| dc.description.abstract |
Despite their long-standing and widespread use in modern medicine, the mechanisms
of action of many anaesthetics still remain unknown. To date, it is mostly
unclear which receptors exactly are targeted by these substances and how they
interact with each other as well as with endogenous substances produced by the
human body itself.
This study aims to examine this issue, specifically the effects and interactions of
GABAergic drugs both on a synaptic as well as on a network level. It focuses on
the action profiles and the interactions of zolpidem, a sedative drug that mainly
targets alpha1 subunit-containing GABA(A) receptors, and XBD173, a TSPO ligand
which supposedly targets GABA(A) receptors indirectly via neurosteroidogenesis.
For this study, electrophysiological recordings of spontaneous neuronal activity in
organotypic slice cultures from the neocortex of neonatal mice were done. Neuronal
activity on a synaptic level was assessed via patch clamp experiments, while
network activity was assessed using extracellular multi-unit recordings.
The patch clamp experiments demonstrated that both XBD173 and zolpidem are
able to affect synaptic GABAergic transmission in organotypic neocortical slice
cultures, although they modify mIPSC kinetics in different ways. While zolpidem
alone produced a strong increase in mIPSC decay time, XBD173 altered mIPSC
kinetics in a much more complex way and, when co-applied with zolpidem, significantly
reduced its effect.
In the extracellular experiments, XBD173 and zolpidem both significantly reduced
action potential activity, while again displaying different patterns of effect. Zolpidem
strongly decreased high frequency action potential activity, while XBD173
only affected phases of moderate sustained action potential activity. During those
phases, a synergistic effect could be observed after the combined application of
zolpidem and XBD173.
In conclusion, this study was able to confirm that zolpidem and XBD173 have different
profiles of action in organotypic neocortical slice cultures, offering a plausible
explanation for their distinct clinical effects. It also demonstrated a synergistic
effect between both substances on a neuronal network level. Considering the
combined results of the patch clamp and extracellular experiments, however, this
effect cannot be mediated by synaptic GABA(A) receptors alone, indicating that
there have to be other receptors involved in the process.
These findings may offer novel options for clinical anaesthesia – making use
of synergistic effects, which may come in the form of synergistic interactions between classical anaesthetics and neurosteroids, could quite possibly offer a
new way to reduce anaesthetic dose requirements and thus their unwanted side-effects,
thereby improving the patient-friendly use of anaesthetics overall. |
en |
