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Changes in Anesthetic Sensitivity and Glutamate Receptors in the Aging Canine Brain

^a Department of Anatomy & Neurobiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins
^b Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins
^c Advanced Anaesthesia Specialists, North Ryde, New South Wales, Australia

Kathy R. Magnusson, Department of Anatomy \|[amp ]\| Neurobiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1670 E-mail: kmagnuss{at}lamar.colostate.edu.

Decision Editor: Jay Roberts, PhD

	Abstract

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This study investigated whether the aging process in dogs is associated with an increased sensitivity to inhalation anesthesia and whether age-related changes in glutamate receptors are related to the increased sensitivity. The mean minimum alveolar concentration (MAC) of isoflurane was 1.82 ± .08% for 2–3 year olds and 1.45 ± .06% for 11 years olds, indicating that there was an increased potency of isoflurane in the older dogs as compared to the young. These older animals also showed a significant decrease in binding of [³H]glutamate and [³H]dizocilpine ([³H]MK801) to N-methyl-D-aspartate (NMDA) receptors in multiple cortical and hippocampal regions. The density of binding to NMDA receptors in the cortex, using a single concentration of ligand, correlated significantly with individual MAC values. These results demonstrate that dogs experience an increase in anesthetic potency with increased age, similar to humans, and that age-related changes in the NMDA receptor may represent one mechanism underlying this increased sensitivity to anesthesia.

THERE is an increased rate of mortality for elderly humans (>70 years of age) undergoing general anesthesia compared to that for young adults ^(1)(2)(3), but little is known about the mechanisms that underlie this increased sensitivity. It is a common clinical perception that general anesthesia for geriatric pet animals is associated with increased risk ^(4)(5)(6); however, this has not been well documented. In humans, aging is associated with a reduction of the brain's requirement for general anesthetics in order to achieve a surgical plane of anesthesia (i.e., there is an increased sensitivity to anesthesia). The dose requirement for the inhalation forms of general anesthetics in humans is highest in young children and then declines with increasing age ^(7)(8)(9). Elderly patients also tend to have more silent periods in their electroencephalogram (EEG) recordings during inhalation anesthesia than young patients ⁽¹⁰⁾. In aged rats there is a twofold increase in potency for the inhalation anesthetic halothane, as compared to young rats ⁽¹¹⁾. There is, however, limited information documenting the changes that occur in anesthetic responses in geriatric dogs, which could be a useful animal model for elderly humans, as dogs, unlike rodents, are typically administered inhalation anesthetics in a similar manner to humans. Recommendations for anesthesia of geriatric patients include using anesthetic drugs that have rapid induction, minimal cardiopulmonary effects, minimal hepatic metabolism, and minimal renal excretion resulting in a rapid recovery ⁽⁴⁾⁽⁵⁾. The drug most commonly recommended for maintenance of anesthesia in elderly dogs is the inhalation anesthetic isoflurane, which demonstrates these desirable characteristics ⁽⁴⁾⁽⁵⁾. One purpose of this study was to determine whether dogs show an increase in sensitivity to inhalation anesthetics, similar to humans. This should enable us to determine if dogs could serve as a model system for examining the mechanisms underlying the increased anesthetic sensitivity in elderly people. Dogs have already been shown to be good models for studying the neuropathological changes and cognitive declines that occur during human aging ⁽¹²⁾.

Some of the reasons that older humans and animals may have different responses to anesthesia, compared to young adults, may be due to age-related reductions in metabolic and/or excretory functions ^(13)(14). Hepatic and renal function can be evaluated clinically to assess the degree to which drug biotransformation and excretion may be impaired in a particular patient. What cannot easily be assessed in humans or animals, but could impact on anesthetic responses, is age-related changes occurring in the brain, such as alterations in receptor numbers or function. Both increasing age and inhalation anesthetic agents depress excitatory receptor function in the brain. Glutamate is the most prevalent excitatory transmitter in the brain ^(15)(16), and glutamate receptors are in particularly high concentration in the higher centers of the brain such as the cerebral cortex and hippocampus ⁽¹⁷⁾. Reduction of function of at least two different subtypes of glutamate receptors, the N-methyl-D-aspartate (NMDA) and the -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, by receptor-specific antagonists enhances the potency of inhalation anesthetics ^(18)(19)(20). The NMDA receptor complex also is directly affected by several inhalant anesthetic agents including enflurane ⁽²¹⁾, halothane, and isoflurane ^(22)(23). The direct effects of inhalation anesthetics on the NMDA receptor complex were demonstrated by analyzing the changes in binding of [³H]-dizocilpine ([³H]-MK801) within the channel of the NMDA receptor that were induced by different concentrations of anesthetic ⁽²¹⁾. [³H]-MK801 binding is useful for correlation to anesthetic studies because it shows the density of open channels, which reflects the activity of the NMDA receptor ⁽²⁴⁾. Antagonists act by effectively reducing the number of receptors available for the transmitter to activate. Other factors that reduce the number or function of receptors would also be expected to influence anesthetic potency.

