Different effects of zolpidem and diazepam on hippocampal sharp wave-ripple activity in vitro

Sharp waves and the concurrent high-frequency "ripple" oscillation (100-200 Hz) is a prominent intrinsic hippocampal network activity that occurs during slow-wave sleep and resting wakefulness with an important role in memory processes. Present data suggest that the generation of sharp wave-ripple (SWRs) requires a complex interaction between the various components of the hippocampal network with the important involvement of GABA(A) receptor (GABA(A)R)-mediated transmission. The positive modulators of GABA(A)Rs zolpidem and diazepam differ in their selectivity for the various subtypes of GABA(A)Rs. Only zolpidem preferentially binds to α1-containing receptors whereas diazepam, but not zolpidem, also activates α5-GABA(A)Rs. In this study using an in vitro model of SWRs we examined the hypothesis that the two drugs distinctly affect the various characteristics of SWRs. Remarkably, the two drugs displayed opposite effects on the ripple oscillation. Zolpidem enhanced whereas diazepam suppressed ripples. Furthermore diazepam, but not zolpidem, produced a temporal dissociation between ripples and sharp waves. Both drugs suppressed the generation of SWRs in the form of sequences of multiple events (i.e. clusters). It was also observed that at low concentrations both drugs increased the rate of initiation of episodes of SWR. At high concentration zolpidem but not diazepam continued to increase the rate of episodes of SWRs. We propose that an accurate yet dynamic balance between excitation and inhibition in specific sites of the hippocampal network distinctly regulates the generation of basic features of SWRs such as ripples and sequential activation of the neuronal assemblies which have particular functional roles.