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Background: Anesthesia is produced by a depression of central nervous system function, however, the sites and mechanisms of action underlying this depression remain poorly defined. The present study compared and contrasted effects produced by five general anesthetics on synaptic circuitry in the CA1 region of hippocampal slices. Results: At clinically relevant and equi-effective concentrations, presynaptic and postsynaptic anesthetic actions were evident at glutamate-mediated excitatory synapses and at GABA-mediated inhibitory synapses. In addition, depressant effects on membrane excitability were observed for CA1 neuron discharge in response to direct current depolarization. Combined actions at several of these sites contributed to CA1 circuit depression, but the relative degree of effect at each site was different for each anesthetic studied. For example, most of propofol's depressant effect (> 70 %) was reversed with a GABA antagonist, but only a minor portion of isoflurane's depression was reversed (< 20 %). Differences were also apparent on glutamate synapses-pentobarbital depressed transmission by > 50 %, but thiopental by only < 25 %. Conclusions: These results, in as much as they may be relevant to anesthesia, indicate that general anesthetics act at several discrete sites, supporting a multi-site, agent specific theory for anesthetic actions. No single effect site (e.g. GABA synapses) or mechanism of action (e.g. depressed membrane excitability) could account for all of the effects produced for any anesthetic studied. Background of action, towards a detailed view of anesthetic actions at General anesthetics have been shown to depress neuronal membrane receptor and ion channel targets for these responses in virtually all brain areas studied and this agents [18,19]. It is likely that several anesthetic actions depression has been proposed to result from actions at occurring at independent sites contribute in additive ways GABA -mediated inhibitory synapses and postsynaptic to depress neuronal circuits in higher brain structures. chloride channels [1-4], potassium channels [5-7], or cal- Alternatively, anesthetic effects could result from actions cium channels [8-11], and/or at glutamate-mediated exci- at only a few sites and this should become evident by tatory synapses [12-17]. The last decade has seen a major studying overall effects on the CA1 neural circuit and shift in our understanding of general anesthetic mecha- 'chasing down' the underlying actions. In the present nisms of action, away from a non-specific Unitary theory study, the effects produced by five general anesthetics Page 1 of 10 (page number not for citation purposes) BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 were studied at several possible sites of action within the reverse the anesthetic-induced PS depression. Bicuculline well characterized Schaffer-collateral to CA1 neuron cir- (10 µM) reversed anesthetic-induced PS depression to var- cuit using electrophysiological recordings from rat hip- ying degrees for each agent: isoflurane – 16.2 ± 7.4 %, pocampal slices. The CA1 circuit has previously been halothane – 22.3 ± 18.4 %, pentobarbital – 56.2 ± 12.4 %, shown to be depressed by anesthetics from several chem- thiopental – 64.9 ± 12.9 % and propofol – 69.5 ± 14.3 %. ical classes [20-26] at concentrations which alter hippoc- Similar degrees of reversal were observed using the GABA- ampal electrical activity in chronically instrumented rats chloride channel blocker, picrotoxin (100 µM; a supra- during anesthesia [27-29]. The five agents chosen for this maximal blocking concentration). A GABA receptor study are all clinically used anesthetics and provide a good antagonist, CGP 55845A (10 µM) did not reverse PS representation from unique chemical classes: a halocar- depression for any of the anesthetics studied (see Table 1). bon (halothane), halogenated ether (isoflurane), barbitu- None of the anesthetics produced a significant depression rate (pentobarbital), sulfonated-barbiturate (thiopental), of antidromically stimulated PS responses (± 5 % depres- and a newer di-isopropylphenol compound, propofol. sion, p > 0.15) indicating that CA1 neuron axonal con- duction was not appreciably altered. Thus, enhanced -mediated inhibition appeared to play a major role Results and discussion GABA Anesthetics enhance GABA-mediated