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Anesthesiology:
doi: 10.1097/ALN.0b013e31818d4964
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Xenon and the Pharmacology of Fear

Hemmings, Hugh C. Jr M.D., Ph.D.*; Mantz, Jean M.D., Ph.D.†

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THERE is currently keen interest in the unique anesthetic pharmacology of the gaseous anesthetic xenon, a noble gas with remarkable properties including hemodynamic stability, a favorable pharmacokinetic profile, and organoprotective effects.1 More widespread use of xenon is limited primarily by its low potency and extreme scarcity in Earth's atmosphere that make extraction of commercially viable quantities economically prohibitive. But the mechanisms that lead to this noble element's strange and desirable pharmacologic profile are of obvious interest to anesthesiologists and pharmacologists. The article by Haseneder et al.2 in this issue of Anesthesiology represents a significant step forward in elucidating the molecular mechanisms underlying the anesthetic pharmacology of xenon, particularly those involved in its amnesic actions.
No single anatomic site or molecular mechanism explains the dissociable effects of anesthetics to produce amnesia, unconsciousness, and immobility. Rather, general anesthetics act on specific regions of the central nervous system by agent-specific mechanisms on a relatively few molecular targets to produce the complex pharmacologic interactions recognized as anesthesia.3,4 For intravenous anesthetics such as propofol and etomidate, there is evidence that most of their anesthetic actions can be explained by enhancement of the actions of the transmitter γ-aminobutyric acid (GABA) at the (usually) inhibitory GABAA receptor, a chloride-conducting ion channel that mediates both fast synaptic and tonic inhibition in the nervous system. For the inhaled anesthetics, the picture is not nearly so clear, but mechanisms involved in xenon anesthesia are now coming into clearer focus.
Because, like propofol and etomidate, most inhaled anesthetics markedly potentiate GABAA receptor function, initial studies focused on the effects of xenon on this putative anesthetic target. Studies with heterologously expressed GABAA receptors in nonneuronal cells suggested that xenon had a potentiating effect; however, the absence of xenon's effects on GABAergic transmission in cultured hippocampal neurons cast doubt on this possibility.1 These disparate results obtained using recombinant receptors expressed in nonneuronal cells versus native receptors in cultured neurons illustrate the importance of the cellular environment to receptor pharmacology, and led Haseneder et al. to probe the actions of xenon at a higher level of neuronal organization, the acute brain slice preparation. Brain slices preserve synaptic connections and allow a more integrated assessment of drug effects on native receptors under more physiologic conditions. This provides a useful tool in integrating results obtained with more reductionist studies of isolated receptors, the value of which is clearly illustrated by this study.
The authors chose to study xenon effects in the basolateral nucleus of the amygdala, a brain region that has been implicated in anesthetic-induced amnesia, the formation of aversive memories, and addictive behavior.5,6 The amygdala is an almond-shaped complex in the medial temporal lobe that is critical to a range of cognitive functions, including emotion, learning, memory, attention, and perception. The amygdala plays a particularly important role in negative emotions such as fear, and links these emotions with learning and memory by enhancing memories laid down under fearful conditions as demonstrated in the fear conditioning paradigm.7 Therefore, studies of anesthetic actions in the amygdala are highly relevant to anesthesiologists because our patients enter the operating room with fear that they will either never wake up after anesthesia or will wake up too soon during surgery, a fear justified by the rare but real occurrence of intraoperative awareness that is frequently emphasized in the popular media.8
The effects of xenon on synaptic transmission were analyzed using state-of-the-art patch clamp recordings of basolateral amygdala principal neurons identified by videomicroscopy and stimulated either electrically or with focal laser-induced photolysis of caged glutamate to isolate postsynaptic mechanisms. Currents mediated by N-methyl-d-aspartate (NMDA)–type or α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA)–type glutamate receptors or by GABAA receptors were isolated pharmacologically using selective antagonists. By this elegant approach, Haseneder et al. were able to show that xenon reversibly reduces excitatory glutamatergic transmission by blocking both NMDA- and AMPA-type receptor–mediated transmission roughly equipotently via a postsynaptic mechanism with no apparent presynaptic effect on glutamate release (because the frequency of miniature excitatory postsynaptic currents was not depressed). This occurs at concentrations of xenon relevant to clinical anesthesia, although the limited potency of xenon precludes accurate determination of concentration–effect relations. They also confirmed that, in contrast to most intravenous and other inhaled anesthetics, xenon has no significant effect on GABAA receptor–mediated inhibitory transmission in a slice preparation. This work solidifies the prominent inhibitory effects of xenon on glutamatergic transmission involving NMDA receptor blockade,9–11 and provides additional support for AMPA receptor–mediated effects,12,13 in a brain region intimately involved in amnesia. The gaseous anesthetic nitrous oxide also blocks NMDA receptors in the amygdala but is distinct in also blocking glutamate release presynaptically and in having no effect on AMPA receptor–mediated responses.14 These differences are no laughing matter, and could well explain the potentially greater neuroprotective properties of xenon compared with the more neurotoxic properties of nitrous oxide observed in neonatal rodents.15
The amygdala is important for the recognition of negative emotions such as fear, and neurons in the lateral amygdala encode aversive memories during fear conditioning. Interestingly, the cellular correlate of this is a form of synaptic plasticity known as long-term potentiation that is mediated by both NMDA and AMPA receptor mechanisms.16 This elegant demonstration that xenon blocks both glutamate receptor subtypes in the amygdala provides an appealing mechanism for these potentially memory-ablating effects.
Hugh C. Hemmings, Jr., M.D., Ph.D.,*
Jean Mantz, M.D., Ph.D.†
*Departments of Anesthesiology and Pharmacology, Weill Cornell Medical College, New York, New York. hchemmi@med.cornell.edu. †Department of Anesthesia and Critical Care, Beaujon University Hospital, Clichy, France.
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References

