-withdrawn rats in relation to expression of anxiety-like behavior during BZ withdrawal, AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude was significantly increased in CAI neurons from 1- and 2-day FZP-withdrawn rats, while evoked NMDAR EPSC amplitude was reduced only in neurons from 2-day FZP-withdrawn rats, Withdrawal-anxiety, measured in the elevated plus-maze, was observed 1 day, but not 0, 2, or 4 days, after FZP treatment with 1-day withdrawn rats spending significantly reduced time in open arms compared to controls.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the significant increase in the frequency of extracellular, 4-AP-induced spike discharges in slices from 1-day FZP-withdrawn rats.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MK-801 (0.25 mg/kg) on day 1 of withdrawal prevented reduced NMDAR-mediated currents in CAI neurons from 2-day FZP-withdrawn rats, whereas AMPAR-mediated currents remained upregulated. Furthermore, MK-801 'unmasked' withdrawal-anxiety in the same 2-day FZP-withdrawn rats.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(0.5 mg/kg) at the onset of withdrawal blocked increased AMPAR-mediated currents and withdrawal-anxiety in 1-day FZP-withdrawn rats.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