The N-methyl-D-aspartate receptor (NMDAR) is one of the principal targets of glutamate, the most abundant excitatory neurotransmitter of the CNS. The NMDAR is reportedly responsible for the anesthetic actions of agents such as ketamine and nitrous oxide (Akeju et al., 2016), and in the propagation of CNS injury (Hansen et al., 2017).

The vast majority of electrophysiology experiments within the review identified that xenon exposure reduced the ionic current through the NMDAR when the receptor was activated by either pharmacological or electrical methods. Reduced ionic current was identified in all models of neurons including murine cell cultures, transfected cells, single bouton preparations and tissue slices.

In one study of the ventral spinal cord, xenon did not alter ionic current through the NMDAR (Yamamoto et al., 2012). This study reported the effect of xenon on electrically and pharmacologically evoked excitatory postsynaptic currents (EPSC) in lamina IX neurons in a tissue slice preparation of rat lumbosacral spinal cord. Xenon at 50% did not affect the electrically evoked response, and xenon at 50 or 75% did not affect the pharmacologically evoked response.

Two other studies investigated the effects of xenon in tissue slice preparations of dorsal murine spinal cord neurons. One study measured amplitude and area of EPSC evoked by the application of NMDA (Georgiev et al., 2010) and the other measured relative amplitude of the EPSC evoked by both pharmacological and electrical activation (Haseneder et al., 2009a). Both studies identified a reduction in current amplitude to around 60% of control responses.

Whilst variable responses to xenon at different anatomical sites within the spinal cord were reported, the results of tissue slice studies of the brain were more uniform. Studies of the amygdala, prefrontal cortex, hippocampus, and cortico-striatal pathways all identified reductions in ionic current through NMDAR in the presence of xenon (Haseneder et al., 2008, 2009a,b; Kratzer et al., 2012; Baufreton et al., 2018).

One study (Dickinson et al., 2007) performed a direct comparison of the effect of xenon on ionic current through NR1-NR2A and NR1-NR2B receptors and identified no significant difference in xenon inhibition between them. Another study reported that xenon exposure resulted in inhibition of NMDAR assembled with each of the four NR2 subtypes (NR2A-D) (Weigt et al., 2008).

One study investigated the effect of varying concentrations (5 to 65%) of xenon on electrically and pharmacologically evoked EPSC in murine basolateral amygdala (Haseneder et al., 2008). The reduction in current amplitude was dose dependent and concentrations as low as 18% resulted in a statistically significant reduction in current amplitude. Xenon at 5% did not produce a significant reduction in current. Using similar methodology, the same authors also identified a greater reduction in evoked EPSC in murine prefrontal cortex cells in the presence of 65% xenon when compared to 30% xenon (Haseneder et al., 2009a).

Interestingly, both papers reported no statistical difference in the reductions in current amplitude evoked by pharmacological or electrical means. From this, the authors concluded that xenon's ability to inhibit NMDAR ionic current is likely a postsynaptic phenomenon since their model of photolytic release of caged L-glutamate was designed for specific activation of postsynaptic receptors (Haseneder et al., 2008, 2009a).

The effect of concentration was also investigated in a neuronal/glial co-culture (David et al., 2003). The authors utilized video fluoromicroscopy to measure calcium influx stimulated by varying concentrations of NMDA, in the presence and absence of 50 and 75% xenon. Whilst 50% xenon significantly reduced calcium influx at all concentrations of NMDA, 75% xenon had a “bivalent” effect, reducing influx at concentrations below 25 μM NMDA but potentiating the increase at 50–100 μM.

This “bivalent” effect is in contrast to the electrophysiology literature in which studies at this concentration, and above, all reported significant reductions in ionic current (Dickinson et al., 2007; Weigt et al., 2008, 2009a; Armstrong et al., 2012). Two studies that delivered xenon in a lipid emulsion also suggest that inhibition of NMDAR is dose-dependent (Weigt et al., 2003, 2009b).