inhibition for the PS depression produced by propofol and thiopen- All five anesthetics depressed synaptically evoked dis- tal (~ 75 %), less so for pentobarbital (~ 50 %), and con- charge, measured as a block of population spike (PS) tributed only partially to the depressant effects of the responses recorded from CA1 neurons (Fig. 1). The two volatile anesthetics (< 25 %; Fig. 1E). volatile anesthetics, halothane and isoflurane, produced a nearly complete depression (to 3.3 ± 3.5 and 5.6 ± 7.1 % Anesthetics depress glutamate-mediated excitatory of control respectively) at clinically effective concentra- synapses tions: halothane (1.0 rat MAC; 1.25 vol % ~ 250 µM) and To determine whether anesthetic-induced PS depression isoflurane (1.0 rat MAC; 1.55 vol % ~ 350 µM; for resulted from depressed glutamate-mediated excitatory Sprague-Daley rats ; Minimum Alveolar Concentra- synaptic inputs to CA1 neurons, field excitatory postsyn- tion – the expired anesthetic gas concentration for a 50 % aptic potentials (EPSPs) were recorded from dendritic loss of a tail clamp response – motor reflex in rats). The regions in stratum radiatum. All five anesthetics depressed three intravenous agents, pentobarbital (400 µM), thio- EPSP responses (e.g. Fig. 1C and 1D): isoflurane to 52.2 ± pental (80 µM) and propofol (30 µM), also depressed PS 7.6 (p < 0.001), halothane 61.3 ± 8.4 (p < 0.001), pento- responses to a comparable degree: 1.7 ± 3.1, 3.4 ± 2.8 and barbital 54.5 ± 4.8 (p < 0.001), thiopental 75.5 ± 9.8 (p < 6.2 ± 5.8 % of control responses, respectively (p < 0.001, 0.01) and propofol 72.7 ± 23.5 (p < 0.05) % of control n ≥ 5 slices from individual rats, for all five agents com- responses. Bicuculline did not reverse volatile anesthetic- pared with pre-anesthetic control responses, using induced EPSP depression, but did partially reverse the ANOVA-Tukey). All anesthetic effects were reversible on effect for pentobarbital (11.4 ± 3.6 %) and completely washout of the agent with drug free ACSF. It should be reversed the EPSP depression produced by thiopental and noted that the more lipophilic intravenous anesthetics propofol (Fig. 1F). Thus, depressed glutamate-mediated produce lower effect site concentrations in these brain synaptic excitation appeared to play an important role for slices than the applied concentrations shown, especially PS depression produced by isoflurane, halothane and for these short time periods of application, because it can pentobarbital. The thiopental and propofol-induced EPSP take several hours for these agents to diffuse 200 to 300 depression would also contribute to PS depression for µm into brain slices and achieve steady-state levels . these agents, but appeared to occur via enhanced GABA- For example, an applied concentration of 30 µM propofol mediated inhibition at a dendritic level, since this depres- would be expected to produce only ~ 1.0 to 3.0 µM at a sion was reversed by bicuculline. recording depth of 250 microns within 30 minutes . The volatile anesthetics, in contrast, rapidly equilibrate Pre- and postsynaptic sites of action at GABA synapses throughout the brain slice due to their relatively high Whole cell voltage clamp recordings from CA1 neurons aqueous solubility. were used to examine more closely anesthetic effects on membrane currents at GABA synapses. Spontaneous These equi-effective applied concentrations for PS depres- GABA-mediated inhibitory postsynaptic currents (IPSCs) sion were used in subsequent experiments to determine were observed in all CA1 neurons studied (n = 15) and whether this depression resulted from enhanced GABA - were completely blocked by bicuculline (10 µM; Fig. 2A). mediated inhibition. In the presence of glutamate receptor antagonists (CNQX 17.2 µM and APV 100 µM) the anesthetics produced A GABA receptor antagonist, bicuculline, was applied in agent-specific effects on holding currents needed to clamp the continued presence of each anesthetic to attempt to neurons at the control resting membrane potentials (-60 Page 2 of 10 (page number not for citation purposes) BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 AB CONTROL HALOTHANE (1 MAC) OVERLAY CONTROL PROPOFOL (30 µM) PROPOFOL (30 µM) 10 min 30 min 4.0 mV 4.0 mV 25 ms 25 ms HALOTHANE (1 MAC) PROPOFOL (30 µM) 120 120 BIC (10 µM) 80 BIC (10 µM) 80 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 70 CD CONTROL HALOTHANE (1 MAC) OVERLAY CONTROL