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Anesth Analg 2003;96:1010-1018
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Isoflurane Antagonizes the Capacity of Flurothyl or 1,2-Dichlorohexafluorocyclobutane to Impair Fear Conditioning to Context and Tone

Edmond I Eger, II, MD*, Yilei Xing, MD*, Robert Pearce, MD{dagger}, Steven Shafer, MD{ddagger}, Michael J. Laster, DVM*, Yi Zhang, MD*, Michael S. Fanselow, PhD§, and James M. Sonner, MD*

*Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; {dagger}Department of Anesthesiology, University of Wisconsin, Madison, Wisconsin; {ddagger}Department of Anesthesiology, Stanford University, Stanford, California; and §Department of Psychology, University of California, Los Angeles, California

Address correspondence and reprint requests to Dr. Edmond I Eger II, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In animals, the conventional inhaled anesthetic, isoflurane, impairs learning fear to context and fear to tone, doing so at concentrations that produce amnesia in humans. Nonimmobilizers are inhaled compounds that do not produce immobility in response to noxious stimulation, nor do they decrease the requirement for conventional inhaled anesthetics. Like isoflurane, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) impairs learning at concentrations less than those predicted from its lipophilicity to produce anesthesia. The capacity of the nonimmobilizer di-(2,2,2,-trifluoroethyl) ether (flurothyl) to affect learning and memory has not been studied. Both nonimmobilizers can cause convulsions. We hypothesized that if isoflurane, 2N, and flurothyl act by the same mechanism to impair learning and memory, their effects should be additive. We found that isoflurane, 2N, and flurothyl (each, alone) impaired learning fear to context and fear to tone in rats, with the nonimmobilizers doing so at concentrations less than those that cause convulsions. (Fear was defined by freezing [volitional immobility] in the presence of the conditioned stimulus [context or tone].) However, the combination of isoflurane and 2N or flurothyl produced an antagonistic rather than an additive effect on learning, a finding in conflict with our hypothesis. And flurothyl was no less potent than 2N (at least no less potent relative to the concentration of each that produced convulsions) in its capacity to impair learning. We conclude that conventional inhaled anesthetics and nonimmobilizers impair learning and memory by different mechanisms. The basis for this impairment remains unknown.

IMPLICATIONS: Conventional inhaled anesthetics and nonimmobilizers are antagonistic in their effects on learning and memory, and this finding suggests that they impair learning and memory, at least in part, by different mechanisms.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Although they have a lipophilicity that indicates a capacity to produce anesthesia (1,2) , certain gases and vapors do not prevent movement in response to noxious stimulation. They do not prevent movement when given alone, nor do they add to the capacity of known anesthetics to prevent movement (3). While these compounds, known as nonimmobilizers, do not produce immobility, they can impair learning and memory at concentrations close to those predicted from their lipophilicity to produce such effects (4,5) . Thus, the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) impairs learning at concentrations roughly a third of those predicted to produce anesthesia (4,5) . The concentrations predicted to produce anesthesia actually cause convulsions.

Most nonimmobilizers, such as 2N, differ from conventional inhaled anesthetics by having a lower polarity, manifested by a lower affinity to water (3). This has led to the suggestion that the capacity of conventional anesthetics to produce immobility required that they be amphipathic (have an affinity to both polar and nonpolar phases) and that their capacity to produce immobility resulted from an action at an interface between polar and nonpolar phases (e.g., at the cell membrane surface) (6). In contrast, it was suggested that amnesia (impaired learning and memory) resulted from an action confined to a nonpolar site (e.g., one within the membrane).