Age-associated decreases in NMDA receptor binding and functions have been reported in humans, monkeys, rats, and mice [for reviews see ^(25)(26)]. Binding densities for both NMDA-displaceable [³H]glutamate to the transmitter binding site and [³H]MK801 within the NMDA receptor channel pore are decreased with age in these species ^{(17)(27)(28)(29)(30)(31)}. There is also evidence for decreased function of NMDA receptors in aged rodents, as shown by decreases in electrophysiological responses to NMDA within the cortex ⁽³²⁾ and declines in the ability of NMDA to stimulate release of transmitters, such as norepinephrine and dopamine ^(33)(34). AMPA receptors are much less affected by aging than NMDA receptors in mice ^(17)(31), but show significant decreases in binding in rats that are equivalent to or less than the NMDA receptor changes ^(35)(36). These changes in binding and function suggest that aging may influence anesthetic potency through an action on glutamate receptors.

The purpose of this study was to determine whether aging causes an increase in anesthetic sensitivity in older dogs by experimentally determining the potency of isoflurane for two different ages of dogs. We also began to look at potential mechanisms underlying the increased sensitivity by analyzing age-related binding density changes for two subtypes of glutamate receptors, NMDA and AMPA receptors, and examining the relationships between these binding changes and the alterations in anesthetic potency.

	Methods

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Animals
Six young (2–3 years old) and 6 older (11 years old) beagles were obtained from the Inhalation Toxicology Research Institute in Albuquerque, New Mexico. The young group consisted of 3 males and 3 females and the older group contained 1 male and 5 females. Animals were housed at the Veterinary Teaching Hospital at Colorado State University. They were exposed to isoflurane anesthesia twice with an interanesthetic interval of 1 month. One exposure was used to determine the anesthetic potency for isoflurane and the second was for determining cardiopulmonary responses to isoflurane (not reported here). Animals were euthanized during the second exposure to anesthesia by intravenous injection of pentobarbital (88 mg/kg IV). All efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques when available.

Anesthetic Potency
The potency of isoflurane for each dog was determined as previously described ⁽³⁷⁾. Briefly, anesthesia was induced by delivering isoflurane in 100% oxygen by face mask. Once the dogs were sufficiently relaxed, the trachea was intubated and anesthesia was maintained by isoflurane in 100% oxygen. After maintaining a constant end-tidal isoflurane concentration for at least 15 minutes to allow for alveolar to blood to brain equilibration, two noxious stimuli were applied separately for one minute duration each, and each dog was observed for gross purposeful movement of the head, torso, or limbs. For mechanical stimulation, a large hemostat was clamped across a toe of one foot. For electrical stimulation, a 12–15 mA current at 13 Hz was applied to two skin electrodes placed in the upper lip near the nose. The stimulus was discontinued when a positive response was observed. Each stimulus was applied in turn, 1 minute apart. If no movement occurred after 1 minute, the stimulation was stopped and the alveolar anesthetic concentration, as measured with a polarographic gas analyzer (Biochem 8100, BCI International, Waukesha, WI), was reduced 20%. If movement occurred, the concentration was raised 20%. Minimum alveolar concentration (MAC) for each dog was determined as the end-tidal isoflurane concentration halfway between the lowest concentration preventing a response and the highest concentration allowing a response ⁽³⁷⁾. The distribution of the individual MAC values was normal, so the group MAC (minimum alveolar concentration necessary to produce nonresponsiveness in 50% of animals) was reported as the mean for each group of dogs, and statistical comparison of MAC values was performed by unpaired t test. Because of our location above sea level, these measurements were taken at a barometric pressure of 640 mm Hg. Conversion of MACs to equivalent sea-level percentages was done with the following equation: (MAC x 640 mm Hg) / 760 mm Hg = MAC at sea level.

Glutamate Receptor Binding
Tissue handling..-- Following euthanasia, the brain was removed from the skull and sliced horizontally into 1 cm thick slabs. The slabs were placed on slides, frozen in methylbutane that was chilled in liquid nitrogen, and stored at –70°C. Twenty-micron-thick sections were acquired from the slabs with a Zeiss cryostat, placed on gel-coated slides, and stored at –70°C until used.