Activation of the NMDAR requires a number of conditions which include the binding of both glutamate and glycine (Furukawa et al., 2005). The relationship between glycine concentration and xenon's effect on NMDAR ionic current was investigated by two studies. In both studies, the ability of xenon to reduce ionic current was competitive with, and inversely proportional to, glycine concentration (Dickinson et al., 2007; Armstrong et al., 2012). The effect of 70% xenon on whole cell currents measured at differing concentrations of NMDA reported that xenon non-competitively inhibited ionic current, as the EC50 in the presence and absence of xenon was not significantly different (Nonaka et al., 2019; Kubota et al., 2020).

Several authors explored the effect of point mutations of the NMDAR on xenon inhibition. Two of these studies identified point mutations in the NR1 subunit that reduced xenon inhibition (Ogata et al., 2006; Dickinson et al., 2007). Both mutations were found to increase glycine affinity for the receptor, supporting the hypothesis that xenon's effect is related to competition with glycine. A third study identified NR1 point mutations of the glycine binding site that resulted in reduced xenon inhibition without affecting glycine affinity (Armstrong et al., 2012).

One study investigated the effect of point mutations that altered desensitization of NMDAR (Weigt et al., 2009a). Mutations which greatly diminished or accelerated NMDAR desensitization had no effect on the ability of xenon to inhibit ionic current when compared to wild type NMDAR.

In an attempt to differentiate the action of xenon from open-channel blockers such as magnesium and MK-801, one study (Weigt et al., 2008) identified a point mutation that, after pharmacological manipulation, maintained the NMDAR in a constitutively open state. The authors reported that xenon did not alter the ionic current through such a channel, whilst magnesium and MK-801 maintained their ability to inhibit ionic current.

One study ascertained the minimum alveolar concentration (MAC) to prevent movement in male rats in response to electrical stimulation of the tail in the absence and presence of an infusion of an NMDAR antagonist (MK-801) (Eger et al., 2006). The ability of general anesthetic agents to obtund this response is generally attributed to action at the spinal cord level. The authors reported that the MAC of xenon was maximally reduced to around 60%, when compared to control conditions, by an infusion of 32 μg kg⁻¹ min⁻¹ of MK-801. Although no formal statistics were performed comparing the groups, the average reduction for all inhaled anesthetics, including the volatiles isoflurane, sevoflurane, enflurane, and halothane was ~60%.

In tissue slice studies, treatment with 50% xenon significantly reduced injury, in the form of oxygen-glucose deprivation or focal trauma, quantified by propidium iodide fluorescence. In all three studies, the co-application of glycine with xenon resulted in an injury that was comparable with untreated controls (Banks et al., 2010; Harris et al., 2013; Koziakova et al., 2019).

In a study of cortical cell cultures, low-level excitotoxicity was modeled by applying pyrrolidine-2,4-dicarboxylate (PDC), a glutamate transport inhibitor, to the culture for four days (Lavaur et al., 2016). Cultures housed in a gas chamber containing 75% xenon (balanced with oxygen), during this period had a greater rate of survival than those housed with 75% nitrogen (balanced with oxygen). Interestingly, in this study, the addition of glycine did not alter the survival rate of neurons when compared to the xenon only treatment group.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is an ionotropic glutamate receptor responsible for fast excitatory transmission in the CNS. AMPAR activation also facilitates the activation of NMDAR (Bissen et al., 2019).

In all studies of native cell culture, single bouton and tissue slice preparation, xenon was found to reduce ionic current through AMPAR when compared to control conditions. In these studies, the concentration of xenon ranged from 30 to 84%. Three studies reported the EC50 of agonist in the presence and absence of xenon (Dinse et al., 2005; Nonaka et al., 2019; Kubota et al., 2020). Each reported no statistically significant change in EC50 and concluded that the nature of antagonism was non-competitive.

Xenon reduced AMPA ionic current in single bouton preparations from both the hippocampus and spinal cord dorsal commissural nucleus (Nonaka et al., 2019; Kubota et al., 2020). A reduction in ionic current was also consistent across tissue slice preparations from prefrontal cortex (Haseneder et al., 2009a), amygdala (Haseneder et al., 2008), and lumbosacral dorsal and ventral spinal cord (Haseneder et al., 2009a; Yamamoto et al., 2012).