This reasoning presumes that anesthetics and most nonimmobilizers impair learning and memory by a common mechanism. If correct, then the effects of inhaled anesthetics and nonimmobilizers on learning and memory should be additive. However, at least one nonimmobilizer does not fit this reasoning: flurothyl [di-(2,2,2,-ethyl) ether] has a solubility in water similar to that of conventional inhaled anesthetics (7). Flurothyl and 2N may differ in one other respect: an initial report (but not a more recent report) (8) suggested that 2N does not antagonize the effect of gamma aminobutyric acid (GABA) (9), whereas flurothyl does (10). Thus, the mechanism by which flurothyl impairs learning and memory might differ from the mechanism by which 2N impairs learning and memory (11). If correct, this implies that the mechanism of the capacity of 2N and flurothyl to impair learning and memory might differ. The present investigation tested these hypotheses, finding that both were incorrect. We used two measures of learning and memory: fear conditioning to context and fear conditioning to tone. Fear conditioning to context tests memory of the surroundings associated with application of an unconditioned stimulus (a footshock), whereas fear conditioning to tone tests memory of a tone associated with an unconditioned stimulus. Fear conditioning to tone requires processing by the amygdala but not hippocampus; fear conditioning to context requires processing by both the amygdala and hippocampus (12–18) . Both measures of learning led to the same conclusions.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The Committee on Animal Research of the University of California, San Francisco, approved our study of male [Crl:CD(SD)BR] Sprague-Dawley rats weighing 275 to 325 g obtained from Charles River Laboratories (Hollister, CA). Animals were housed in our animal care facility for a week before study under 12-h cycles of light and dark, two per cage, and had continuous access to standard rat chow and tap water before the study. Rats were handled on each of at least 3 days before training to accustom them to being handled. We purchased the nonimmobilizers 2N and flurothyl from SynQuest Laboratories, Inc. (Alachua, FL).

We assessed the effect of 2N and of flurothyl (separately) on fear conditioning to context, and to tone, in the absence and presence of various concentrations of isoflurane (Tables 1 and 2). Fear was defined by freezing (volitional immobility) in the presence of the conditioned stimulus (context or tone). A rat was given one dose of one nonimmobilizer alone or in combination with one concentration of isoflurane (i.e., was studied only once).


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  		Table 1. Isoflurane, 1,2-Dichlorohexafluorocyclobutane (2N), and Di-(2,2,2-Trifluoroethyl) Ether (Flurothyl) Effects on Freezing to Context
 

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  		Table 2. Isoflurane, 1,2-Dichlorohexafluorocyclobutane (2N), and Di-(2,2,2,-Trifluoroethyl) Ether (Flurothyl) Effects on Freezing to Tone
 
On the training day, the rats (two/cage) were brought to the training area and their tails marked with a permanent felt-tipped pen for identification. They were placed in clear plastic containers covered with a clear plastic plate surmounted by a chimney broad enough to allow us to easily reach into the container and extract a rat (equilibration chamber, Fig. 1). The clear plastic plate was pierced to allow delivery of a >2 L/min inflow of oxygen with or without 2N, flurothyl, and/or isoflurane. The concentrations of 2N, flurothyl, and/or isoflurane were established at predetermined target values before placement of the rats in the containers. These concentrations were the same as those provided in the training chambers (see below). Isoflurane, 2N, and flurothyl concentrations were separately measured by gas chromatography. The gas chromatograph was calibrated with secondary standards from tanks. Rat temperatures were not measured because we previously found that 2N does not affect temperature regulation (19).



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  		Figure 1. Three chambers were used in this study. The equilibration chamber was used to preequilibrate rats to the concentration(s) of isoflurane and/or nonimmobilizers for 30 min before insertion into the training chamber (which also served as the test chamber for context). The rats were taken from the equilibration chamber via the chimney and immediately (within a few seconds) placed through a hole (not shown) in the test chamber that otherwise was closed with a large rubber stopper (not shown). The training chamber had a shock grid as the floor on which the rats stood and had a speaker that could be activated for training to tone. The tone testing chamber was of a different shape from the training chamber. It smelled different, had different lighting, and had a flat smooth floor surface rather than a grid.