PROPOFOL (30 µM) PROPOFOL + BIC 0.5 mV 0.5 mV 25 ms 25 ms PROPOFOL (30 µM) HALOTHANE (1 MAC) BIC (10 µM) BIC (10 µM) 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 TIME (MINUTES) TIME (MINUTES) EF POPULATION SPIKE GLUTAMATE-MEDIATED EPSP DEPRESSION 60 BIC RECOVERY 0 0 ISO HAL PEN THIO PRO ISO HAL PEN THIO PRO Anestheti Figure 1 c-induced depression of CA1 neuron responses involve actions at both glutamate and GABA-mediated synapses Anesthetic-induced depression of CA1 neuron responses involve actions at both glutamate and GABA-mediated synapses. (A) Halothane depressed population spike (PS) responses at clinically relevant concentrations (1 rat MAC = 1.2 vol % ~ 250 µM) and this depression was only partially reversed using a GABA receptor antagonist, bicuculline (BIC). (B) Propofol (30 µM) produced a comparable degree of population spike depression compared to halothane, but this depression was substantially reversed with BIC, indicating that enhanced GABA-mediated inhibition contributes > 75 % of the depressant effect of propofol. The representative recordings shown are for propofol effects at 10 minutes following exposure to anesthetic (i.e. at 30 min on the x axis for the grouped data) and after 30 minutes of exposure, when a nearly complete block of the population spike was apparent. (C) Excitatory postsynaptic potentials (EPSP) were also depressed by halothane and this effect was not reversed by BIC, indicating a direct effect of the anesthetic on glutamate-mediated synapses. (D) Propofol-induced depression of glutamate- mediated EPSPs, in contrast, appeared to involve enhanced GABA-mediated inhibition, since this depression was completely reversed by BIC. The two anesthetics exhibited quite different sensitivities to reversal by BIC, indicating that actions at GABA synapses vary for these agents. For each graph, data were normalized and each point represents the mean ± SD for at least five measures from different slices made from separate animals. Horizontal bars indicate the time of exposure to each drug. Sample recordings from representative experiments are shown in the top traces. (E) BIC reversal of anesthetic-induced population spike depression was agent specific for equieffective levels of depression, and data are summarized for four anesthetics as bar graphs. Shaded bars represent the degree of depression produced by each anesthetic and open bars show the extent of reversal produced by BIC, error bars indicate SD for at least five measures from different slices. Volatile agents (isoflurane – ISO, 350 µM; halothane – HAL, 250 µM) were only weakly reversed by BIC, while intravenous agents (pentobarbital – PEN, 400 µM; thiopental – THIO, 80 µM; propofol-PRO, 30 µM) were more sensitive to the GABA receptor antagonist. (F) A simi- lar profile of agent specific effects for BIC reversal was evident for glutamate-mediated EPSP responses, volatile agent effects were poorly reversed while intravenous agents appeared to be more sensitive to the GABA antagonist. Page 3 of 10 (page number not for citation purposes) EPSP (% CONTROL) PS (% CONTROL) % EFFECT BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 Table 1: GABA antagonist effects on anesthetic-induced depression of population spike responses Anesthetic Percent reversal of anesthetic-induced depression Bicuculline Pictrotoxin CGP-GABA Propofol 69.5 ± 14.3 % 72.3 ± 8.2 % 3.1 ± 4.1% Thiopental 64.9 ± 12.9 % 68.3 ± 9.7 % 1.3 ± 3.0% Pentobarbital 56.2 ± 12.4 % 54.3 ± 11. 5% 0.8 ± 6.3 % Halothane 22.3 ± 18.4 % 20.8 ± 15.3 % 0.5 ± 3.3 % Isoflurane 16.2 ± 7.4 % 19.5 ± 10.2 % 3.4 ± 4.8 % Notes: Bicuculline effects on propofol, thiopental and pentobarbital p < 0.01 Bicuculline effects on halothane and isoflurane p < 0.1 Picrotoxin effects on propofol, thiopental and pentobarbital p < 0.01 Picrotoxin effects on halothane and isoflurane p < 0.1 CGP effects were not significant for any anesthetic studied. to -70 mV). Propofol was most effective at increasing [4,40-42]. All of the anesthetics studied increased inhibi- holding currents (376 ± 83 pA, n = 3), followed by thio- tory charge transfer and the degree of enhancement corre- pental (320 ± 72 pA, n = 4) and pentobarbital (127 ± 65 sponded well with the ability of bicuculline to reverse the pA, n = 3). Halothane (n = 6) and isoflurane (n = 3) pro- anesthetic-induced depression of population spike duced weaker and more variable responses (< 50 pA). The