In one study xenon was applied to a lumbosacral spinal cord segment in vivo following laminectomy under urethane anesthesia (Georgiev et al., 2010). The current responses to noxious and non-noxious limb stimuli at the dorsal horn were measured using a voltage clamp technique in the presence of pharmacological NMDAR blockade. The EPSC associated with both touch and pinch stimulation were significantly reduced on exposure of the lumbosacral segment to 50% xenon.

Two studies compared the effect of two different concentrations of xenon. One study identified a greater reduction in ionic current in the prefrontal cortex in the presence of 65% xenon when compared to 30% xenon (Haseneder et al., 2009a). In the other study, of ventral spinal cord neurons, the authors identified a similar significant reduction in ionic current in the presence of 50 and 75% xenon, although no formal comparison of the two concentrations was performed (Yamamoto et al., 2012).

One study also investigated miniature EPSC and the paired pulse ratio in the presence of NMDA blockade in both substantial gelatinosa and prefrontal cortex tissue slices (Haseneder et al., 2009a). Whilst miniature EPSC were reduced in amplitude, the frequency was unchanged in the presence of xenon. The authors also reported no change in paired pulse ratio in the presence of xenon. The authors concluded that these findings, in conjunction with the similar results obtained from pharmacological and electrical stimulation in their experiments, suggest that xenon's action at AMPAR is likely postsynaptic in nature (Haseneder et al., 2009a).

The effect of xenon on AMPAR of differing subunit composition was investigated in transfected cell studies. One study identified significant reductions in ionic current through homomeric GluR1, GLuR3 and GLuR4 AMPAR in response to kainite and glutamate in the presence of desensitization blockade (Plested et al., 2004). However, for heteromeric subtypes the authors identified that only the GluR1-GluR2 subtype was sensitive to xenon. The authors also reported that in a rapid glutamate application system, designed to imitate synaptic conditions, homomeric GluR1 and GluR4 subtypes were relatively insensitive to xenon (Plested et al., 2004).

The effect of point mutations that reduced AMPAR desensitization was reported by two studies (Plested et al., 2004; Weigt et al., 2009a). One study examined the effect of point mutations which reduced AMPAR desensitization in both GluR1 and GluR2 homomeric receptors. The authors reported that the ability of xenon to inhibit ionic current in these AMPAR was significantly reduced, hypothesizing that the sensitivity of AMPAR to xenon is associated with receptor desensitization. This is consistent with an earlier study which identified a non-desensitizing mutant of AMPAR which was also insensitive to xenon (Plested et al., 2004).

Kainate receptors (KAR) are a key facilitator of synaptic transmission capable of both inhibition and facilitation of excitatory and inhibitory transmission (Contractor et al., 2011). KAR activation is also implicated in glutamate-induced neurotoxicity (Srivastava et al., 2020).

In three studies of native cells, from cortex, hippocampus and spinal cord, 70 and 84% xenon reduced ionic current in response to bath application of kainate when compared to control conditions (Dinse et al., 2005; Nonaka et al., 2019; Kubota et al., 2020). One study reported that the magnitude of this reduction was 42% at the control EC50 of kainate. Two of the studies determined that the nature of the blockade was non-competitive (Dinse et al., 2005; Nonaka et al., 2019), whilst the third was inconclusive (Kubota et al., 2020).

It is well recognized that application of kainate activates AMPAR in addition to kainate-specific receptors (Plested et al., 2004; Dinse et al., 2005). To address this potential confounder, one study utilized a transfected cell line expressing the murine GLuR6 receptor which is specific in its sensitivity to kainate. They reported a reduction in ionic current in response to 84% xenon with no change in the EC50 of kainate, suggesting non-competitive blockade.

