Abstract
Propofol is a widely used intravenous sedative-hypnotic agent, which causes rapid and reliable loss of consciousness via activation of γ -aminobutyric acid A (GABAA) receptors. We previously found that propofol inhibited cerebellar Purkinje cells (PC) activity via both GABAA and glycine receptors in vivo in mice. We here examined the effect of propofol on the cerebellar parallel fiber (PF)-PC synaptic transmission in mouse cerebellar slices by whole-cell recording technique and pharmacological methods. We found that following blockade of GABAA and glycine receptors activity, propofol reversely decreased the amplitude of PF-PC excitatory postsynaptic currents (PF-PC EPSCs), and significantly increased paired-pulse ratio (PPR). The propofol-induced decrease in amplitude of PF-PC EPSCs was concentration-dependent. The half-inhibitory concentration (IC50) of propofol for inhibiting PF-PC EPSCs was 4.7 μM. Notably, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by GABAB receptor antagonist, saclofen (10 μM), but not blocked by N-methyl-D-aspartate receptor (NMDA) receptor antagonist, D-APV (50 μM). Application of the GABAB receptor agonist baclofen induced a decrease in amplitude and an increase in PPR of PF-PC EPSCs, as well masked the propofol-induced changes in PF-PC EPSCs. Moreover, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by a specific protein kinase A (PKA) inhibitor, KT5720. These results indicate that application of propofol facilitates presynaptic GABAB receptors, resulting in a depression of PF-PC synaptic transmission via PKA signaling pathway in mouse cerebellar cortex. The results suggest that the interaction with GABAB receptors may contribute to the general anesthetic action of propofol.
Highlights
Propofol, an emulsion formulation of 2,6-diisopropylphenol, which is a rapid-acting sedative-hypnotic medication, has been widely used for the induction and maintenance of anesthesia
In the presence of KT5720 and propofol, the mean amplitude of N1 was 84.9 ± 9.35 pA, which was no significant difference than that in control conditions (86.1 ± 9.8 pA; P = 0.71; n = 5) (Figure 6C), and the mean paired-pulse ratio (PPR) value was 1.8 ± 0.15, which was similar to control conditions (1.9 ± 0.13-fold; P = 0.63; n = 5) (Figure 6D). These results indicate that inhibition of protein kinase A (PKA) abolishes the effects of propofol on amplitude and PPR of parallel fiber (PF)-Purkinje cells (PC) EPSCs, suggesting that propofol-induced depression of PF-PC EPSCs through activation of presynaptic GABAB receptors and PKA signaling in the absence of GABAA and glycine receptors activity
The propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by blockade of GABAB receptors activity, as well by inhibition of PKA signaling pathway
Summary
An emulsion formulation of 2,6-diisopropylphenol, which is a rapid-acting sedative-hypnotic medication, has been widely used for the induction and maintenance of anesthesia. The electrophysiological studies demonstrated that propofol significantly increased GABA-mediated inhibitory transmission in rat olfactory cortex slices (Collins, 1988), and reversibly enhanced the amplitude of GABA-evoked Cl− currents in rat cortical neurons (Hales and Lambert, 1991). Extracellular administration of propofol evoked inward Cl− currents in acutely dissociated hippocampal pyramidal neurons and depressed rat spinal cords neuronal activity through activation of GABAA receptors activity (Jewett et al, 1992; Hara et al, 1994; Grasshoff and Antkowiak, 2004). The hypnotic effects of propofol are primarily attributed to the enhancement of GABAA receptor function by extending GABAA channels open times (Kitamura et al, 2004) and slowing desensitization (Bai et al, 1999, 2001). Propofol decreased the facial stimulation-evoked spike firing activity of molecular layer interneurons through enhancement of GABAA receptors activity (He et al, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