responses (Fig. 1 and Table 1). For halothane and isoflu- changes in holding currents produced by propofol and rane, this enhanced inhibitory charge transfer played a rel- the barbiturates were reversed by bicuculline (10 µM) or atively minor role in population spike depression picrotoxin (100 µM), indicating that they involved activa- compared with their ability to depress glutamate-medi- -mediated chloride channels. tion of GABA ated excitatory inputs to the CA1 neurons. The most dramatic effect produced by all five anesthetics Anesthetics increase paired-pulse facilitation was observed on IPSCs (e.g. Fig. 2B). Membrane charge To determine whether presynaptic actions also contribute transfer, for example, was increased by 3 to 4 fold in the to anesthetic effects at glutamate synapses, paired pulse presence of halothane and came about by at least two sep- (120 ms) facilitation of Schaffer-collateral evoked EPSPs arate mechanisms. The first mechanism was a prolonga- were studied. In the presence of either halothane or isoflu- tion of IPSC time course (Fig. 2C) resulting in nearly a 3 rane no apparent change in EPSP rise time or decay kinet- fold increase in charge transfer for each IPSC (284 ± 33 % ics were observed (Fig. 3A), contrasting with the marked of control, p < 0.005, n = 6). This result was in good agree- prolongation of IPSC decay time produced by the anes- ment with previous findings showing that anesthetics pro- thetics. Facilitation was increased to nearly 115 % of con- long IPSCs by increasing the open time of GABA-gated trol and this effect was independent of GABA -mediated actions, since they persisted in the presence of the antago- channels in the postsynaptic membrane [33-35]. The sec- ond mechanism appeared to involve presynaptic sites, nist – bicuculline (Fig. 3B). This increase in facilitation is observed as an increase in frequency of IPSCs (143 ± 28 % consistent with a presynaptic depression of glutamate of control, p < 0.005, n = 6 neurons from separate slices) release from nerve terminals, perhaps via depressant and occurred with a small, but significant, depression in actions on voltage activated calcium or sodium channels IPSC amplitudes (92 ± 6 % of control, p < 0.05, n = 6). The which couple axon spike depolarization to the release of anesthetic-induced IPSC frequency increase was also transmitter [8,9,17,43,44]. observed in the presence of tetrodotoxin, used to block Anesthetics increase paired-pulse inhibition action potentials (n = 5 for halothane, n = 4 for propofol), indicating a direct action on GABA nerve terminals. This Agent-specific effects were observed for paired pulse confirms earlier findings that anesthetics can increase inhibitory responses (120 ms separation) recorded from IPSC frequency and the release of GABA from nerve termi- CA1 neurons (Fig. 3C). Halothane and isoflurane pro- nals [36-39]. This presynaptic effect combines with posts- duced no apparent change in paired pulse responses, both ynaptic prolongation of IPSCs to account for the marked the first and second population spike following a pair of increase in membrane charge transfer observed, and stimuli were depressed to a similar degree by these anes- would contribute to the anesthetic-induced postsynaptic thetics. In contrast, propofol, thiopental and pentobarbi- hyperpolarization of CA1 neurons previously reported tal increased paired pulse inhibition, evident in a greater Page 4 of 10 (page number not for citation purposes) BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 Wh revealed Figure 2 ole cell two sites of patch clamp action for anesth recordings of sp etic-induc ontaneous GABA-mediated in ed enhanced inhibitionhibitory postsynaptic currents (IPSC) in CA1 neurons Whole cell patch clamp recordings of spontaneous GABA-mediated inhibitory postsynaptic currents (IPSC) in CA1 neurons revealed two sites of action for anesthetic-induced enhanced inhibition. (A) Spontaneous synaptic currents were blocked by a GABA -receptor antagonist bicuculline (BIC), indicating that they were GABA -mediated Cl currents. Traces on the top show A A 20 s of continuous recording from a CA1 neuron in control and in the presence of BIC. A rate meter graph (bottom) shows the relatively stable frequency of IPSCs during 20 min of control recording, followed by a rapid and complete block of responses produced by BIC (indicated by the bar). (B) Halothane produced a