One study described the effect of xenon on the EPSC recorded in murine autaptic hippocampal neurones (de Sousa et al., 2000). The authors reported a number of features of the EPSC in the presence and absence of xenon including the current peak, total charge transfer and the “slow” and “fast” components of the EPSC. They reported that whilst the peak, total charge transfer and “slow” component were significantly reduced in the presence of xenon, the “fast” component remained unchanged. This led the authors to conclude that the observed effects were likely due to inhibition of NMDAR, rather than AMPAR. This contrasts with multiple subsequent studies discussed in Section 4.1.1.2 that characterized the subtypes of glutamate receptor by utilizing channel specific transfection of cells and pharmacological isolation of NMDAR and AMPAR ionic currents.

Several studies reported outcomes such as miniature EPSC and spontaneous EPSC, and the failure rate and paired pulse ratio of evoked potentials. The study designs and outcomes of these studies were intended to identify if xenon's actions at glutamatergic synapses can be considered presynaptic, postsynaptic or a combination of both.

Three studies investigated the effect of xenon on miniature EPSC in tissue slices of basolateral amygdala as well as the dorsal and ventral spinal cord (Haseneder et al., 2008; Georgiev et al., 2010; Yamamoto et al., 2012). Each study was performed in the presence of tetrodotoxin, to block sodium channels and prevent action potential related release of neurotransmitter, and the concentration of xenon in these studies was either 50 or 65%. Each of these three studies reported that in the presence of xenon the amplitude of miniature EPSC was reduced whilst the frequency remained unchanged. These studies suggest that xenon acts predominantly at the postsynaptic terminal. A fourth study reported similar findings in conditions in which AMPAR miniature EPSC were pharmacologically isolated (Haseneder et al., 2009a).

One study investigated the effect of xenon on miniature EPSC in hippocampal CA3 neurones utilizing the single bouton technique (Nonaka et al., 2019). In contrast with the results from tissue slice studies, this study reported that xenon at a concentration of 70% significantly reduced the frequency of miniature EPSC whilst the amplitude remained unchanged. This study also reported the effect of xenon on amplitude and frequency of spontaneous EPSC. The authors reported that xenon at 30 and 70% reduced frequency but not amplitude of spontaneous EPSC, consistent with a presynaptic mechanism of action.

In a single bouton preparation of sacral dorsal commissural neurones, another study reported that 70% xenon reduced both the frequency and amplitude of spontaneous EPSC (Kubota et al., 2020). Both studies of the single bouton preparation also reported the effects of xenon on a paired pulse electrical stimulus (Nonaka et al., 2019; Kubota et al., 2020). The studies reported that xenon increased the failure rate and increased the paired pulse ratio of evoked EPSC, suggesting the involvement of presynaptic mechanisms.

The most abundant inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA) and the GABA-A receptor (GABAR) is the target of the majority of commercially developed general anesthetic agents, with the notable exception of ketamine and nitrous oxide. Activation of the GABA-B receptor can also influence neuronal excitability but is not thought to contribute significantly to the anesthetic action of conventional anesthetics (Brohan and Goudra, 2017). There were no studies identified that reported results for the GABA-B receptor.

In a study of autaptic cultured hippocampal cells, the authors reported that 80% xenon did not alter the peak, total current or inhibitory current dynamics observed following electrical stimulation of inhibitory neurons when compared to control (de Sousa et al., 2000). The authors also reported that the current observed following bath application of GABA 3μM was also unaffected by xenon.

Three studies have investigated the effects of xenon on murine GABAR in transfected cell lines with somewhat conflicting results. All three studies investigated the α1, β2, γ2 subunit composition in either HEK 293 or xenopus oocytes. One study reported that a solution saturated with xenon at room temperature increased ionic current evoked by bath application of GABA (Hapfelmeier et al., 2000). They noted that the potentiation was only present at lower doses of GABA (10⁻⁷-10⁻⁵ M) and that no potentiation was seen at higher doses. Another study also reported that 46% xenon significantly potentiated currents measured following bath application of GABA (at a concentration of EC5 of maximal response) (Yamakura and Harris, 2000). In contrast, another study reported that 80% xenon had no effect on the current induced by bath application of 10μM GABA (10⁻⁵ M) (Gruss et al., 2004).