Receptor binding..-- Binding for NMDA, MK801, and AMPA binding sites was performed as previously described ^(31)(38), with minor modifications. Table 1 contains information about the buffers, incubation times, the contents of the incubation solutions, and the unlabeled competitor used to assess nonspecific binding for each of the receptor binding assays. Conditions such as equilibrium binding times for incubation, dissociation constant (K_d) for binding, and optimal film exposure times were determined for each tritiated ligand on tissue from young (2–3 years old) dogs. Tritiated AMPA and MK801 were used at concentrations near the K_d (21 nM and 11 nM, respectively), but the [³H]glutamate concentration was below the K_d (244 nM; Table 1 ). Slides were preincubated in cold (4°C) buffer for 30–50 minutes. Sections were then exposed to incubation solution at 4° or 25°C for the time periods indicated in Table 1 , rinsed in four changes of buffer for a total of 30 seconds (NMDA and AMPA assays), or rinsed once for 80 minutes (MK801 assay) at 4°C, and blown dry with room temperature air. Unlabeled competitor was added to the incubation solution of some slides for determination of nonspecific binding.

Statistical analysis..-- The binding data were normalized between assays as previously described ^(40)(41), in order to decrease variability due to different batches of tritiated ligand and film apposition. Significant differences in binding density between age groups were determined by analysis of variance (ANOVA) for repeated measures (brain regions), followed by Fisher's least significant difference (LSD) post-hoc analysis, using SPSS (SPSS, Inc, Chicago, IL) software. The analysis of the effect of aging on individual brain regions was planned in the original experimental design. Pearson correlation coefficients for each ligand were obtained with SPSS software by correlating normalized binding density within brain regions from each animal with individual MAC values.

Materials
Tritiated glutamate, AMPA, and MK801 were purchased from New England Nuclear (Boston, MA). Unlabeled additives were purchased from Tocris Cookson (Essex, UK). Tritium sensitive film (Hyperfilm) and tritium standards (Microscales) were purchased from Amersham (Arlington, IL).

	Results

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Anesthetic Potency
The distribution of individual MAC values was statistically normal and there was a significant difference (p = .0039) between MAC values for the young (mean ± SEM = 1.82 ± .08%) and the older (1.45 ± .06%) dogs (Fig. 1). The older animals, therefore, required less isoflurane to produce nonresponsiveness than did the young dogs. The equivalent mean MAC values at sea level were 1.53% and 1.22% for the young and the older dogs, respectively.

View larger version (24K): [in this window] [in a new window]   Figure 1. Graph showing the mean (± SEM) minimum alveolar concentration (MAC) values for isoflurane in young (2–3 years old) and older (11 years old) dogs. There was a significant difference in MAC values for the different ages of dogs (p = .0039). n = 6.

View larger version (93K): [in this window] [in a new window]   Figure 2. Age-related changes in autoradiographic density of N-methyl-D-aspartate (NMDA)-displaceable [3H]glutamate binding. A-B: Autoradiograms of total binding on horizontal brain sections from representative young (2–3 years old; A) and older (11 years old; B) dogs. Nonspecific binding was negligible (not shown). C: Gray scale bar indicates the pmol/mg protein equivalents for each level of film density obtained from tritium standards. D: The binding density (fmol/mg protein) comparisons between the different ages of dogs within individual brain regions. * indicates p < .05 for difference from 2–3-year-olds (ANOVA and Fisher's LSD post-hoc test). Error bars = SEM. Analyzed brain regions are indicated in B. Cortical regions included all six layers of cortex. Fr, frontal cortex; IR, insular region of the cortex; Tp, temporal cortex; Occ, occipital cortex; DG, molecular layer of the dentate gyrus; CA1, strata oriens, pyramidal and radiatum of the CA1 region of the hippocampus; CA3, strata oriens, pyramidal and radiatum of the CA3 region of the hippocampus (39). n = 6.

View larger version (97K): [in this window] [in a new window]   Figure 3. Age-related changes in autoradiographic density of [3H]MK801 binding to N-methyl-D-aspartate (NMDA) receptor complexes. A-B: Autoradiograms of total binding on horizontal brain sections from representative young (2–3 years old; A) and older (11 years old; B) dogs. Nonspecific binding was negligible (not shown). C: Gray scale bar indicates the pmol/mg protein equivalents for each level of film density obtained from tritium standards. D: The binding density (fmol/mg protein) comparisons between the different ages of dogs within individual brain regions. * indicates p < .05 for difference from 2–3-year-olds (ANOVA and Fisher's LSD post-hoc test). Error bars = SEM. Analyzed brain regions are indicated in Fig. 2. Cortical regions included all six layers of cortex. n = 6.

View larger version (97K): [in this window] [in a new window]   Figure 4. Age-related changes in autoradiographic density of [3H]AMPA binding. A–B: Autoradiograms of total binding on horizontal brain sections from representative young (2–3 years old; A) and older (11 years old; B) dogs. Nonspecific binding was negligible (not shown). C: Gray scale bar indicates the pmol/mg protein equivalents for each level of film density obtained from tritium standards. D: Graph showing the binding density (fmol/mg protein) comparisons between the different ages of dogs within individual brain regions. * indicates p < .05 for difference from 2–3-year-olds (ANOVA and Fisher's LSD post-hoc test). Error bars = SEM. Analyzed brain regions are indicated in Fig. 2. Cortical regions included all six layers of cortex. n = 6.