 
The rats were continuously observed during the period of equilibration before training. Ten to 15 minutes after placement of the rats in the containers, each animal was rapidly (<10 s) transferred from the equilibration chamber via the chimney to a training chamber (Fig. 1) via an 8-cm port in the chamber top otherwise sealed with a rubber cork. (We separately determined that the introduction of the rats did not materially change the chamber concentrations of the delivered gases.) Animals were allowed to explore the chamber for 3 min before training began.

The training chambers were 4 identically shaped chambers (25 x 20 x 17 cm) constructed of clear acrylic and located in a well lit room. Inlet and outlet ports allowed continuous ventilation through the chambers. A circular flow through the 4 chambers was maintained by a fan producing a background noise of 70 dB (A-scale) (Sound Level Meter; Radio Shack, Ft. Worth, TX). A 5 L/min oxygen fresh gas inflow conveyed the target concentrations of isoflurane, 2N, and/or flurothyl. Carbon dioxide was removed with a soda lime canister, and gas concentrations were sampled from a port in the circle system. A shock grid formed the floor of each training chamber. The shock grid consisted of 14 stainless steel rods (6-mm diameter), spaced 1.8 cm center to center and wired to a shock scrambler (Gemini Avoidance System; San Diego Instruments, San Diego, CA). A speaker was mounted on the rear wall of each training chamber. Training chambers were cleaned with 2% ammonium hydroxide before and after each animal occupied them.

For tone conditioning, animals received three tone-shock pairs consisting of a 30-s tone (90 dB, A-scale, 2000 Hz) co-terminating with a 2-s electric shock (11-Hz bipolar square waves, 2 mA for all groups); shock pairs were 90 s apart. Animals were returned to their home cages (free of isoflurane) within 60 s after the last shock. For context conditioning, an identical procedure was followed except that no tone was delivered.

The next day, we tested freezing to tone or to context. The chambers for tone testing (tone testing chamber, Fig. 1) provided a different environment from that provided by the training chambers. The clear acrylic testing chambers for tone testing had an A-frame roof. Each had a 25 x 28 cm base and 21 x 28 cm sides and had a smooth floor. They were in a different room from the training chambers. The tone test room was lit with a 25-W red lightbulb, whereas the training room was lit with conventional white-light fluorescent ceiling lamps. The testing cages were cleaned with a pine-scented solution, and there was no background noise. A speaker was mounted on the rear wall of each testing chamber.

For context testing, each animal was returned to the chamber in which it was trained (the training chamber) and allowed to explore the chamber for 8 min; neither tone nor shock was administered. Four animals were observed simultaneously, one in each of the four chambers.

For tone testing, each animal that had received tone training was placed in the A-frame testing chamber in the different room (see above), and, after 3 min of exploration, a tone (90 dB, A-scale, 2000 Hz) was continuously sounded for 8 min; shocks were not administered. Again, four animals were observed simultaneously, one in each of the four chambers. Animal observations for both the test of freezing to context and freezing to tone were via a video camera that allowed observation of all rats simultaneously. No personnel were in the test rooms during this period.

Freezing was assessed by a trained observer. To score freezing 24 h after training, an observation of one of the four animals was made every 2 s (20). Therefore, each animal was scored once every 8 s. Behavior was judged as freezing if there was no visible movement except for breathing. The observation periods were also videorecorded for scoring at a later time, if needed.

We studied a minimum of 4 and a maximum of 24 rats at each concentration or combination of concentrations.

For each group, the gas concentrations were calculated as the mean and SE of the concentrations measured in the clear plastic containers and in the training chambers before and after training of that group. The percentage of time an animal froze during the 8-min observation periods 24 h after training was calculated as the number of observations judged to be freezing divided by the total number of observations in 8 min, i.e., 60 observations (20). For each group score for conditioning to context and to tone, the mean and SE of the mean were calculated.

The effects of isoflurane, 2N, and flurothyl on freezing to context and freezing to tone were modeled using a sigmoidal curve, described by the relationship


where Effect is freezing to context or freezing to tone, E0 is the baseline effect when no drug is present, Emin is the lowest score (i.e., maximal effect; 0 for freezing to context and about 10 for freezing to tone), C is the drug concentration, and {gamma} is the Hill coefficient indicating the steepness of the relationship.