Four subsequent studies have investigated the effect of xenon on ionic current through GABAR in murine tissue slices (Haseneder et al., 2008, 2009a; Georgiev et al., 2010; Yamamoto et al., 2012). These studies were performed in both brain (prefrontal cortex, basolateral amygdala) and spinal cord slices (dorsal and ventral horn) and xenon concentration was between 50 and 65%. Currents were evoked either by electrical stimulation or application of GABA, in concentrations of 0.5–1 mM. All four studies reported that xenon did not affect peak or total charge transfer through GABAR. Two of these studies also reported the effect of xenon on miniature inhibitory postsynaptic currents (IPSC), in the presence of tetrodotoxin, and reported that 50% xenon had no effect on either the amplitude or frequency of miniature IPSC (Georgiev et al., 2010; Yamamoto et al., 2012).

Two studies have utilized the single bouton preparation, from hippocampal CA3 neurons and neurons of the sacral dorsal commissural nucleus, to investigate the effect of xenon on ionic current through GABAR (Nonaka et al., 2019; Kubota et al., 2020). In both studies, 70% xenon had no effect on the current induced by bath application of 10⁻⁵ M of GABA. Both studies investigated the effects of 70% xenon on spontaneous IPSC and both reported that xenon reduced the frequency, but not the amplitude of spontaneous IPSC. Both studies also reported that xenon increased the failure rate and paired pulse ratio of currents induced by paired pulse electrical activation, suggesting a presynaptic site of action.

Glycine receptor activation leads to neuronal hyperpolarization and inhibitory glycine function is critical to many physiological processes including control of muscle tone and sensory processing. The glycine receptor is also modulated by several conventional anesthetics and ethanol (Burgos et al., 2016).

In two cell transfection studies, xenon in concentrations from 40 to 70% were reported to increase ionic current through glycine receptors in response to bath application of glycine when compared to control conditions (Daniels and Roberts, 1998; Yamakura and Harris, 2000). One study reported the effect of a number of volatile anesthetics as well as nitrous oxide. At clinically relevant concentrations they reported that xenon potentiated glycine receptors by 50% whilst volatiles potentiated the response by 200% and nitrous oxide by 75%.

In contrast, two studies of spinal cord slices suggest xenon has negligible effect on glycine receptors. In an in vitro spinal cord tissue slice, 50% xenon did not affect the ionic current evoked in lamina IX neurons by bath application of 0.5 mM of glycine (Yamamoto et al., 2012). In an in vivo model, the ionic current measured in substantia gelatinosa neurons, activated following bath application of 1 mM of glycine to the lumbosacral spinal cord in an anesthetized rat model, was not affected by the presence or absence of 50% xenon (Georgiev et al., 2010).

Several general anesthetic agents interact with the nicotinic acetylcholine receptor (nAChR), although to date there is animal data to suggest these interactions are essential to their anesthetic action (Chau, 2010). Activation of nAChR leads to inward flux of positive charge, mainly sodium, and depolarization of the cell.

The ability of xenon to interact with nAChR was investigated in two studies. Both were performed in xenopus oocytes transfected with different receptor subtypes, the heteromeric α4β2 and the homomeric α7 (Yamakura and Harris, 2000; Suzuki et al., 2002). Both studies reported a significant reduction in ionic current on exposure to xenon. The reduction was dose dependent in the study of the homomeric α7 subtype.

One study of xenopus oocytes transfected with human 5-hydroxytryptamine 3A (5HT3A) receptors reported that xenon inhibited ionic current in a competitive, dose dependent manner, with ionic current reduced in response to 5-hydroxytryptamine agonist to around 50% and around 20% of control response, in the presence of 30 and 70% xenon, respectively (Suzuki et al., 2002).

The review identified five studies investigating the interaction of xenon with membrane bound potassium channels. The classes of potassium channels investigated included two pore domain potassium channels (P2K), ATP sensitive potassium channels (KATP) and hyperpolarization-activated cyclic nucleotide gated channels (HCN).