View larger version (19K): [in this window] [in a new window]   Figure 5. Correlations between anesthetic potency, as indicated by individual minimum alveolar concentration (MAC) values, and NMDA-displaceable [3H]glutamate (A), [3H]MK801 (B), and [3H]AMPA (C) binding densities (fmol/mg protein) within the insular cortex. A,B: Graphs show significant correlations (p < .05; see Table 2 for correlation coefficients). Closed squares represent 2–3-year-old beagles. Circles represent 11-year-old beagles. n = 6.

	Discussion

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There is an inverse relationship between MAC and potency, so that lower MAC values reflect a higher potency of the inhalation anesthetic ⁽⁴³⁾. Because the average MAC value for isoflurane in the older dogs was less than for the younger animals, isoflurane was more potent in the older, as compared to the younger, dogs. Thus, aging in dogs was associated with an increased sensitivity to inhalation anesthetics, similar to what humans and rats show with halothane, another inhalation anesthetic ^(7)(8)(11). There is a 30% drop in the MAC for halothane in humans from the teenage years (12–18 years of age) to old age (72–91 years of age) ⁽⁷⁾. This increased potency may account for some of the increased risk associated with anesthesia in elderly humans and animals. Aging is also associated with a decrease in the brain/gas partition coefficients for volatile anesthetics ⁽⁴⁴⁾, indicating that the increased risk of anesthesia cannot be accounted for by an increased solubility in the brain.

The decreases in binding to NMDA and AMPA receptors in the older dogs were similar to our findings on age-related changes in C57Bl/6 mice ⁽³¹⁾. Binding of glutamate to the transmitter binding site of the NMDA receptor showed the highest percent declines of the three binding sites analyzed, and the cortex appeared to show more percent change in the NMDA binding site than the hippocampus ⁽³¹⁾. We were unable to satisfactorily determine whether the changes in binding were due to declines in affinity and/or decreases in the total number of binding sites. The decline in binding of [³H]MK801 in the frontal cortex fits well with changes in binding in human frontal cortex, in which a 36% drop in Bmax was seen between 20 and 90 years of age ⁽³⁰⁾. AMPA binding showed less change with increased age in both dogs and mice ⁽³¹⁾ than either of the two binding sites of the NMDA receptor complex.

The significant correlations seen between anesthetic potency and binding changes were only found in cortical regions, as opposed to hippocampal. These regions contain primary sensory (insular–gustatory, temporal–audition, and occipital–vision) ^(45)(46), primary motor (frontal) ⁽⁴⁵⁾, and associational cortices (frontal, temporal, and occipital) ⁽⁴⁷⁾; they perform functions such as consciousness, motor response, nociception, and memory that are typically lost under the influence of anesthesia ⁽⁴⁸⁾. The high number of correlations that were analyzed within this study and the relatively few significant correlations that were found, with none having p < .01, raised the possibility that these were false positive results (type I errors). The fact that the significant correlations were consistently found only within cortical regions and only with binding sites associated with the NMDA receptor, along with the fact that all correlations performed with all age groups were positive, argue against the significant correlations being due solely to chance.

A significant relationship was only seen when all ages were considered. This could be due to the small numbers of available dogs for each age group or that the correlation is merely due to similar, but independent, effects of aging on the two parameters. There was a trend for the NMDA-displaceable glutamate binding to be negatively correlated with MAC values in the older dogs. This suggests that there may be a change in the receptors during aging that results in greater binding being related to increased sensitivity. This could occur through alterations in the expression of some of the subunits that compose the NMDA receptor, as has been seen in aged mice ⁽⁴⁹⁾. This needs to be verified with increased numbers of animals or an examination of direct effects of isoflurane on receptor function. Because the older group that was available for this study was predominantly female, it also needs to be determined whether gender influenced the results.

These results demonstrate that dogs experienced changes similar to humans and rodents in both anesthetic sensitivity and glutamate receptors during the aging process. Understanding what mechanisms affect the NMDA receptor during aging may provide clues to the optimal interventions for making anesthesia safer for geriatric patients.

	Acknowledgments

 
This work was supported by the Miki Society of the College of Veterinary Medicine and Biomedical Sciences at Colorado State University.

The authors wish to thank Dr. B.A. Muggenberg of the Inhalation Toxicology Research Institute in Albuquerque, New Mexico for providing us with dogs of different ages for this study. We also wish to acknowledge the excellent technical assistance provided by Ms. Ginger Sammonds and Dr. Barbara Capwell.

Received May 3, 1999

Accepted February 21, 2000

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