marked increase of the inhibitory charge transfer in CA1 neurons measured as the integral of current recordings (shaded area in top traces). A three fold increase of inhibitory charge (pico Colombs – pC) was reversibly produced by halothane and appeared to come about through both a prolongation of IPSC time course (C) and from an increased frequency of synaptic currents (D). Both effects persisted in the presence of 10 µM tetrodotoxin (TTX) and/or glutamate receptor antagonists indicating that action potential dependent activity and glutamate synapses were not required for anesthetic action. For the rate meter histograms in (A) and (D), each bin represents the number of events recorded in 4 s divided by 4 to give a frequency in Hz (events/second). For all IPSC recordings a CsCl based internal solution was used in the patch pipette. degree of depression for the second of a pair of responses. pulse responses, pentobarbital produced a 134 ± 8 % To quantify these increases in paired pulse inhibition, increase in second pulse inhibition, thiopental produced effects on second pulse responses were compared at con- a 156 ± 15 % increase and propofol produced a 149 ± centrations that produced a half maximal depression of 13% increase (p < 0.001, n = 5 for each agent compared to first spike responses. At a level of 50 % depression of first first pulse responses). This effect is consistent with in vivo Page 5 of 10 (page number not for citation purposes) BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 A Figure 3 nesthetics act at several sites to depress CA1 neuron synaptically evoked discharge Anesthetics act at several sites to depress CA1 neuron synaptically evoked discharge. (A) Halothane appears to act presynapti- cally to depress glutamate release, evidenced by an increase in paired pulse facilitation concomitant with EPSP depression. A similar increase in facilitation was produced by isoflurane and pentobarbital, but not by thiopental or propofol. No change in EPSP rise or decay time was apparent in the presence any anesthetic. (B) The increased facilitation produced by halothane, iso- flurane and pentobarbital was not reversed by bicuculline (BIC) indicating a depressant effect on glutamate nerve terminals – independent of anesthetic effects at GABA receptors. (C) Differential GABA effects were also evident for paired pulse inhibi- tion of population spike responses. Volatile agents like halothane produced little or no paired pulse inhibition at concentrations that produced a half maximal depression of first pulse responses. In contrast, propofol increased paired pulse inhibition and similar effects were observed with thiopental and pentobarbital. This increase in paired pulse inhibition was reversed by bicuc- ulline indicating that these anesthetics enhanced recurrent GABA -mediated inhibition. (D) The anesthetics also appeared to act directly on CA1 pyramidal neuron membrane excitability to slow action potential discharge activity, although the intrave- nous agents were much more effective compared to volatile anesthetics. None of the anesthetics produced an appreciable effect on individual action potential amplitude or time course (right: control – solid line; anesthetic – dotted, for halothane on top and propofol on bottom). (E) Anesthetics act at multiple sites to depress the CA1 neuron circuit. Sites of action are indi- cated on a diagram of CA1 circuitry showing input from Schaffer-collateral fibers, local inhibitory interneurons (IN) and a CA1 pyramidal neuron (triangle). Action potential propagation in Schaffer-collateral fibers (1) was depressed by ~ 15% by halothane and this contributes about 25 % to EPSP depression [60, 61]; see also . This effect did not contribute to anesthetic-induced increases in facilitation, because no change in facilitation occurred when a comparable amount of action potential depression was produced by tetrodotoxin . Further presynaptic depression at glutamate nerve terminals (2) was evident from the increased facilitation observed (Fig. 3A&3B) and there is also good evidence for postsynaptic depressant effects on both NMDA and AMPA receptors (3) [16, 19, 62, 63]. Anesthetics also act pre- and postsynaptically at GABA-mediated synapses (4, see Fig. 2) and can also increase tonic GABA-mediated inhibition by acting as GABA agonists in the absence of synaptically released GABA (5) [46-48]. Perisynaptic and extrasynaptic tonic