Clinically most active anxiolytic drugs are positive allosteric
modulators (PAMs) of GABAA receptors, represented by benzodiazepine
compounds. Due to their non-selective profile, however, they potently
modulate several sup-type specific GABAA receptors, contributing to
their broad-range side effects. Based on observations in genetically
altered mice, however, it has been proposed that anxiolytic action of
benzodiazepines is predominantly mediated by GABAA alpha 2/3
subunit-containing receptors. In the present study we analyzed the
actions of the preferential GABA(A) alpha 1 and alpha 2/3 PAMs,
zolpidem and L-838417, respectively on hippocampal EEG and medial
septum neuronal activity in anesthetized rats. In parallel, a
computational model was constructed to model pharmacological actions of
these compounds on the septo-hippocampal circuitry. The present results
demonstrated that zolpidem inhibited theta oscillation both in the
hippocampus and septum, and profoundly inhibited firing activity of
septal neurons. L-838417 also inhibited hippocampal and septal theta
oscillation, however, it did not significantly alter firing rate
activity of septal neurons. Our computational model showed that
cessation of periodic firing of hippocamposeptal neurons, representing
absence of hippocampal theta activity, disrupted oscillation of septal
units, without altering their overall firing activity, similar to
changes observed in our in vivo experiments following administration of
L-838417. Understanding the correlation between changes in
septo-hippocampal activity and actions of selective modulators of GABAA
subtype receptor modulators would further advance design of anxiolytic
drugs. (c) 2006 Elsevier Ltd. All rights reserved.