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2. Haseneder R, Kratzer S, Kochs E, Eckle V-S, Zieglgänsberger W, Rammes G: Xenon reduces N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated synaptic transmission in the amygdala. Anesthesiology 2008; 109:998–1006

3. Rudolph U, Antkowiak B: Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 2004; 5:709–20

4. Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL: Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 2005; 26:503–10

5. Alkire MT, Nathan SV: Does the amygdala mediate anesthetic-induced amnesia? Basolateral amygdala lesions block sevoflurane-induced amnesia. Anesthesiology 2005; 102:754–60

6. Alkire MT, Gruver R, Miller J, McReynolds JR, Hahn EL, Cahill L: Neuroimaging analysis of an anesthetic gas that blocks human emotional memory. Proc Natl Acad Sci U S A 2008; 105:1722–7

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8. Orser BA, Mazer CD, Baker AJ: Awareness during anesthesia. CMAJ 2008; 178:185–8

9. Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR: How does xenon produce anaesthesia? Nature 1998; 396:324

10. De Sousa S, Dickinson R, Lieb WR, Franks NP: Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon. Anesthesiology 2000; 92:1055–66

11. Dickinson R, Peterson BK, Banks P, Simillis C, Martin JC, Valenzuela CA, Maze M, Franks NP: Competitive inhibition at the glycine site of the N-methyl-d-aspartate receptor by the anesthetics xenon and isoflurane: Evidence from molecular modeling and electrophysiology. Anesthesiology 2007; 107:756–67

12. Preckel B, Weber NC, Sanders RD, Maze M, Schlack W: Molecular mechanisms transducing the anesthetic, analgesic, and organ-protective actions of xenon. Anesthesiology 2006; 105:187–97

13. Plested AJ, Wildman SS, Lieb WR, Franks NP: Determinants of the sensitivity of AMPA receptors to xenon. Anesthesiology 2004; 100:347–58

14. Ranft A, Kurz J, Becker K, Dodt HU, Zieglgänsberger W, Rammes G, Kochs E, Eder M: Nitrous oxide (N2O) pre- and postsynaptically attenuates NMDA receptor-mediated neurotransmission in the amygdala. Neuropharmacology 2007; 52:716–23

15. Ma D, Williamson P, Januszewski A, Nogaro MC, Hossain M, Ong LP, Shu Y, Franks NP, Maze M: Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology 2007; 106:746–53

16. Fanselow MS, Poulos AM: The neuroscience of mammalian associative learning. Annu Rev Psychol 2005; 56:207–34

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