The interaction between isoflurane and each nonimmobilizer was analyzed with the response-surface interaction model of Minto et al. (21). The response-surface approach follows closely the approach for single drugs, in that the drug effect is still described by a sigmoidal relationship:


where effect, E0, and Emin are as previously defined. C is the sum of normalized concentrations. In other words,




depending on which nonimmobilizer was being given in conjunction with isoflurane. {theta} is the fraction of the (normalized) nonimmobilizer in the total drug given:




depending on which nonimmobilizer was being studied. The drug interaction is captured by C50({theta}), which acts to either magnify or reduce the concentration beyond simple additivity for the drugs in combination. We chose a simple quadratic model for the interaction shape, as is commonly the practice in interaction modeling:




depending on which nonimmobilizer was being studied. The parameter ß captures the shape of the interaction. If ß = 0, then C50({theta}) is always 1, and the interaction is additive. If ß > 0, then C50({theta}) becomes <1 except when {theta} is 0 or 1, which acts to magnify the effect of the drug, producing a supraadditive (e.g., synergistic) relationship. If ß < 0, then C50({theta}) becomes greater than 1 except when {theta} is 0 or 1, which acts to diminish the effect of the two drugs, producing an infraadditive (e.g., antagonistic) relationship.

The function {gamma}({theta}) permitted each drug to have its own steepness for the concentration versus response relationship. {gamma}({theta}) varied linearly with {theta} (i.e., varied linearly depending on the fraction of total drug made up by the nonimmobilizer):




depending on which nonimmobilizer was being studied.

Parameter estimation was performed with NONMEM (University of California, San Francisco, CA). We used the NONMEM objective function to test whether the relationship between isoflurane and the nonimmobilizers significantly differed from additivity and whether the interaction term, ß, and the Hill coefficient, {gamma}, were statistically distinguishable between 2N and flurothyl. Specifically, we examined the decrease in the NONMEM objective function with the addition of each parameter, since this decrease approximately follows the {chi}2 distribution for the degrees of freedom (i.e., number of parameters) added to the model. For example, a decrease of 3.84 with the addition of a single parameter indicates that the expanded model is significantly better, with a probability of <0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Isoflurane, 2N, and flurothyl each suppressed freezing to context in a dose-related manner (Table 1), but isoflurane antagonized the effect of 2N (Fig. 2, top graph) and flurothyl (Fig. 2, bottom graph).



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  		Figure 2. In the absence of a nonimmobilizer, increasing concentrations of isoflurane applied during training fear to context decrease percent freezing in a dose-related manner. Similarly, increasing concentrations of each nonimmobilizer in the absence of isoflurane (first point for each graph) decrease percent freezing in a dose-related manner. However, the addition of isoflurane to a given concentration of 1,2-dichlorohexafluorocyclobutane (2N) (upper panel, A) or flurothyl (lower panel, B) increases the percent freezing (i.e., learning fear to context), indicating an antagonism of the effects of the two compounds. Points for the percent isoflurane in this and subsequent graphs are offset slightly to improve clarity.

 
The response-surface modeling for fear to context (Fig. 3) demonstrated a highly significant interaction (P < 0.001). Flurothyl and 2N did not differ in (fear was defined by freezing [volitional immobility] in the presence of the conditioned stimulus [context or tone]) either ß or {gamma}, suggesting that these drugs act via the same mechanism. The parameters of the final interaction model were as follows: C50,isoflurane = 0.22, C50,2N = 0.90, C50,flurothyl = 0.059, {gamma}isoflurane = 3.2, {gamma}nonimmobilizer = 2.3, and ß = -4.8. In Figure 3, the black line is the "isobole" showing 50% drug effect. The upper projection demonstrates the shape of the surface, while the lower projection, a view from directly above the surface, shows the extreme antagonism evident in the 50% isobole.