GABA receptors (7) also contribute to the postsynaptic depression produced by isoflurane  as well as thiopental and propofol [4, 65]. Enhanced recurrent inhibition (6) plays and important role for anesthetics in vivo  and strong effects were evident in the present study for propofol, thiopental and pentobarbital (Fig. 3C), similar to effects previously reported for halothane in hippocampal slices . In addition, anesthetics also directly depress CA1 neuron excitability by blocking calcium channels and enhancing potassium currents contributing to hyperpolarization (8) and increased discharge thresholds [40, 41, 42, also Nishikawa, Beida & Maclver, unpublished]. These lat- ter effects could influence CA1 neuron discharge activity for near threshold responses, but for the stronger stimuli used in the present study, effects on GABA and glutamate synapses and on postsynaptic receptors for these transmitters appear to con- tribute most (~ 80 %) to the depressant actions observed. Page 6 of 10 (page number not for citation purposes) BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 findings  and is thought to reflect a greater degree of Differing degrees of action (efficacy) were evident at both GABA-mediated inhibition contributing to the second of glutamate and GABA synapses for each anesthetic. For a pair of stimuli, via recurrent (feedback) activation of example, our results demonstrate that the two barbitu- inhibitory interneurons caused by the first pulse . rates studied appear to have differing degrees of effect at GABA synapses since thiopental's depressant effects were Anesthetics depress CA1 neuron excitability reversed ~ 65 % by a GABA antagonist, but pentobarbital's To determine whether the anesthetics could alter postsyn- effects were only reversed by ~ 55 %. Similarly, these two aptic membrane excitability, effects on action potentials barbiturates exhibited differing degrees of depression for evoked by direct current injection into CA1 neurons were glutamate-mediated excitatory inputs to the CA1 neurons, studied. Differences in effect were apparent across anes- pentobarbital produced a 45 % depression in contrast to thetic agents – hardly any effect was evident for halothane thiopental with only a 25 % depression. It was interesting and isoflurane, but the barbiturates and propofol pro- that opposite actions were seen at presynaptic sites (GABA duced a significant depression of action potential dis- release was increased by anesthetics, while glutamate charge (Fig. 3D). When measured as a reduction in the release was depressed) and at postsynaptic sites (GABA- number of action potentials produced in response to a mediated synaptic currents were prolonged, glutamate- one second long depolarizing current step, halothane pro- mediated currents were not). The MAS theory can readily duced an 8.2 ± 2.2 % depression and isoflurane an 11.6 ± account for the unique agent-specific profiles of effects 6.1 % depression (p < 0.01 for both agents compared to observed in various experimental models, and also seen control responses). Propofol was much more effective at clinically – a long standing weakness of Unitary theories depressing CA1 discharge, producing a 93.5 ± 6.1 % . Finally, the MAS theory predicts that agents which depression (p < 0.001). Thiopental produced a 90.3 ± 9.9 selectively target GABA and glutamate synapses could lead % depression and pentobarbital a 79.5 ± 7.4 % depression to the design of safer and more effective therapeutic agents (p < 0.001 for both anesthetics compared with control). for anesthesia, that exhibit fewer undesirable side effects. The anesthetic-induced depression of spike discharge activity was accompanied by decreases in membrane Glutamate and GABA synapses in the hippocampus are resistance and to a lesser extent by small changes in mem- among the best characterized synapses in the brain and brane resting potential. In spite of the marked depressant appear to utilize receptor subtypes which are similar to effects observed for the intravenous anesthetics on spike those in neocortex, thalamus and other higher brain discharge, none of the anesthetics appeared to alter action regions. Thus, the effects described in the present study potential amplitude, rise time or decay profiles (Fig. 3D), would be expected to occur in these other brain regions as suggesting that the major depressant effect was accounted well, but it should