Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1–10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal Ih amplitude (relative reduction: 0.86 [0.78–0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V1/2 occurred exclusively in the presence of the very high concentration of 100 µM (−4,7 [−7.5–−4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τfast: +135.1 [+64.7–+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function.
Despite ongoing research efforts and routine clinical use, the neuronal mechanisms underlying the anesthesia-induced loss of consciousness are still under debate. Unlike most anesthetics, ketamine increases thalamic and cortical activity. Ketamine is considered to act via a NMDA-receptor antagonism-mediated reduction of inhibition, i.e., disinhibition. Intact interactions between the thalamus and cortex constitute a prerequisite for the maintenance of consciousness and are thus a promising target for anesthetics to induce loss of consciousness. In this study, we aim to characterize the influence of s-ketamine on the thalamocortical network using acute brain-slice preparation. We performed whole-cell patch-clamp recordings from pyramidal neurons in cortical lamina IV and thalamocortical relay neurons in acute brain slices from CB57BL/6N mice. Excitatory postsynaptic potentials (EPSPs) were obtained via electrical stimulation of the cortex with a bipolar electrode that was positioned to lamina II/III (electrically induced EPSPs, eEPSPs) or via optogenetic activation of thalamocortical relay neurons (optogenetically induced EPSPs, oEPSPs). Intrinsic neuronal properties (like resting membrane potential, membrane threshold for action potential generation, input resistance, and tonic action potential frequency), as well as NMDA-receptor-dependent and independent spontaneous GABAA-receptor-mediated inhibitory postsynaptic currents (sIPSCs) were evaluated. Wilcoxon signed-rank test (level of significance < 0.05) served as a statistical test and Cohen’s U3_1 was used to determine the actual effect size. Within 20 min, s-ketamine (5 μM) significantly increased both intracortical eEPSPs as well as thalamocortical oEPSPs. NMDA-receptor-mediated intracortical eEPSPs were significantly reduced. Intrinsic neuronal properties of cortical pyramidal neurons from lamina IV and thalamocortical relay neurons in the ventrobasal thalamic complex were not substantially affected. Neither a significant effect on NMDA-receptor-dependent GABAA sIPSCs (thought to underly a disinhibitory effect) nor a reduction of NMDA-receptor independent GABAA sIPSCs was observed. Both thalamocortical and intracortical AMPA-receptor-mediated EPSPs were significantly increased.In conclusion, our findings show no evidence for a NMDA-receptor antagonism-based disinhibition, but rather suggest an enhanced thalamocortical and intracortical synaptic transmission, which appears to be driven via increased AMPA-receptor-mediated transmission.
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