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  		Figure 3. The antagonism between isoflurane and nonimmobilizers on learning fear to context can be visualized as the bowing of the interaction surface away from the origin and the vertical axis. In an interaction surface, synergy would appear as bowing towards the origin and vertical axis. Simple additivity would appear as a straight line on any horizontal slice through the vertical axis. The profound antagonism (bowing away from the origin and vertical axis) is most easily visualized in the lower projection, where the surface is viewed from directly above. Isoflurane concentration is expressed in percent partial pressure. The nonimmobilizer concentrations have been normalized by dividing each concentration by the C50 for learning fear to context, allowing 1,2-dichlorohexafluorocyclobutane (2N) and flurothyl to share a common axis.

 
As with freezing to context, isoflurane, 2N, and flurothyl each suppressed freezing to tone in a dose-related manner (Table 2), but isoflurane antagonized the effect of 2N (Fig. 4, top graph) and flurothyl (Fig. 4, bottom graph). Isoflurane appeared to enhance learning fear to tone in the presence of a nonimmobilizer.



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  		Figure 4. As in Figure 2, in the absence of a nonimmobilizer, increasing concentrations of isoflurane applied during training fear to tone decrease the percent freezing in a dose-related manner. Similarly, increasing the concentrations of 1,2-dichlorohexafluorocyclobutane (2N) (upper panel, A) or flurothyl (lower panel, B) applied during training fear to tone decreases the percent freezing in a dose-related manner (see the first points for each nonimmobilizer’s concentration). As in Figure 2, isoflurane reverses the effects of each nonimmobilizer, indicating an antagonism of the effects of the compounds.

 
The response-surface modeling for fear to tone (Fig. 5) demonstrated a highly significant interaction (P < 0.001). Flurothyl and 2N did not differ in either ß or {gamma}, suggesting that these drugs act via the same mechanism. The parameters of the final interaction model were as follows: C50,isoflurane = 0.37, C50,2N = 1.9, C50,flurothyl = 0.138, {gamma}isoflurane = 4.8, {gamma}nonimmobilizer = 8.8, and ß = -6.4. As observed for freezing to context, the relationship was profoundly antagonistic, a finding particularly evident in the Figure 5, bottom graph, viewing the surface from directly above, where the extreme shape of the 50% isobole can be directly observed.



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  		Figure 5. As in Figure 3, the outward bowing of the interaction surface away from the origin and vertical axis demonstrates antagonism between isoflurane and nonimmobilizers, seen here for learning fear to tone. The profound antagonism is most readily visualized in the lower graph, where the surface is viewed from above. Isoflurane concentration is expressed as percent partial pressure. The nonimmobilizer concentrations have been normalized by dividing each concentration by the C50 for learning fear to tone, allowing 1,2-dichlorohexafluorocyclobutane (2N) and flurothyl to share a common axis.

 
Suppression of freezing to tone required larger concentrations of all vapors than were required to produce freezing to context. The minimum average of freezing to tone was 12% and was 0% with freezing to context. These results suggest that tone creates a more profound association than context with the noxious electrical shock; i.e., it requires larger concentrations to block the learning process.

None of the rats gave evidence of convulsive activity in the presence of isoflurane. In the absence of isoflurane, rats convulsed at flurothyl concentrations of 0.15% and larger.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results indicate that the effects of isoflurane on learning antagonize rather than add to the effects of the two nonimmobilizers, 2N and flurothyl. This is not a subtle result. The outward bowing of the isobolograms seen in Figures 3 and 5 shows tremendous antagonism. The log-likelihood ratios for antagonism of fear to context and fear to tone were 29 and 7, respectively. Since twice the log-likelihood ratio approximates the {chi}2 distribution, these correspond to P values for antagonism approximately equal to 2 x 10-13 and 9 x 10-4, respectively. Because these are approximations, in our results we have listed the significance as P < 0.001.