be noted that different GABA and gluta- for by actions on spike threshold – not on the sodium cur- mate receptor subtype distributions are known to occur in rents which underlie action potentials per se. cerebellum, spinal and some brain stem nuclei, and it remains to be determined whether anesthetics alter these Conclusions synapses in a similar manner to their hippocampal coun- Two conclusions can be drawn from these results: 1) for a terparts. Ted Eger's group at UCSF has recently found that given anesthetic, like halothane, multiple sites of action enhanced GABA-mediated synaptic transmission at the contributed in an additive manner to produce an overall spinal level plays an important role for propofol-induced depression of transmission through the CA1 neuronal cir- immobility in response to a noxious stimulus , but cuitry (Fig. 3E); 2) for each anesthetic the degree of effect this was not the case for isoflurane-induced immobility was agent specific at some of these sites. Together the . This agrees well with our findings that the volatile results support a Multisite Agent Specific (MAS) mecha- anesthetic-induced depression of synaptic signaling nism of action for general anesthetics. This represents a involves mechanisms other than enhanced GABA inhibi- departure from traditional Unitary theories of action in tion (see also ), while the depression produced by the several important respects. Unitary theories posit that all barbiturates and propofol are more dependent on anesthetics act via a common molecular mechanism, such enhanced GABA-mediated inhibition. Additional in vivo as to change the fluidity of nerve cell membranes, or to support comes from studies utilizing a GABA beta 3 recep- enhance a potassium current, or most recently to enhance tor mutant mouse model – proprofol-induced anesthesia GABA-mediated inhibition [2,3]. With the MAS theory, was blocked in these mice, while volatile anesthetic effects no common site of action is required (nor apparent) for were not . Taken together with these in vivo findings, anesthetics. This is consistent with observations at the our results indicate that effects on GABA synapses play a molecular, [46-50] cellular [22,51] and behavioral levels role in anesthetic actions, especially for propofol, thio- [52-55]. pental and pentobarbital; but the results also indicate that effects on glutamate synapses and postsynaptic mem- brane excitability contribute to the CNS depression Page 7 of 10 (page number not for citation purposes) BMC Neuroscience 2004, 5:52 http://www.biomedcentral.com/1471-2202/5/52 produced by all anesthetics. Given the multiple effects (Grass Instruments, SIU 6D) from a Grass S8800 two observed for anesthetic actions on the two types of syn- channel stimulator; at stimulus rates of 0.05 Hz. Field apses studied here, it is likely that effects on other neuro- potential signals were amplified (× 1000), filtered (1 Hz transmitter systems also contribute to anesthetic-induced to 10 KHz, bandpass), conditioned (DC offset), and digit- depression of the CNS. ally stored for later analysis (A/D with 20 µs resolution on a 486, and 50 MHz microcomputer using Data Wave Sys- Methods tems Corp. or Strathclyde Electrophysiological software). Male Sprague-Dawley rats were anesthetized with ether (22 vol % in air) and the brain was rapidly removed and Whole cell patch-clamp recordings were made using thin- placed in ice cold (5°C) and pregassed (95/5 % O /CO , walled borosilicate capillaries (1.5 mm O.D.) pulled in 2 2 carbogen) artificial cerebral spinal fluid (ACSF). The ACSF two stages on a Narishige PP83 pipette puller. Patch elec- had the following composition (in mM): Na 151.25; K trodes were filled with the following intracellular solution 2.5; Ca 2.0; Mg 2.0; Cl 131.5; HCO 26.0; SO 2.0; H PO (in mM): potassium gluconate or CsCl2 – 100, EGTA – 3 4 2 4 1.25; and glucose 10. Whole brain coronal slices (450 10, MgCl2 – 5, HEPES free acid – 40, ATP disodium salt – µm) were cut using a vibratome (Campden Instruments), 0.3, and GTP sodium salt -0.3. The electrode solution also following careful removal of the dura and pia mem- contained the local anesthetic QX 314 (1.0 mM) in some branes. Hemisected brain slices were equilibrated for at experiments, to prevent action potential discharge that least one hour at room temperature in an incubation would contaminate recordings of IPSCs. Electrode solu- chamber filled