Two studies reported that 80% xenon increased ionic current through the human TREK-1 channel expressed in HEK293 cells when compared to control conditions (Gruss et al., 2004; Harris et al., 2013). One study reported that this potentiation of ionic current was significantly reduced in TREK-1 channels in which the C-terminus was truncated (Gruss et al., 2004). Another study reported that xenon was the only gas to exhibit such an effect among several noble gases investigated (Harris et al., 2013). One study also investigated the effects of xenon on TASK-3, a P2K known to be sensitive to volatile anesthetic agents (Gruss et al., 2004). The authors reported that 80% xenon had no effect on ionic current in continuous recordings, or in response to a voltage ramp.

Two studies investigated the effects of xenon on KATP channels (Bantel et al., 2009, 2010). Both studies, from the same authors, were conducted utilizing HEK293 cells transfected with murine subunits of the KATP receptor. Both studies reported that 80% xenon increased current activation of the Kir6.2-SUR1 channel. In contrast, of the volatile agents investigated, including sevoflurane, isoflurane and halothane, all inhibited KATP current activation (Bantel et al., 2009).

The effects of 50% xenon were also reported in the first study. Xenon at this concentration also increased ionic current but the increase was not statistically significant (Bantel et al., 2009). The differential effects of xenon at cell surface and mitochondrial KATP channels was also clarified in this study by the use of specific inhibitors, and the authors reported that xenon's potentiation was specific for plasmalemmal KATP channels (Bantel et al., 2009).

In the second study, the authors reported that xenon potentiation was unchanged in a Kir6.2 mutant that forms active channels in the absence of the SUR1 subunit, suggesting that xenon's effect is due to interaction with the Kir6.2 subunit (Bantel et al., 2010). The authors also investigated the effect of xenon on Kir1.1, an inwardly rectifying potassium channel, and reported that xenon did not alter ionic current through this channel (Bantel et al., 2010).

One study utilized a murine derived neuronal and glial cell culture to investigate the effect of xenon preconditioning on cell viability following an oxygen and glucose deprivation injury (Bantel et al., 2009). The authors reported that cell viability measured 24 h following the injury was completely reversed in cell cultures exposed to 75% xenon for 2 h prior to injury. The ability of xenon to prevent injury was abolished in the presence of the cell surface KATP inhibitor tolbutamide. The authors reported that the ability of sevoflurane to prevent injury was not significantly different in the presence or absence of tolbutamide, suggesting that KATP is not involved in protection provided by sevoflurane.

One study investigated the effect of xenon on the hyperpolarization-activated cyclic nucleotide gated channel 2 (HCN2) utilizing both HEK293 cells transfected with murine HCN2, and thalamocortical tissue slices from both wild type and HCN2 knock-out mice (Mattusch et al., 2015). HCN2 are voltage sensitive, becoming activated at hyperpolarizing voltages and passing an inward current which favors depolarization (Santoro et al., 2000).

The authors reported that in whole cell patch clamps of thalamocortical neurons, 65% xenon decreased the maximum current amplitude and the voltage required to achieve half maximal activation, i.e., greater hyperpolarization was required to achieve the same ionic current flow. The authors also reported that the effects of xenon were abolished in the presence of high concentrations of cyclic AMP.

The authors also reported the effect of xenon on two important features of post-hyperpolarization HCN2 behavior in thalamocortical neurons, sag amplitude and time to rebound burst. Xenon reduced sag amplitude and increased the time to rebound bursting when compared to control (Mattusch et al., 2015). This effect was also abolished in the presence of a high concentration of cAMP. The effects of xenon on current activation and post-hyperpolarization behavior were duplicated in HEK293 cells transfected with murine HCN2.

Finally, the authors utilized a voltage sensitive dye imaging technique to measure cortical depolarization following activation of thalamocortical neurons. The authors reported that 65% xenon reduced cortical depolarization when compared to control. This effect was not observed in HCN2 knock-out mice, suggesting that HCN2 was responsible for the observed effects of xenon on cortical depolarization (Mattusch et al., 2015).

Given its crucial role in neurotransmitter release, second messenger signaling, and potential as a cellular toxin, the concentration of intracellular calcium is tightly controlled within neurons. Both plasmalemmal calcium ATPase (PMCA) and voltage gated calcium channels (VGCC) have been investigated as potential targets for anesthetic action and neuroprotectants (Yamakage and Namiki, 2002; Kopecky et al., 2014).