The results from this study are not consistent with our hypothesis that conventional anesthetics and nonimmobilizers act in the same manner to impair learning and memory. It suggests that at least two sites of action are important to this impairment. It undermines the argument that conventional inhaled anesthetics and nonimmobilizers both must act in a nonpolar environment to impair learning and memory. The finding that flurothyl, a polar compound, also potently impairs learning and memory also suggests that an action limited to a nonpolar environment may not be essential to the impairment of learning and memory.

Our results demonstrate that both 2N and flurothyl impair learning and memory. The effect of 2N had been demonstrated previously (4,5) , but no such demonstration had been made for flurothyl. For both nonimmobilizers, the concentrations that produce convulsions [approximately 4%–5% for 2N (3) and 0.12%–0.15% for flurothyl (22)] exceed, by a factor of 3 to 6, the concentrations that impair learning fear to context (Table 1, Figs. 2 and 3). They also exceed the concentrations that impair learning fear to tone, but the difference is much less (Table 2, Figs. 4 and 5).

These results do not indicate that 2N and flurothyl differ in their capacities to impair learning and memory. Clearly, the capacity of nonimmobilizers to impair learning and memory does not correlate with their lipophilicity. That is, the product of the concentration of nonimmobilizer producing a 50% impairment of learning fear to context (perhaps 0.6% 2N and 0.05% flurothyl; Tables 1 and 2, Figs. 2 and 4) times the oil/gas partition coefficient [43.5 for 2N (3) and 46.9 for flurothyl (7)] differs by an order of magnitude. It may correlate with the capacity of nonimmobilizers to inhibit neuronal nicotinic acetylcholine receptors. Both flurothyl and 2N inhibit such receptors, doing so at concentrations close to those that impair learning (23). They share this capacity with that of conventional inhaled anesthetics (24,25) , and one might be tempted to consider that this underlies the capacity of both conventional anesthetics and nonimmobilizers to impair learning and memory. However, as noted above, the absence of an additive effect of isoflurane with 2N or flurothyl makes a common mechanism unlikely.

Does the impairment of learning and memory by the nonimmobilizers correlate with their capacity to produce convulsions? None of the rats gave overt evidence of convulsive activity at concentrations that compromised learning fear to context. We previously found that concentrations of up to 4.2% 2N do not produce evidence of epileptiform activity in spontaneous (unstimulated) electroencephalographic recordings (26). Indeed, in that study we found no effect of 2N on the middle latency auditory-evoked potential.

Another explanation for the capacity of the nonimmobilizers to impair learning and memory is that the nonimmobilizers make the rat anxious. An inhaled anesthetic such as isoflurane might decrease this anxiety and thereby antagonize the effect of the nonimmobilizers. Other investigators have suggested that the blockade of the effect of GABA by the anxiogenic drug DMCM induces a state of panic and that this blocks fear conditioning (27). Like 2N and flurothyl, DMCM can produce convulsions. Both flurothyl (10) and DMCM (28) can inhibit the action of GABA on GABAA receptors. One report suggests that 2N does not produce inhibition (9), but another report (8) finds an effect.

Inhaled anesthetics can produce antianalgesia at 0.1 to 0.2 minimum alveolar anesthetic concentration (MAC) (29). This might partly explain the antagonistic effects seen at these concentrations. However, concentrations larger than 0.2 MAC have analgesic effects (29), and yet such concentrations also antagonized the impairment of learning and memory produced by flurothyl and 2N.

We conclude that conventional inhaled anesthetics and nonimmobilizers can, at least in part, impair learning and memory by different mechanisms. If they do partly share a common mechanism, one or both have additional mechanisms that come into play.


   Acknowledgments
 
This work was supported by National Institutes of Health Grant 1PO1GM47818-08.


   Footnotes
 
Dr. Eger is a paid consultant to Baxter Healthcare Corp. Dr. Shafer has received research grants from and/or has been a consultant to Abbott Laboratories, Baxter Healthcare, and Zeneca.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 17, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press