with ACSF and continually bubbled with tions were filtered and pH adjusted to 7.2 using KOH or carbogen. Individual slices were transferred to a recording CsOH and had a final osmolarity of 260 to 270 mOSM. chamber and equilibrated for an additional 10 minutes Patch electrodes with a DC resistance of 4 to 5 MOhm prior to electrophysiological recording. Oxygenated ACSF were used. Recordings were made using an Axoclamp 2A solution was continuously perfused through the chamber preamplifier (Axon Instruments) in single electrode volt- at a flow rate of 3.0 ml/min and maintained at 22 ± 1°C. age clamp mode with > 80 % series resistance compensa- The present studies were carried out at room temperature tion and > 5 GOhm seals. Patch-clamp current signals because synaptic responses recorded from cooler brain were filtered (0.1 Hz to 10 KHz, bandpass), amplified (× slices exhibit considerably better baseline stability and the 100) and digitized (10 KHz) for storage and analysis. Fre- tissue remains viable for many more hours in vitro com- quency and amplitudes of IPSCs were analyzed using pared to slices maintained at physiological temperatures. Data Wave Technologies and Strathclyde Electrophysio- Room temperature also facilitates the use of submerged logical software in a continuous data recording preparations (oxygen solubility and delivery to slices is configuration. increased), which allows the use of 60× optics to visualize single neurons for the patch clamp recordings used in The intravenous anesthetics (propofol and pentobarbital) some experiments. Previous studies comparing both vola- were made fresh for each experiment, solubilized using tile and intravenous anesthetic effects at physiological and 0.5% dimethyl sulfoxide (DMSO) and sonicated immedi- cooler temperatures in brain slices found that there were ately prior to test administration in stock solutions and no apparent differences in effects [43,61,66]. The most serially diluted into ACSF to achieve the final concentra- important effect of lower temperature is to increase the tions for testing. Volatile anesthetics (halothane and iso- aqueous solubility of the volatile anesthetics and previous flurane) were applied in the perfusate at equilibrated work from our laboratory has described in detail the solu- concentrations, delivered from calibrated vaporizers and bility changes observed at 22 vs. 35°C and our methods bubbled into the perfusate for at least 10 min prior to for measuring and compensating for changed aqueous switching from control ACSF, to ensure steady-state solubility, as well as the remarkably similar physiological concentrations were achieved. The concentration of vola- responses recorded from brain slices at these two temper- tile anesthetics in the gas phase were continually meas- atures [43,66]. ured using a Puritan-Bennett anesthetic monitor. Only a single concentration of a given anesthetic was tested on To measure population spikes, bipolar tungsten microe- each brain slice. lectrodes were placed on Schaffer-collateral fibers to elec- trically stimulate inputs to hippocampal CA1 pyramidal Data are expressed as the mean ± standard deviation and neurons. Glass recording electrodes filled with ACSF (2 to statistical analysis (ANOVA with post Tukey test) was per- 5 KOhm) were placed in stratum pyramidale to record formed using Instat from GraphPad Software. For drug stimulus-evoked population spike field potentials, or in effects on paired pulse inhibition, the percent change was stratum radiatum to record field EPSPs. Single stimulus first calculated as: Drug 1st/Control 1st = (0.5 × 100) - 100 pulses (0.01 to 0.05 ms duration; 10 to 80 µA @ 1.0 to 5.0 % = 50 % depression; and Drug 2nd/Control 2nd = (X × V) were delivered via constant current isolation units 100) - 100 % = X % depression. 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Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg peer reviewed and published immediately upon acceptance M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U: General anes- cited in PubMed and archived on PubMed Central thetic actions in vivo strongly attenuated by a point muta- tion in the GABA(A) receptor beta3 subunit. FASEB Journal yours — you keep the copyright 2003, 17(2):250-252. BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 10 of 10 (page number not for citation purposes)
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