Etomidate Modulates the Tactile Stimulation-Evoked Field Potential Responses in Cerebellar Granule Cell Layer in vivo in Mice

Abstract

Etomidate (ET) produces sedation by binding on the γ-aminobutyric acid type A (GABAA) receptors. We previously found that ET inhibited cerebellar Purkinje cells activity via both GABAA and glycine receptors in vivo in mice, suggesting that ET modulated sensory information synaptic transmission in cerebellar cortex. In this study, we investigated the effect of ET on the sensory stimulation-evoked responses in the cerebellar granule layer (GL) in urethane-anesthetized mice, using electrophysiological and pharmacological methods. Our results showed that cerebellar surface perfusion of ET (100 μmol/L) significantly decreased amplitude and area under the curve (AUC) of the sensory stimulation-evoked excitatory component (N1) in the cerebellar GL. Application of GABAA receptor antagonist, SR95531 (20 μmol/L) significantly attenuated, but not abolished the ET-induced decrease in amplitude and AUC of facial stimulation-evoked responses. However, application of a mixture of SR95531 (20 μmol/L) and cannabinoid 1 receptor (CB1) antagonist, AM-251 (5 μmol/L), completely blocked the ET-induced decrease in amplitude and AUC of facial stimulation-evoked responses. Furthermore, application of the CB1 receptor agonist, WIN55212-2, induced a decrease in amplitude and AUC of N1 in the absence of GABAA receptors activity, as well occluded the ET-induced depression of N1. Moreover, the ET-induced changes in amplitude and AUC of N1 in absence of GABAA receptors activity were abolished by a specific protein kinase A (PKA) inhibitor, KT5720. These results indicate that ET facilitates CB1 receptors in the absence of GABAA receptors activity, resulting in a depression of the sensory stimulation-evoked synaptic transmission via PKA signaling pathway in mouse cerebellar GL.

Etomidate Depresses Spontaneous Complex Spikes Activity of Cerebellar Purkinje Cells via Cannabinoid 1 Receptor in vivo in Mice

“…It has been reported that etomidate reduced glutamate uptake in rat-cultured glial cells through PKA signaling pathway [31]. Consistent with our previous study [24], etomidateinduced depression of the sensory stimulation-evoked excitatory component in the cerebellar GL through PKA signaling pathway in the absence of GABA A and glycine receptors activity. The present results suggest that etomidate couples to CB1 receptor that induces a depression of adenylyl cyclase-cyclic AMP signal transduction, which might lead to downregulation of proteins phosphorylation on synaptic vesicles in CF-Purkinje cell synapses, resulting in a decrease in glutamate release from CF onto Purkinje cells.…”

“…Previous studies demonstrate that activation of CB1 receptor by etomidate depresses neuronal activity in hippocampus and basolateral amygdale [18] and inhibits the facial stimulation-evoked mossy fiber-granule cell synaptic transmission in mouse cerebellar cortex [24]. Therefore, we used a selective CB1 receptor antagonist, AM-251 (5 μmol/L), to determine whether etomidate-induced inhibition of spontaneous CSs activity of Purkinje cells via activation of CB1 receptor in the absence of GABA A and glycine receptors activity.…”

“…Importantly, numerous evidences show that cerebellar Purkinje cell expresses abundant CB1 receptors, suggesting that etomidate may modulate Purkinje cell activity via activation of CB1 receptors [20–23]. Our previous results show that etomidate facilitates CB1 receptors in the absence of GABA A receptors activity, resulting in a depression of the sensory stimulation-evoked synaptic transmission via PKA signaling pathway in mouse cerebellar granular layer [24]. Our present results showed that etomidate decreased spontaneous CSs activity of Purkinje cells in the absence of GABA A and glycine receptors activity, suggesting that etomidate-depressed CSs activity of Purkinje cells was independent on GABA A and glycine receptors activity.…”

“…Importantly, numerous evidences show that cerebellar Purkinje cell expresses abundant CB1 receptors, suggesting that etomidate may modulate Purkinje cell activity via activation of CB1 receptors [20–23]. Our previous results show that etomidate facilitates CB1 receptors in the absence of GABA A receptors activity, resulting in a depression of the sensory stimulation-evoked synaptic transmission via protein kinase A (PKA) signaling pathway in mouse cerebellar granular layer [24]. Previous studies have demonstrated that etomidate impaired the sensory processing and sensorimotor coordination, slowed the electromotor discharge rhythm via potentiation of GABA A receptors [25], which has been involved in sensory processing and synaptic plasticity during anesthesia [26].…”