Analysis of spontaneous hippocampal activity allows sensitive detection of XXXX -mediated effects.

@entity410 @entity35 @entity1249 @entity20052 @entity4833 @entity1617 @entity3897 @entity2607 @entity5402 @entity8161 @entity934
INTRODUCTION: Excitation of @entity934 -mediated (Ach) transmission (especially if irreversible) may pose life-threatening adverse events by increasing neuronal network activity. Unfortunately, adequate detection of this liability during early drug development is hampered, because published ex vivo electrophysiological models are very insensitive to this regard. For example, @entity2607 , which reversibly inhibits @entity4833 ( @entity4833 ) in the double digit nM range, affects electrically evoked potentials in hippocampal slices only at >= 10 M. Here, a significantly more sensitive method for detecting @entity1617 -mediated alternations is presented by analyzing spontaneous neuronal network activity in hippocampal slices. METHODS: The microelectrode array (MEA) technique with an 8*8 electrode grid was applied to analyze evoked and spontaneous extracellular field recordings in parallel from acute @entity35 hippocampal slices. For evoked potentials, the Schaffer collateral @entity20052 pathway was electrically stimulated and the resulting field potential analyzed at the @entity1249 pyramidal layer. Spontaneous spike activity was detected as negative inflections from the 100Hz high pass filtered signal. Spike frequency was analyzed within the whole @entity1249 region. RESULTS: Modification of Ach-mediated neuronal transmission via @entity5402 , @entity2607 , or @entity8161 ( @entity8161 ) does not induce any effects on evoked field potentials at physiologically relevant concentrations. Similar to previous reports, subtle effects were detectable at very high concentrations. By contrast, spontaneous spike frequency was already increased within the expected concentration range. @entity2607 -induced effects can also be reversed by @entity3897 and washout. On the contrary, effects by the irreversible @entity4833 -blocker DFP could not be washed out. DISCUSSION: Compared to evoked field potentials, spontaneous spike activity in the hippocampal @entity1249 region appears to be a significantly more sensitive parameter for functional electrophysiological analysis of drug induced Ach-mediated effects. This finding may supplement existing models for detection and prediction of drug-related adverse effects like @entity410 liability already during early development stages.