The review identified four studies in which the effect of xenon on PMCA was reported. Three of these studies utilized synaptosomes from murine neurons which were exposed to helium or xenon (Franks et al., 1995; Horn et al., 1995; Singh et al., 1995). In these studies, xenon was reported to reduce the activity of PMCA in a dose dependent manner in the range of 0.5–1.5 atm (Singh et al., 1995).

Xenon also increased calcium uptake measured by calcium fluorescence in murine cortical cultures (Franks J. J. et al., 1998). Whilst 20 and 40% xenon in solution had no effect on baseline or evoked calcium uptake, xenon at 60 and 80% significantly reduced calcium uptake at baseline and following NMDA administration.

Xenon at a concentration of 80% had no effect on ionic current flow in response to a depolarizing voltage step protocol when compared to control conditions in HEK293 cells transfected with N-type calcium channels (White et al., 2005). Xenon also had no effect on current transfer in response to depolarizing voltage steps in CA1 pyramidal neurons in the presence of pharmacological isolation of the L-type channel (Kratzer et al., 2012). Finally, 70% xenon had no effect on the barium current (a surrogate for calcium current) in response to depolarization of a sacral dorsal commissural nucleus neuron (Kubota et al., 2020).

The monoamines dopamine and norepinephrine are neurochemical modulators that are important regulators of sleep and wakefulness and have been identified as potential mediators of the anesthetic effect of several commonly utilized anesthetic agents (Purdon et al., 2015).

Two studies investigated dopamine transport in a murine brain slice preparations exposed to xenon and control gases in a recording chamber. In the first study, dopamine release in nucleus accumbens was recorded following amphetamine and potassium chloride stimulation (David et al., 2006). Xenon at 50 and 75% reduced dopamine release in response to amphetamine, whilst 75% xenon increased dopamine release in response to potassium chloride and 50% xenon had no effect.

In the second study, striatal brain slices were exposed to an oxygen-glucose deprivation injury either in the presence of various concentrations of xenon gas (balanced with nitrogen) or nitrogen alone (David et al., 2008). Dopamine release was significantly reduced in slices exposed to xenon ranging from 25 to 75%. Release in the presence of 15% xenon was not significantly different from controls. The response of slices to subsequent exposure to potassium chloride was similar for control and xenon treated slices.

One study investigated the effect of xenon on norepinephrine uptake utilizing two transfected cell lines, HEK293 transfected with human norepinephrine transporter (NET) and SH-SY5Y transfected with both human NET and NMDAR (Neukirchen et al., 2012). Utilizing fluorometric measurement, the authors reported that 65% xenon had no effect on xenon uptake in the HEK293 cell lines expressing only NET. In contrast, xenon increased uptake of NE in the SH-SY5Y expressing both NET and NMDAR. The effect was non-significant for 32.5% xenon, whilst 50 and 65% resulted in significantly reduced uptake. This was confirmed utilizing radiometric analysis.

One study investigated the interaction between xenon and voltage-gated sodium channels in a single bouton preparation of the sacral commissural nucleus of the spinal cord and reported that 70% xenon had no effect on ionic current (Kubota et al., 2020).

Acid sensing ion channels (ASIC) are sodium channels, insensitive to voltage but sensitive to pH changes, that might have a role in regulating neurotransmitter release. In xenopus oocytes transfected with various rat ASIC subtypes, One study reported that xenon reduced the decay time of currents induced by acidic environments for the three ASIC subtypes expressed in the CNS, as well as reducing current amplitude for the ASIC 1α homomeric subtype (Lehmke et al., 2018).

One study investigated the effect of xenon on the transient receptor potential vanilloid 1 (TRPV1) receptor in cultures of murine primary sensory neurons, and in HEK293 cells transfected with human TRPV1. Whilst traditionally associated with the capsaicin evoked response in the peripheral nervous system, TRPV1 is also widely expressed in the CNS (Ho et al., 2012). The authors reported that 75% xenon reduced cobalt uptake, a measure of TRPV1 activation, only at low doses of capsaicin (White et al., 2011).